Clinical trial NCT02141659
Conditions: Hormone Treatment-naïve Participants With Prostate Cancer
Sponsor: Takeda
Start date: 2014-05-01; Completion date: 2017-04-20
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the tolerability and safety of TAK-385 in hormone treatment-naïve participants with non-metastatic prostate cancer.

Detailed description:
The objective of this study is to evaluate the tolerability and safety of TAK-385 in hormone treatment-naive participants with non-metastatic prostate cancer. This study consists of two parts: Part A, multiple dose-rising (MRD) phase and Part B, an expansion phase.

Arms: arm 1: TAK-385 320 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 80 mg maintenance dose, tablet, orally, once daily through Days 2 to 28. arm 2: TAK-385 320 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 120 mg maintenance dose, tablet, orally, once daily through Days 2 to 28. arm 3: TAK-385 320 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 160 mg maintenance dose, tablet, orally, once daily through Days 2 to 28. arm 4: TAK-385 360 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 120 mg maintenance dose, tablet, orally, once daily through Days 2 to 28. arm 5: TAK-385 320 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 80 mg maintenance dose, tablet, orally, once daily through Days 2 to 672. arm 6: TAK-385 320 mg loading dose, tablet, orally, once on Day 1, followed by TAK-385 120 mg maintenance dose, tablet, orally, once daily through Days 2 to 672.
Interventions: intervention 1: TAK-385
Intervention descriptions: intervention 1: TAK-385 Tablets.

Protocol documents:
Prot_000.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 


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CLINICAL STUDY PROTOCOL
Study Title: A Phase 1, Open-label, Multicenter Study to Evaluate the Tolerability, 
Safety, Pharmacokinetics, and Pharmacodynamics of TAK-385 Alone in Hormone 
Treatment-naive Japanese Patients With Non-metastatic Prostate Cancer
Short Title: A Phase 1 Study of TAK-385 in Hormone
Treatment-naive Patients With Prostate Cancer
Sponsor:
Takeda Pharmaceutical Company Limited
1-1 Doshomachi 4-chome, Chuo-ku, Osaka
Study Number:
TB-AK160108
Version
Amendment 2
IND Number:
NA
EudraCT 
Number:
NA
Study Drug:
TAK-385
Date:
1 July 2015
Amendment History:
Date
Amendment Number
Region
12 February 2014
Initial Protocol
All sites
23 January 2015
1
All sites
1 July 2015
2
All sites
CONFIDENTIAL PROPERTY
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered. Furthermore, the information is only meant for review and 
compliance by the recipient, his or her staff, and applicable institutional review committee and regulatory 
agencies to enable conduct of the study.


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1.0
STUDY ADMINISTRATION INFORMATION
1.1
Contacts and Responsibilities for Study-Related Activities
A separate contact information list will be provided to each site.
1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in 
accordance with requirements of this clinical study protocol and also in accordance with 
the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws,
clinical trial disclosure laws, and regulations.
1.3
Protocol Amendment Summary of Changes
This document describes the changes in reference to the Protocol Incorporating 
Amendment No. 2.
The primary purpose of this amendment is to update the protocol regarding the addition 
of a new cohort, Cohort 4, to Part A. Minor grammatical and editorial changes are also 
included. Detailed description of amendments to texts are given in Appendix J. The 
following is a summary of the changes made in the amendment:
1.
Addition of a new cohort, Cohort 4 (loading dose of 360 mg and a maintenance dose 
of 120 mg) to Part A.
Justification: 320 mg or 360 mg may be selected as the loading dose in the planned 
phase 3 multinational study. Based on this situation, a new cohort, Cohort 4, is added 
to Part A, designed to evaluate the tolerability of loading dose of 360 mg in Japanese 
patients before joining the phase 3 multinational study.
2.
Correction of inconsistencies within the original protocol.


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TABLE OF CONTENTS
1.0
STUDY ADMINISTRATION INFORMATION .................................................. 2
1.1
Contacts and Responsibilities for Study-Related Activities............................. 2
1.2
Principles of Clinical Studies ......................................................................... 2
1.3
Protocol Amendment Summary of Changes................................................... 2
2.0
STUDY SUMMARY........................................................................................... 8
3.0
LIST OF ABBREVIATIONS............................................................................. 12
4.0
INTRODUCTION............................................................................................. 14
4.1
Summary ..................................................................................................... 14
4.1.1
Nonclinical Summary...................................................................... 15
4.1.2
Clinical Studies............................................................................... 19
4.2
Rationale for the Proposed Study................................................................. 25
5.0
STUDY OBJECTIVES AND ENDPOINTS...................................................... 26
5.1
Objectives.................................................................................................... 26
5.1.1
Primary Objectives.......................................................................... 26
5.1.2
Secondary Objectives...................................................................... 26
5.2
Endpoints..................................................................................................... 26
5.2.1
Primary Endpoints .......................................................................... 26
5.2.2
Secondary Endpoints....................................................................... 26
5.2.3
Additional Endpoints ...................................................................... 27
6.0
STUDY DESIGN AND DESCRIPTION........................................................... 28
6.1
Study Design ............................................................................................... 28
6.1.1
Cohort/Part Advancement Criteria................................................... 31
6.1.2
DLT ................................................................................................ 32
6.2
Rationale for Study Design, Dosage, and Endpoints..................................... 33
6.3
Premature Termination or Suspension of Study or Investigational Site ......... 36
6.3.1
Criteria for Premature Termination or Suspension of the Study ....... 36
6.3.2
Criteria for Premature Termination or Suspension of 
Investigational Sites ........................................................................ 37
6.3.3
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s)................................... 37
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ... 38
7.1
Inclusion Criteria ......................................................................................... 38
7.2
Exclusion Criteria ........................................................................................ 39
7.3
Prohibited Concomitant Medications, Therapies, and Foods ........................ 41
7.3.1
Prohibited Concomitant Medications............................................... 41
7.3.2
Prohibited Concomitant Therapies .................................................. 41


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7.3.3
Food ............................................................................................... 42
7.4
Subject Management.................................................................................... 42
7.5
Criteria for Discontinuation or Withdrawal of a Subject ............................... 43
7.6
Procedures for Discontinuation or Withdrawal of a Subject.......................... 45
8.0
STUDY DRUG MANAGEMENT..................................................................... 46
8.1
Study Drug .................................................................................................. 46
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.................. 46
8.1.2
Storage............................................................................................ 47
8.1.3
Dose and Regimen .......................................................................... 47
8.1.4
Overdose......................................................................................... 50
8.2
Study Drug Allocation and Prescribing Procedures ...................................... 51
8.3
Randomization Code Creation and Storage .................................................. 51
8.4
Control and Disposal of Drugs Provided by the Study Sponsor .................... 51
9.0
STUDY PLAN .................................................................................................. 52
9.1
Study Proceduress........................................................................................ 52
9.1.1
Informed Consent............................................................................ 52
9.1.2
Demographics, Medical History, and Treatment History.................. 52
9.1.3
Physical Examination...................................................................... 53
9.1.4
Weight, Height, and ECOG Performance Status .............................. 53
9.1.5
Vital Signs ...................................................................................... 53
9.1.6
Electrocardiogram........................................................................... 53
9.1.7
Imaging Assessment........................................................................ 54
9.1.8
Clinical Laboratory Tests ................................................................ 54
9.1.9
Cardiac Tests................................................................................... 55
9.1.10
Tumor Marker................................................................................. 55
9.1.11
Collection of Pharmacogenomic Sample ......................................... 55
9.1.12
Bone Mineral Density (Part B Only) ............................................... 56
9.1.13
Ophthalmological Examination (Part B Only) ................................. 56
9.1.14
BMP Concentrations (Part B Only) ................................................. 56
9.1.15
QOL Assessment (Part B Only)....................................................... 56
9.1.16
Concomitant Medications................................................................ 56
9.1.17
Concomitant Therapies ................................................................... 57
9.1.18
Concurrent Medical Conditions....................................................... 57
9.1.19
Contraception.................................................................................. 57
9.1.20
Pregnancy ....................................................................................... 57
9.1.21
Pharmacokinetic Assessments ......................................................... 57
9.1.22
Pharmacodynamic Assessments ...................................................... 57


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9.1.23
Documentation of Subjects Withdrawing From the Study Prior to 
Study Treatment Initiation or Prior to Randomization...................... 58
9.1.24
Documentation of Study Enrollment/Randomization....................... 58
9.2
Monitoring Subject Treatment Compliance.................................................. 58
9.3
Schedule of Observations and Procedures.................................................... 59
9.3.1
Screening........................................................................................ 59
9.3.2
Study Enrollment/Randomization.................................................... 60
9.3.3
Day of Study Treatment Initiation ................................................... 60
9.3.4
Study Drug Treatment Period (Except for the Day of Study 
Treatment Initiation) ....................................................................... 60
9.3.5
Post-treatment Observation Period (Performed Only in Part A) ....... 61
9.3.6
Continuation Treatment Period........................................................ 62
9.3.7
At Study Withdrawal....................................................................... 62
9.3.8
Safety Follow-up............................................................................. 63
9.3.9
Handling After the End of the Study................................................ 64
9.4
Biological Sample Storage and Disposal...................................................... 64
9.5
Blood Sample Volumes and Numbers of Samples Collected......................... 64
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS................................. 67
10.1
Definition .................................................................................................... 67
10.1.1
Pretreatment Events ........................................................................ 67
10.1.2
Adverse Events ............................................................................... 67
10.1.3
Additional Points to Consider for Pretreatment Events and 
Adverse Events ............................................................................... 67
10.1.4
Serious Adverse Events................................................................... 69
10.1.5
Special Interest Adverse Events....................................................... 70
10.1.6
Severity of Pretreatment Events and Adverse Events....................... 71
10.1.7
Causality of Adverse Events............................................................ 71
10.1.8
Relationship to Study Procedures.................................................... 72
10.1.9
Date of Onset.................................................................................. 72
10.1.10
Date Resolved................................................................................. 72
10.1.11
Frequency ....................................................................................... 72
10.1.12
Action Taken for Study Drug........................................................... 73
10.1.13
Outcome ......................................................................................... 73
10.2
Procedures................................................................................................... 74
10.2.1
Collection and Reporting of Adverse Events ................................... 74
10.2.2
Collection and Reporting of Serious Adverse Events....................... 75
10.2.3
Reporting of Drug-Induced LFT Abnormalities Potentially 
Leading to Severe Liver Disorders .................................................. 76


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10.3
Follow-up of Serious Adverse Events .......................................................... 76
10.3.1
Reporting of Serious Adverse Events to Principal Investigators, 
IRB, and Regulatory Authorities ..................................................... 77
11.0
STUDY SPECIFIC COMMITTEES.................................................................. 78
12.0
DATA HANDLING AND RECORDKEEPING................................................. 79
12.1
Electronic Case Report Form....................................................................... 79
12.2
Record Retention ......................................................................................... 79
13.0
STATISTICAL METHODS............................................................................... 81
13.1
Statistical and Analytical Plans .................................................................... 81
13.1.1
Analysis Sets................................................................................... 81
13.1.2
Analysis of Demographics and Other Baseline Characteristics ........ 81
13.1.3
Efficacy Analysis ............................................................................ 81
13.1.4
Pharmacokinetic Analysis ............................................................... 82
13.1.5
Pharmacodynamic Analysis............................................................. 82
13.1.6
Other Analysis ................................................................................ 83
13.1.7
Safety Analysis ............................................................................... 83
13.2
Interim Analysis and Criteria for Early Termination..................................... 84
13.3
Determination of Planned Sample Size ........................................................ 84
14.0
QUALITY CONTROL AND QUALITY ASSURANCE ................................... 85
14.1
Monitoring of Investigational Site................................................................ 85
14.2
Protocol Deviations...................................................................................... 85
14.3
Quality Assurance Audits and Regulatory Authority Inspections .................. 85
15.0
ETHICAL ASPECTS OF THE STUDY ............................................................ 86
15.1
IRB Approval .............................................................................................. 86
15.2
Patient Information, Informed Consent, and Subject Authorization .............. 86
15.3
Subject Confidentiality ................................................................................ 87
15.4
Publication, Disclosure, and Clinical Trial Registration Policy..................... 88
15.4.1
Publication and Disclosure.............................................................. 88
15.4.2
Clinical Trial Registration ............................................................... 88
15.4.3
Clinical Trial Results Disclosure ..................................................... 89
15.5
Insurance and Compensation for Injury........................................................ 89
16.0
REFERENCES.................................................................................................. 90
LIST OF TABLES IN THE PROTOCOL
Table 4.a
............................................ 18
Table 4.b
................................................ 19
Table 6.a
Study Schedule (Part A)......................................................................... 30


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Table 6.b
Study Schedule (Part B)......................................................................... 31
Table 6.c
Cohort/Part Advancement Criteria.......................................................... 32
Table 6.d
Criteria for Advancing From an Additional Cohort to Part B.................. 32
Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A) ............................... 48
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B) ............... 48
Table 8.c
Guidelines for Handling Liver Function Test Abnormalities................... 50
Table 9.a
Clinical Laboratory Tests ....................................................................... 54
Table 9.b
Blood Sample Volumes and Numbers of Samples Collected (Part A) ..... 65
Table 9.c
Blood Sample Volumes and Numbers of Samples Collected  (Part B –
Screening Through Week 48, Safety Follow-up) .................................... 65
Table 9.d
Blood Sample Volumes and Numbers of Samples Collected  (Part B –
Weeks 49 to 96) ..................................................................................... 66
Table 10.a
Takeda Medically Significant AE List .................................................... 70
LIST OF FIGURES IN THE PROTOCOL
Figure 6.a.
Study Design and Treatment Schema (Part A)........................................ 29
Figure 6.b
Study Design and Treatment Schema (Part B)........................................ 30
Figure 8.a
Sample TAK-385 Bottle Label ............................................................... 47
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures (Part A)................................................... 92
Appendix B
Schedule of Study Procedures (Part B – Screening to Week 48, SFU) .... 94
Appendix C
Schedule of Study Procedures (Part B – Weeks 49 to 96) ....................... 96
Appendix D
Schedule of Blood Samples Collection for Pharmacokinetic Analysis 
(Part A).................................................................................................. 97
Appendix E
Schedule of Blood Samples Collection for Pharmacokinetic Analysis 
(Part B).................................................................................................. 98
Appendix F
Responsibilities of Principal Investigator ............................................... 99
Appendix G
ECOG Performance Status................................................................... 100
Appendix H
New York Heart Association (NYHA) Functional Classification .......... 101
Appendix I
Liver Function Test Abnormality Reporting Checklist.......................... 102
Appendix J
Detailed Description of Amendments to Text ....................................... 103


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Study Drug:
TAK-385
Study Title: A Phase 1, Open-label, Multicenter Study 
to Evaluate the Tolerability, Safety, Pharmacokinetics, 
and Pharmacodynamics of TAK-385 Alone in Hormone 
Treatment-naive Japanese Patients With Non-metastatic 
Prostate Cancer
IND Number:
NA
EudraCT Number:
NA
Study Number: TB-AK160108
Phase: 1
Study Design:
This study consists of two parts: Part A, a dose-rising phase, and Part B, an expansion phase.
In Part A, three to six patients will be enrolled in each cohort. Whether or not the study will proceed to the 
next cohort or Part B will be determined through assessment of tolerability at the dose in question, based on 
the incidence of dose-limiting toxicity (DLT) in the evaluation period. TAK-385 will be taken once a day 
for 28 days at the doses assigned to each cohort. Cohort 1 will receive a loading dose of 320 mg and a 
maintenance dose of 80 mg, Cohort 2 will receive a loading dose of 320 mg and a maintenance dose of 
120 mg, Cohort 3 will receive a loading dose of 320 mg and a maintenance dose of 160 mg, and Cohort 4
will receive a loading dose of 360 mg and a maintenance dose of 120 mg. Patients being switched to a 
gonadotropin-releasing hormone (GnRH) agonist (eg, leuprorelin) or a GnRH antagonist (eg, degarelix) 
following the completion of TAK-385 treatment in Part A will first pass through a 1-week observation 
period (except for study withdrawals). Whether or not the study will proceed to Part B will be determined 
by the study sponsor after consulting the study monitoring committee (SMC) based on a comprehensive 
evaluation of the tolerability and safety data from Cohort 2 of Part A.
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 320 mg and 
maintenance dose of either 80 mg or 120 mg – equal numbers of subjects will be randomized to 80 mg and 
120 mg) once a day orally to evaluate safety. In addition to the safety assessments, efficacy assessments 
will also be performed according to the study schedule, and study drug will be administered until the 
discontinuation criteria (Section 7.5) are met for each individual subject. After completing 48 weeks of 
treatment, subject may, at the discretion of the investigator, and depending on the wishes of the subject, 
continue receiving study drug (for a maximum of 96 weeks), or they may complete the study and be 
switched to a GnRH agonist or a GnHR antagonist, starting from the day after the day of the last dose of 
TAK-385.
All subjects who receive study drug will undergo safety follow-up 30 to 40 days after the last dose of 
TAK-385.
Part A (Dose-rising phase)
Primary Objectives:
To evaluate the tolerability and safety of TAK-385 in hormone treatment-naive patients with non-
metastatic prostate cancer.
Secondary Objectives:
To evaluate the pharmacokinetics (PK) and the effects on serum testosterone of TAK-385 in hormone 
treatment-naive patients with non-metastatic prostate cancer.
Part B (Expansion phase)
Primary Objectives:
To evaluate the safety of TAK-385 in hormone treatment-naive patients with non-metastatic prostate 
cancer.
Secondary Objectives:
To evaluate the change over time in the prostate-specific antigen (PSA) levels and the PK and effects on 
serum testosterone of TAK-385 in hormone treatment-naive patients with non-metastatic prostate cancer.


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Subject Population: Japanese patients with hormone treatment-naive non-metastatic prostate cancer
Numbers of Subjects
Part A: 3 to 6 subjects in each cohort (3 to 24
subjects in total)
Part B: 15 subjects in each group (30 subjects in 
total)
Number of Sites
Part A: 2 to 3 sites
Part B: Approximately 7 sites (some of the sites will 
be the same as the sites in Part A)
Dosage
Dosage: TAK-385 once a day orally at least 30 
minutes before breakfast
Part A
Cohort 1: Loading dose of 320 mg and maintenance 
dose of 80 mg
Cohort 2: Loading dose of 320 mg and maintenance 
dose of 120 mg
Cohort 3: Loading dose of 320 mg and maintenance 
dose of 160 mg
Cohort 4: Loading dose of 360 mg and maintenance 
dose of 120 mg
(Additional cohort: Loading dose of 320 mg and 
maintenance dose of 40 mg)
Part B
80 mg group: Loading dose of 320 mg and 
maintenance dose of 80 mg
120 mg group: Loading dose of 320 mg and 
maintenance dose of 120 mg
(If there is an additional cohort in Part A, then 
instead of a 120 mg group, there will be a 40 mg 
group, which will received a loading dose of 
320 mg and a maintenance dose of 40 mg.)
Route of Administration
Oral
Duration of Treatment
Part A: 28 days
Part B: 48 weeks (may be continued for up to a total 
of 96 weeks maximum)
Period of Evaluation
Part A: Approximately 2 months
Part B: Approximately 1 year (approx. 2 years if 
therapy is continued)
Main Criteria for Inclusion
1.
Patients with histologically or cytologically confirmed prostate cancer
2.
Patients whose clinical diagnosis is T1-4 N0 M0, or Tx N0 M0 for patients who have undergone 
radical prostatectomy
3.
Patients who have not received hormone therapy (eg, GnRH agonist, GnRH antagonist, steroidal 
antiandrogen, non-steroidal androgen) for prostate cancer
4.
Patients with serum testosterone at screening > 150 ng/dL
5.
Patients meeting either of the following criteria for PSA at screening
Untreated prostate cancer:
PSA at screening > 4.0 ng/mL
Treated prostate cancer:
PSA at screening > 0.2 ng/mL
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1


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Main Criteria for Exclusion
1.
Patients exhibiting symptoms judged related to prostate cancer by the investigator (eg, bone pain, 
pelvic pain, ureteral obstruction) who urgently require hormone therapy such as GnRH agonist, GnRH 
antagonist, or combined androgen blockade (CAB)/maximum androgen blockade (MAB) therapy, 
chemotherapy, or radiotherapy
2.
Patients who have received 5-alpha reductase inhibitors (except for patients who have been treated for 
male-pattern alopecias)
3.
Treatment with any investigational compound within the 4 weeks (28 days) prior to the first dose of 
study drug or ongoing participation in another experimental trial related to the treatment of prostate 
cancer
4.
Known hypersensitivity to TAK-385, TAK-385 excipients, or GnRH antagonists
5.
Clinically relevant ECG abnormalities, or the following ECG abnormalities, at screening

Q-wave infarction, unless identified 6 or more months prior to TAK-385 treatment initiation

Fridericia corrected QT (QTcF) interval > 450 msec (when calculating the QTc interval, 
Fridericia’s equation [QT/RR0.33] will be used)
6.
Patients with congenital QT prolongation
Endpoints
Part A
Primary endpoints

DLTs, adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead ECGs
Secondary endpoints

Plasma concentrations of unchanged TAK-385

Serum testosterone concentrations
Part B
Primary endpoints

AEs, clinical laboratory tests, vital signs, and 12-lead ECGs
Secondary endpoints

PSA levels

Plasma concentrations of unchanged TAK-385

Serum testosterone concentrations
Statistical Consideations
Safety analyses
1)
Incidences of AEs
The following analysis will be performed for the safety analysis set.
Treatment-emergent adverse events (TEAEs) will be tabulated by part and dose. TEAEs will be coded 
according to Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ 
class (SOC) and preferred term (PT).
2)
DLTs
The following analysis will be performed for the DLT analysis set.
The incidences of TEAEs judged to be DLTs in Part A will be tabulated by PT and dose.
3)
Clinical laboratory test value profiles, vital signs, and 12-lead ECGs
The following analyses will be performed for the safety analysis set.
For continuous data, summary statistics will be calculated for the baseline values, the values observed at 
each assessment time point, and the changes from baseline by part and dose.
For categorical data and assessments based on reference values, cross tabulation of the values before and 


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after treatment (eg, normal/abnormal, qualitative clinical laboratory test values) will be performed by part 
and dose for each test parameter.
Pharmacokinetic analyses
Pharmacokinetic parameters (eg, maximum observed plasma concentration [Cmax], area under the plasma 
concentration - time curve [AUC]) will be evaluated using the plasma TAK-385 concentrations, and 
summary statistics will be calculated for the plasma concentrations and each of the pharmacokinetic 
parameters. Figures showing the changes over time in the plasma concentration of TAK-385 will also be 
prepared.
Rationale for the Planned Sample Size
Part A
Each cohort will have 3 or 6 subjects, based on the the guidelines on the clinical evaluation of 
antineoplastics 
Part B
In order to detect less frequent AEs, 15 subjects per group (total of 30 subjects) were established as the 
number of cases enabling an approximately 80% chance of detecting AEs characterized by a true incidence 
of 10%.


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AMS
Aging Male's Symptoms
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMI
body mass index
BMP
di-docosahexaenoyl (22:6)-bis(monoacylglycerol)
phosphate
CAB
combined androgen blockade
CK-MB
creatine kinase MB
Cmax
maximum observed plasma concentration
CTCAE
Common Terminology Criteria for Adverse Events
DHT
dihydrotestosterone
DLT
dose-limiting toxicity
eCRF
electronic case report form
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
EPIC
Expanded Prostate Cancer Index Composite
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin-releasing hormone
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
LFT
liver function test
LH
luteinizing hormone
MAB
maximum androgen blockade
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PK
pharmacokinetics
P-gp
P-glycoprotein
PGx
pharmacogenomics
PSA
prostate-specific antigen
PT-INR
Prothrombin Time-International Normalized Ratio


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PTE
Pretreatment Event
QTc
corrected QT (interval)
QTcB
Bazett corrected QT
QTcF
Fridericia corrected QT
SHBG
sex hormone binding globulin
SMC
study monitoring committee
Tmax
maximum drug concentration time
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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4.0
INTRODUCTION
4.1
Summary
In 2008 prostate cancer reached approximately 900,000 cases/year worldwide and is now 
the second leading cancer in men, accounting for 13.7% of cancer cases in men [1]. The 
median age of diagnosis is 70, and prostate cancer is rarely diagnosed in men under 40 
[2]. Incidence increases with age and is expected to rise in the future as the population 
ages. In Japan, 2008 statistics show that prostate cancer ranks a high fourth in morbidity 
among cancers in men [3]. Prostate cancer in Japan also occurs more often with age, and 
the incidences increases rapidly in men 60 and older.
It is known that prostate cancer is to responsive to surgical castration and that the 
effectiveness of this therapy results from the elimination of androgen. This knowledge 
led to the understanding that most prostate cancers are growth hormone dependent and 
ever since this discovery, hormone therapy has played an important role in the treatment 
of prostate cancer.
Castration by orchiectomy or a gonadotropin-releasing hormone (GnRH) agonist is the 
main mode of therapy for localized progressive and metastatic cancers, and GnRH 
agonists such as leuprorelin acetate are widely used [4]. When multiple doses of a GnRH 
agonist are administered, a temporary increase in gonadotropin secretion (flare up) 
occurs. That is followed by a decrease in responsiveness (desensitization) in the pituitary 
gland and gonads, which appears to work effectively by inhibiting the secretion of sex 
hormones. The flare up sometimes leads to a temporary worsening of symptoms, and the 
effectiveness of GnRH agonist begins to appear about 3 to 4 weeks after the initial dose.  
In addition, the GnRH is a peptide formulation and is unable to be administered orally. 
Consequently, development of a new medication that is easy to administer and does not 
cause flare ups is needed.
TAK-385 is a non-peptide orally active GnRH antagonist with a novel structure that was 
discovered by Takeda Pharmaceutical Company, Ltd. TAK-385 antagonizes GnRH at 
the GnRH receptors present in the basophils (secreting cells) of the anterior pituitary 
gland and inhibits the GnRH-stimulated secretion of gonadotropin luteinizing hormone 
(LH) and follicle-stimulating hormone (FSH) from those cells. This action lowers the 
serum testosterone concentration in the blood. An antitumor effect is expected in prostate 
cancer patients due to the suppression of serum testosterone production by the testes. 
TAK-385 is also expected to manifest its effects rapidly without causing flare ups like 
GnRH agonists. Moreover, because it is a non-peptide formulation, TAK-385 can be 
administered orally, unlike peptide-based GnRH agonists that must be absorbed 
subcutaneously. The clinical pharmacokinetic and pharmacodynamic profiles may offer 
additional advantages compared with a depot peptide formulations, such as more rapid 
recovery from short term medical castration.
Takeda Pharmaceutical Co., Ltd. decided to develop TAK-385 for the treatment of 
prostate cancer both overseas and in Japan. Moreover, development of TAK-385 in 
Japan and Asia for endometriosis and uterine fibroids is already underway.


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4.1.1
Nonclinical Summary
4.1.1.1
Pharmacology Related to the Proposed Mechanism of Action
A series of in vitro and in vivo pharmacological studies have demonstrated that TAK-385 
acts as a potent and highly selective antagonist for human GnRHR (hGnRHR).
 
 
 
 
 
[5].
4.1.1.2
Safety Pharmacology
In safety pharmacology studies, 
 
 
 
 
 
 
 
 
 
 
 
[5].
4.1.1.3
Pharmacokinetics and Product Metabolism in Animals
 
 
 
 
 
 
 


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 [5].
4.1.1.4
Toxicology
TAK-385 has been evaluated for safety in single- and repeat-dose toxicity studies, with 
supportive toxicokinetic analyses, in mice, rats, and monkeys.  Genetic, carcinogenicity, 
reproductive, and phototoxicity studies have also been performed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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[5].


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4.1.2
Clinical Studies
4.1.2.1
Japanese Phase 1 Single- and Multiple-dose Study (
)
A placebo-controlled double-blind single dose study of the safety, pharmacokinetics
(PK), and pharmacodynamics of TAK-385 was conducted in 72 premenopausal healthy 
adult Japanese women (including 12 in the placebo group). Moreover, a crossover study 
comparing fasted state/postprandial administration, and fasted/preprandial administration 
was conducted in 24 premenopausal healthy women to investigate the effect of meals on 
TAK-385 PK. In addition, a placebo-controlled double-blind, 14-day multiple dose study 
of safety, PK, and pharmacodynamics during of TAK-385 was conducted in 48 
premenopausal healthy adult women (including 12 in the placebo group).
 
 
 
 


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[5].


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4.1.2.2
Overseas Phase 1 Single- and Multiple-dose Study (
)
A placebo-controlled double-blind single-dose study of the safety, PK, and 
pharmacodynamics of TAK-385 was conducted in 72 premenopausal healthy adult 
American women (including 12 in the placebo group). Moreover, a crossover study 
comparing fasted with fed (post-breakfast) administration was conducted in 12 
premenopausal healthy women to investigate the effect of food on the PK of TAK-385. 
In addition, a placebo-controlled double-blind, 14-day multiple dose study of safety, PK, 
and pharmacodynamics during of TAK-385 was conducted in 36 premenopausal healthy
adult women (including 9 in the placebo group).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [5].


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4.1.2.3
Japanese Phase 1 Study of Drug-drug Interactions With Erythromycin 
(
)
A phase 1 open-label drug-drug interaction study was carried out in healthy Japanese 
male and female subjects to evaluate the effect of multiple doses (300 mg, q.i.d.) of 
erythromycin (moderate CYP3A4 inhibitor and P-gp inhibitor) on the single-dose PK of 
TAK-385 (20 mg).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[5].
4.1.2.4
Overseas Phase 1 Drug-drug Interaction Study (
)
 
 
 
 
 
 


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 [5].
4.1.2.5
Overseas Phase 1 Single- and Multiple-dose Study (TAK-385_C27001)
Study C27001 was a phase 1 study that evaluated the safety, tolerability, PK, and PD of 
TAK-385 in 176 healthy English adult male subjects (128 subjects received TAK-385) 
receiving single doses of TAK-385 up to 360 mg QD and multiple doses of TAK-385 up 
to 180 mg QD for up to 28 days. The study had 4 parts: Part 1 included single-dose 
administration of TAK-385 to 32 subjects across 4 dose cohorts plus placebo and had a 
fed/fasted arm; Part 2 included multiple dose administration of TAK-385 for 14 days to 
40 subjects across 5 dose cohorts plus placebo; and Parts 3 and 4 included multiple dose 
administration of TAK-385 for 28 days to 66 and 38 subjects, respectively, across 2 dose 
cohorts (a total of 4 dose levels), plus placebo.
There were no deaths or SAEs following single-dose or multiple-dose treatment with 
TAK-385 for 14 or 28 days.
Following 28 days of QD dosing, there were 3 discontinuations due to drug-related, 
hepatic AEs: 2 subjects in the 160 mg dose cohort in Part 3 of the study discontinued 
treatment due to Grade 1 AEs of hepatic enzyme increased (ALT and AST); and 1 
subject in the 60 mg dose cohort in Part 4 of the study discontinued treatment due to a 
Grade 2 AE of liver function test (LFT) abnormal (ALT and AST). There was no clear 
trend between dose level and toxicity, although abnormal liver transaminase levels 
appeared more likely to occur within 2 weeks at higher dose levels. All AEs resolved by 
the end of the study.
The majority of subjects had at least 1 AE, but no increase in the incidence of AEs with 
increasing dose of TAK-385 was observed. The most common AEs observed across all 
dose cohorts were bradycardia, hot flush, and headache, and the most common, drug-
related AE was hot flush.
A number of cardiac AEs according to Common Terminology Criteria for Adverse 
Events (CTCAE) were reported, but for these subjects the ECG interpretation was 
considered to be not clinically significant by the investigator. These cardiac AEs 
included electrocardiogram QT prolonged (1 AE in Part 1, 4 AEs in Part 2, and 7 AEs in 
Part 3) and first degree atrioventricular block (2 AEs in Part 1 and 6 AEs in Part 2). 
Changes in mean QTc interval of approximately 15 to 20 msec were noted before 
administration on Day 14 (80 to 180 mg QD) in adult male subjects in this study. The 
QTc changes were independent of drug administration, not correlated to drug levels, and 
are similar to those observed in surgical and medical castration studies with other 


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compounds. No major safety concerns were noted in healthy male subjects receiving 
single (80 to 360 mg) and multiple (20 to 180 mg) doses of TAK-385, and TAK-385 was 
well tolerated.
Single doses of 80 to 360 mg of TAK-385 administered orally (fasted state) were 
absorbed rapidly in plasma with median Tmax values ranging from 1.75 to 4.00 hours 
after administration across the entire dose range. After attaining Cmax, TAK-385 plasma 
concentrations declined in a multi-exponential manner with a mean T1/2 ranging from 
19.1 to 21.7 hours. The mean Cmax and AUC values for TAK-385 generally increased 
in an approximately dose-proportional manner over the 80 to 360 mg dose range.
When a multiple dose of 20 to 180 mg QD of TAK-385 was administered, the drug was 
readily absorbed in plasma on Days 1 and 14, and Cmax typically occurred within 1 to 2 
hours after dosing. After attaining Cmax, individual PK profiles on Day 14 exhibited a 
multi-exponential elimination phase with a mean elimination phase T1/2 of 
approximately 36 to 65 hours at doses of 20 to 180 mg QD. The trough concentration-
time data (Day 2, and Days 11 to 14) implied that steady-state conditions were attained 
within approximately 10 days.
Similarly, the effect of food was studied in 6 male subjects in the crossover period (Part 
1). Compared to fasting conditions, the absorption of TAK-385 in plasma decreased and 
was delayed following a single 180 mg dose taken 30 minutes after the start of a standard 
FDA high-fat, high-calorie breakfast. Least square mean Cmax and AUC(0-inf) values 
decreased by approximately 52% and 47%, respectively. Furthermore, median Tmax 
increased from 1.75 hours to 5.00 hours under fed conditions. When the dose was 
administered 30 minutes prior to the standardized morning meal (Part 2), systemic 
exposure to TAK-385 appeared to be reduced to a lesser extent (approximately 28% on 
average) and no changes in the absorption rate were observed.
In this study, serum LH, FSH, dihydrotestosterone (DHT), and testosterone 
concentrations were determined following single and multiple oral doses of TAK-385 or 
placebo for up to 28 days. TAK-385 caused an immediate and effective suppression of 
gonadotropins (LH, FSH) and testosterone. While no changes were observed in the 
placebo group, serum testosterone levels were markedly suppressed in all TAK-385 dose 
groups within the first 3 days of administration. Loading doses of 320/240/160 mg for up 
to 3 days and doses of 180 mg or greater led to testosterone levels below the conventional 
castration level within 48 hours. The onset of the testosterone lowering response 
shortened as the loading dose increased. This phenemon was likely a result of higher 
TAK-385concentrations in the blood. Similar dose-dependent suppressive effects were 
observed after a single oral dose. These findings support the principal mechanism of 
action that, as a GnRH antagonist, TAK-385 competitively binds with the pituitary GnRH 
receptors.
In administration over 28 days in Part 3 and 4, both 160 mg and 80 mg QD were effective 
at achieving conventional medical castration levels during the third and fourth weeks of 
multiple administration. Despite the loading dose regimen, however, the 40-mg QD dose 
was ineffective in maintaining castration levels between Days 14 and 28. The results at 
60 mg QD were intermediate to those of 40 and 80 mg QD and suggested that the likely 


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minimal, fully effective maintenance dose for medical castration would be 80 mg QD or 
above [5].
4.1.2.6
Overseas Thorough QTc Study in Healthy Adults (
)
 (US) is a double-blind (open-label moxifloxacin), randomized study that 
evaluated the effect of single doses of TAK-385 on QT/QTc intervals in healthy adults. 
 
 
 
 
 
 
 
 
[5].
4.2
Rationale for the Proposed Study
The results of the phase 1 study conducted in England (TAK-385_C27001) demonstrate 
the tolerability of multiple doses of TAK-385 (20 to 80 mg) in healthy adult men. 
Moreover, the plasma concentration of TAK-385 increased as the dose increased, and 
rose slightly greater than dose proportionality. The blood concentrations of the measured 
hormones all decreased rapidly with multiple doses of TAK-385 and effective 
suppression of serum testosterone was sustained throughout the adminsitration period.
 
 
Because prostate cancer is a sex-hormone dependent disease, and an antitumor effect is 
expected as a result of lowering hormone concentrations in the blood through 
administration of TAK-385, it was decided to conduct a phase 1 study in patients with
prostate cancer.
This protocol was prepared in accordance with the Good Clinical Practice (GCP).


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
Part A
To evaluate the tolerability and safety of TAK-385 in hormone treatment-naive 
patients with non-metastatic prostate cancer.
Part B
To evaluate the safety of TAK-385 in hormone treatment-naive patients with non-
metastatic prostate cancer.
5.1.2
Secondary Objectives
Part A
To evaluate the PK and the effects on serum testosterone of TAK-385 in hormone 
treatment-naive patients with non-metastatic prostate cancer.
Part B
To evaluate the change over time in the prostate-specific antigen (PSA) levels and the 
PK and effects on serum testosterone of TAK-385 in hormone treatment-naive patients 
with non-metastatic prostate cancer.
5.2
Endpoints
5.2.1
Primary Endpoints
Part A
Safety: Dose-limiting toxicities (DLTs), AEs, clinical laboratory tests, vital signs, and 
12-lead ECGs
Part B
Safety: AEs, clinical laboratory tests, vital signs, and 12-lead ECGs
5.2.2
Secondary Endpoints
Part A
PK: Plasma concentrations of unchanged TAK-385
Pharmacodynamics: Serum testosterone concentrations
Part B
Efficacy: PSA levels
PK: Plasma concentrations of unchanged TAK-385
Pharmacodynamics: Serum testosterone concentrations


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5.2.3
Additional Endpoints
Part A
Efficacy: PSA levels
Pharmacodynamics: LH, FSH, DHT, and sex hormone binding globulin (SHBG) 
serum concentrations
Part B
Safety: Bone density [6]
Efficacy: Disease progression assessed by PSA, disease progression assessed by 
imaging
Pharmacodynamics: LH, FSH, DHT, and SHBG serum concentrations
Other: QOL assessments based on the Aging Male's Symptoms (AMS) [7], European 
Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 [8, 9, 10], 
and the Expanded Prostate Cancer Index Composite (EPIC) [11, 12]


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a multicenter phase 1, open-label, dose range-finding study to evaluate the 
tolerability, safety, PK, and pharmacodynamics of TAK-385 alone in hormone treatment-
naive Japanese patients with non-metastatic prostate cancer.
This study consists of two parts: Part A, a dose-rising phase, and Part B, an expansion 
phase. The designs of Part A and Part B are shown in “Study Design and Treatment 
Schema” (Figure 6.a and Figure 6.b).
In Part A, three to six patients will be enrolled in each cohort. Whether or not the study 
will proceed to the next cohort or Part B will be determined through assessment of 
tolerability at the dose in question, based on the incidence of DLT in the evaluation
period (treatment initiation to Day 28).
TAK-385 will be taken once a day for 28 days at the doses assigned to each cohort. 
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, Cohort 3 will 
receive a loading dose of 320 mg and a maintenance dose of 160 mg, and Cohort 4 will 
receive a loading dose of 360 mg and a maintenance dose of 120 mg. The doses will be 
taken orally at least 30 minutes before breakfast. Patients being switched to a GnRH 
agonist (eg, leuprorelin) or a GnRH antagonist (eg, degarelix) following the completion 
of TAK-385 treatment in Part A will first pass through a 1-week observation (no-
treatment) period. However, patients whose treatments were discontinued because they 
met the discontinuation criteria (Section 7.5) during the 28-day treatment period will not 
have to pass through this observation period.
If tolerability is confirmed in Cohort 2, then the study will proceed to Cohort 3 and Part B 
simultaneously. The tolerability in Japanese of the maximum dose at which tolerability 
was found in 28-day multiple dosing in the overseas phase 1 single-/multiple-dose study 
(TAK-385_C27001) (160 mg) will be evaluated for the purpose of checking the 
tolerability of dose escalation to 160 mg in Part B as well as the PK. In the overseas 
phase 1 single-/multiple-dose study (TAK-385_C27001), no findings indicative of safety 
problems were obtained in multiple dosing for 28 days with 160 mg. However, if 
tolerability is not confirmed in Cohort 2, then a cohort will be added that will receive a 
loading dose of TAK-385 320 mg and a maintenance dose of 40 mg.
Cohort 4 will be conducted after tolerability is confirmed in Cohort 2. Cohort 4 will be 
conducted for the purpose of evaluating the tolerability of 360 mg as loading dose in 
Japanese. 360 mg has been found tolerable in single dosing in the overseas phase 1 
single-/multiple-dose study (TAK-385_C27001) 
 
.
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 
320 mg and maintenance dose of either 80 mg or 120 mg – equal numbers of subjects 
will be randomized to 80 mg and 120 mg) once a day orally to evaluate safety. In 
addition to the safety assessments, efficacy assessments will also be performed according 


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to the study schedule, and study drug will be administered until the discontinuation 
criteria (Section 7.5) are met for each individual subject. After completing 48 weeks of 
treatment, subjects may, at the discretion of the investigator, and depending on the 
wished of the subhect, continue receiving study drug (for a maximum of 96 weeks), or 
they may complete the study and be switched to a GnRH agonist (eg, leuprorelin) or a 
GnHR antagonist (eg, degarelix), starting from the day after the day of the last dose of 
TAK-385. Subjects withdrawing from the study will not be replaced.
If no problems with tolerability are found in the additional cohort in Part A, then the 
study will proceed to Part B with a 40 mg group instead of a 120 mg group (TAK-385 
loading dose of 320 mg and maintenance dose of 40 mg).
All subjects who receive study drug, whether in Part A or Part B, will undergo safety 
follow-up 30 to 40 days after the last dose of TAK-385.
*1: If tolerability is not confirmed in Cohort 2, then a cohort will be added which will receive a loading 
dose of 320 mg and a maintenance dose of 40 mg.
*2: If a cohort is added, and the additional cohort continues to the end and no problems with tolerability are 
found, then the study will proceed to Part B.
Figure 6.a.
Study Design and Treatment Schema (Part A)
Evaluation of Transition
Evaluation of Transition
Cohort 2 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)
Evaluation of Transition*1
Cohort 3 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 160 mg (Days 2-28)
Evaluation of Transition*2
Part B (Expansion phase)
Part A (Dose-rising phase)
Cohort 1 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Days 2-28)
Cohort 4 (n = 3-6)
TAK-385
Loading dose 360 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)


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*1: If a cohort is added in Part A, then in Part B 120 mg group will be replaced to 40 mg group, in which 
subjects will receive loading dose of 320 mg and maintenance dose of 40 mg.
Figure 6.b
Study Design and Treatment Schema (Part B)
Figure 6.a and Figure 6.b show an overview of the study schedule. See Appendix A
through Appendix E for a more detailed schedule of the study tests, observations, and 
assessments.
Table 6.a
Study Schedule (Part A)
Screening
Treatment Period
Post-treatment 
Observation Period
Safety Follow-up
DLT Evaluation Period (treatment initiation to Day 28)
Outpatient
Inpatient
Outpatient
Outpatient/Inpatient
Outpatient
Day -28 to Day -1*1
Day 1*1 to Day 15
Day 16 to Day 28*2
Day 29 to Day 35*2
...
30 to 40 days after 
the last dose
of TAK-385
Assessment of eligibility
Screening tests
Admission
Discharge
Tests/observations
Treatment initiation
Treatment completion
Tests/observations
Initiation of other 
treatment
Tests/observations
Observations
Tests/observations
*1: Day -1 and Day 1 are the day before treatment initiation and the day of treatment initiation, respectively.
*2: Days 27 to 35 are performed either on an outpatient or an inpatient basis.
Part B (Expansion phase)
Eligibility assessment/randomization (1:1)
(performed by the day before treatment initiation)
TAK-385 80 mg
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Day 2 on)
TAK-385 120 mg *1
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Day 2 on)
Screening
(1 to 28 days before treatment initiation)
Visit at end of TAK-385 treatment
(Safety follow-up 30 to 40 days after the last dose of TAK-385)
End of treatment (Week 48)
TAK-385 continuation treatment
(Up to Week 96 at most)


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Table 6.b
Study Schedule (Part B)
Screening
Treatment Period
Continuation Treatment Period
Safety Follow-up
Outpatient
Days -28 to -1*1
Week 1, Day 1*1 to Week 48, 
Day 7*2
Week 49, Day 1 to Week 96, 
Day 7*2
30 to 40 days after the last dose 
of TAK-385
Assessment of eligibility, 
randomization
Screening tests
Treatment completion
Tests, observations
Treatment initiation
Treatment completion
Tests, observations
Treatment initiation
Tests, observations
Initiation of other treatment
*1: Day -1 and Day 1 are the day before treatment initiation and the day of treatment initiation, respectively.
*2: Other treatments may be initiated starting on the day after the day of the last dose of TAK-385 (Week 48, Day 8 or Week 96, Day 
8).
6.1.1
Cohort/Part Advancement Criteria
Whether or not the study will proceed to the next cohort in Part A will be determined by 
the study sponsor after consulting the study monitoring committee (SMC) and following 
a comprehensive evaluation of the safety data based on the number of subjects 
experiencing DLT in each cohort (Table 6.c). Drug will be administered to the subjects 
in the next cohort after the decision on cohort advancement is made. See the separately 
prepared written procedures for detailed study advancement criteria.
In each cohort, if no DLT occurs in even 1 of the 3 subjects during the DLT evaluation 
period (see Section 6.1.2.2), then the dose will be judged tolerable, and the study will 
proceed to the next cohort. If a DLT occurs in 1 subject in the DLT evaluation period, 
and additional 3 subjects will be enrolled in this cohort, and DLT will be evaluated in a 
total of 6 subjects. If DLT occurs in 1 of these 6 subjects, this dose will be judged 
tolerable, and the study will proceed to the next cohort. If DLT occurs in 2 or more 
subjects, the study will be stopped, but if it is determined, after consulting the SMC, that 
this dose is tolerable, then the study will proceed to the next cohort.
Cohort 3, Cohort 4 and Part B will be conducted after tolerability is confirmed in Cohort 
2. Whether or not the study will proceed to Part B will be determined by the study 
sponsor after consulting the SMC based on a comprehensive evaluation of the tolerability 
and safety data from Cohort 2 of Part A.
If the study cannot proceed from Cohort 2 to Cohort 3 and Part B because of a tolerability 
problem, the study will proceed to an additional cohort that will receive a TAK-385 
loading dose of 320 mg and a maintenance dose of 40 mg. In this case, as well, 3 
subjects will be enrolled, and assessed in the same manner as described above. If the 
study proceeds to the additional cohort, and continues until the treatment of the additional 
cohort has been completed, and it is confirmed that no problems with tolerability are 
found, then the study will proceed to Part B.
If DLT occurs in 2 or more subjects in Cohort 3, then whether or not to increase the dose 
to 160 mg in Part B will be determined in consultation with the SMC.


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Because assessment of the MTD is not the objective of this study, additional subjects will 
not be enrolled if TAK-385 is found to be tolerable in an evaluation of the 3 subjects in 
Cohort 3 or Cohort 4, nor will additional subjects be enrolled at lower dose levels if 
TAK-385 is not found to be tolerable at the dose level initially investigated.
Table 6.c
Cohort/Part Advancement Criteria
Number of Subjects With 
DLT
(DLT evaluable subjects)
Cohort
Procedure
0/3
1
Proceed to Cohort 2
2
Proceed to Cohort 3, Cohort 4 and Part B
3, 4
Stop
1/3
1 to 4
Add 3 subjects in the same cohort
2/3 or 3/3
1
Stop
2
Add a cohort*1
3, 4
Stop
1/6
1
Proceed to Cohort 2
2
Proceed to Cohort 3, Cohort 4 and Part B
3, 4
Stop
≥ 2/6
1
Stop
2
Add a cohort*1
3, 4
Stop
*1: TAK-385 loading dose of 320 mg and maintenance dose of 40 mg
Table 6.d
Criteria for Advancing From an Additional Cohort to Part B
Number of Subjects With 
DLT
(DLT evaluable subjects)
Procedure
0/3
Proceed to Part B
1/3
Add 3 subjects
2/3 or 3/3
Stop
1/6
Proceed to Part B
≥ 2/6
Stop
6.1.2
DLT
6.1.2.1
Definition of DLT
DLTs are defined at treatment-related AEs that occur within the first 28 days of treatment 
and that meet one of the criteria described below based on CTCAE Version 4.03 (issued 
June 14, 2010) [13].


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1.
Grade 3 or higher toxicity
Clinical laboratory abnormalities meet this criterion if they are found at 2 
consecutive time points 7 or more days apart, except for ALT or AST > 3 upper 
limit of normal(ULN), total bilirubin > 2 ULN, or prothrombin time-international 
normalized ratio (PT-INR) > 1.5 at 2 time points 2 or more days apart.
2.
Either of the following ECG findings at 2 time points 7 or more days apart
QT/Fridericia corrected QT (QTcF) > 500 msec after treatment initiation
QT/QTcF interval prolongation > 60 msec postdose
The QTcF interval will be calculated using Fridericia’s equation (QT/RR0.33).
If it is difficult to determine whether or not an event is a DLT and the subject who 
experienced the event should be included in the DLT analysis set, the sponsor will 
consult the SMC before making a final decision on whether or not the event is a DLT.
Study treatment will be continued until the end of the 28-day treatment period unless a 
DLT occurs. If a subject is withdrawn from the study for a reason other than a DLT or if 
treatment compliance is below 80% (23 doses), the subject will be considered ineligible 
for inclusion in the DLT analysis set, and replacement subjects will be added in order to 
obtain 3 or 6 evaluable subjects.
6.1.2.2
DLT Evaluation Period
From treatment initiation until Day 28 in Part A.
6.1.2.3
DLT Evaluable Subjects
Subjects meeting any of the following criteria enrolled in a cohort in Part A.

Subjects who have taken at least 80% of the doses of TAK-385 (23 doses) during the 
DLT evaluation period and for whom the DLT evaluation period observations have 
been completed.

Subjects who experienced DLTs during the DLT evaluation period.
6.2
Rationale for Study Design, Dosage, and Endpoints
(1) Rationale for the target patient population and the study design
The novel GnRH antagonist TAK-385 is expected to compensate for the deficiencies 
of the GnRH agonists that have been widely used in the treatment of prostate cancer 
to date, and is being developed as a novel therapeutic medication for prostate cancer. 
The target patient population for this study was therefore made Japanese patients 
with prostate cancer.
Because this study will be the first time in Japan that TAK-385 will be administered 
to patients with prostate cancer, and the safety and efficacy of TAK-385 for the 
target population have not been sufficiently demonstrated, the TAK-385 treatment 
period in Part A was set at 28 days. The treatment period would minimize the 


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inconvenience to subjects with safety concerns or insufficient efficacy. Because 
TAK-385 will be administered alone to hormone treatment-naive patients with 
prostate cancer, a placebo would not be used, and that the study would be conducted 
as an open-label study. It was also decided that if a subject is going to be switched to 
some other therapy after receiving the last dose of TAK-385 in Part A, then the 
patient would have to first pass through a 1-week observation (no-treatment) period 
because of concerns about the safety of the temporary concomitant use of TAK-385 
with other therapies. However, subjects meeting the discontinuation criteria (Section 
7.5) during the 28-day treatment period would not need to first pass through a 1-
week observation period if they need to be switched to some other therapy 
immediately.
The treatment period in Part B was made 48 weeks long in order to investigate safety 
and efficacy over a longer period, in light of the fact that the safety and efficacy of 
TAK-385 in multiple dosing for 28 days will have been confirmed in Part A. If the 
investigator or sub-investigator determines after 48 weeks that there are no safety 
problems and that TAK-385 treatment may be continued, then treatment may be 
continued for up to a total of 96 weeks. Part B was made an open-label phase with 
randomization to one of two doses the tolerability of which will have been confirmed 
in Part A. An open-label study design was used because TAK-385 is being 
administered alone to hormone treatment-naive patient with prostate cancer. In 
addition, if a subject is going to be switched to some other treatment after the last 
dose of TAK-385 then, unlike in Part A, and assuming use in the actual clinical 
setting, it was decided that the other therapy could be initiated without any 
intervening observation period for confirming the safety of temporary concomitant 
use with the other therapy.
Furthermore, TAK-385 has been found to be affected by food, and the results that 
have been obtained suggest that TAK-385 absorption is decreased and delayed when 
a single dose is taken 30 minutes after food compared to when it is taken in a fasted 
condition (TAK-385_C27001). It was therefore decided that TAK-385 should be 
taken at least 30 minutes before breakfast.
Because the company plans to participate in multinational studies in the future, it was 
decided that Part B would be conducted using the same dosage and administration as 
that being used in the phase 2 studies being conducted overseas. Because Part B will 
be conducted using a dosage the tolerability of which will have been confirmed in 
Cohorts 1 and 2 in Part A, it was decided that Part A Cohort 3 and Part B could be 
conducted in parallel.
(2) Rationale for loading dose (Part A, Cohort 1)
In a phase 1 study in healthy adult males that was conducted in Europe 
(TAK-385_C27001), the tolerability of single doses as high as 360 mg and multiple
doses as high as 160 mg was confirmed. In order to keep serum testosterone at 
castration levels and maintain this effect, it was felt that a dose of at least TAK-385 
80 mg a day would be necessary as a maintenance dose. In addition, in study 


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TAK-385_C27001, single doses of TAK-385 180 mg and above reduced serum 
testosterone levels to castration levels within 48 hours.
 
 
 
 
Based on these existing data on TAK-385 and on the development plan, it was 
decided that the loading dose for Cohort 1 in Part A of this study should be 320 mg, 
a dose that is within the range of doses that have been confirmed to be safe in single 
dosing, and that can be reliably expected to suppress serum testosterone levels within 
48 hours. Given that TAK-385 is going to be used in patients with prostate cancer, 
the company concluded that it would be necessary to use a dose that could be 
expected to be effective from the beginning, and that this dose would be tolerated as 
the loading dose in Japanese. The maintenance dose was set at 80 mg, which can be 
expected to suppress serum testosterone levels.
(3) Rationale for dosage in Part A, Cohort 4
320 mg or 360 mg may be selected as the loading dose in the planned phase 3 
multinational study. Based on this situation, a new cohort, Cohort 4, was added to 
Part A in Amendment 2 of the study protocol, designed to evaluate the tolerability of 
loading dose of 360 mg in Japanese patients before joining the phase 3 multinational 
study. As for the maintenance dose, the same dose as Part A, Cohort 2 (120 mg) was 
selected, since this dose is expected to keep serum testosterone at castration levels 
and maintain this effect.
As described in the section above, the tolerability of single doses of 360 mg and 
multiple doses as high as 160 mg (for 28 days) has been confirmed in a phase 1 study 
in healthy adult males that was conducted in Europe (TAK-385_C27001).
  Based on the fact that there are no major differences 
between Japanese and Americans in the pharmacokinetic or pharmacodynamic 
profiles of TAK-385, and that there are no major differences between the 
pharmacokinetic profiles obtained in healthy adult men and women, there are no 
safety concerns in using the loading dose of 360 mg and maintenance dose of 
120 mg in Part A, Cohort 4.
(4) Rationale for endpoints
1) Rationale for the primary endpoints


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The endpoint in Part A is DLT, in order to confirm the tolerability of TAK-385 in 
multiple dosing. AEs, clinical laboratory tests, vital signs, and 12-lead ECGs 
were also made primary endpoints, in order to confirm safety.
In part B, the primary endpoints were made AEs, clinical laboratory tests, vital 
signs, and 12-lead ECGs, in order to confirm the safety of the use of TAK-385 in 
multiple dosing for 48 weeks.
2) Rationale for secondary endpoints
In both Part A and Part B, the plasma concentrations of unchanged TAK-385 will 
be investigated in order to confirm the PK of TAK-385 in multiple dosing. The 
change in serum testosterone levels over time will also be investigated, in order to 
confirm the pharmacodynamics. In addition, in Part B, PSA levels will also be 
evaluated in order to investigate the efficacy of TAK-385 in prostate cancer.
3) Rationale for other endpoints
In Part A, the changes over time in the blood levels of LH, FSH, DHT, and 
SHBG, which are involved in testosterone synthesis, will be investigated. PSA 
levels will also be evaluated, in order to preliminarily investigate the efficacy of 
TAK-385 in prostate cancer.
In Part B, disease progression assessed on the basis of PSA and disease 
progression assessed on the basis of imaging assessments will be evaluated in 
accordance with the Prostate Cancer Handling Guidelines, Fourth Edition [16], in 
order to preliminarily investigate the efficacy of TAK-385 in prostate cancer. In 
addition, as in Part A, the changes over time in the blood levels of LH, FSH, 
DHT, and SHBG will also be investigated. Moreover, because androgen-
deprivation therapy is known to promote loss of bone mineral density and 
increase the potential for bone fractures, bone density tests were specified in order 
to evaluate the effects of TAK-385 on bone mineral density. In nonclinical 
studies, changes suggesting systemic phospholipidosis have been found in the 
organs/tissues of animals. Therefore, in order to closely monitor subjects for 
phospholipidosis, ophthalmology tests were specified, as was assessment of the 
level of di-docosahexaenoyl (22:6)-bis(monoacylglycero)phosphate (BMP) [14, 
15]. Furthermore, in order to evaluate the effects of TAK-385 on quality of life in 
patients with prostate cancer, quality of life assessments will be performed using 
the Japanese versions of AMS, EORTC-QLQ-C30, and EPIC, which are widely 
used in clinical studies overseas.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study.


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
New information or other evaluation regarding the safety or efficacy of the study drug
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

The SMC recommends that the study be suspended or terminated.

Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites 
An investigational site may be terminated prematurely or suspended if the site (including 
the investigator) is found in significant violation of GCP, protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise 
permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics 
committee (IEC) or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All inclusion and exclusion criterial, including test results, need to be checked before 
study treatment initiation (Part A) or randomization (Part B).
7.1
Inclusion Criteria
Subject eligibility will be determined based on the following criteria.
1. Patients judged by the investigator to have the capacity to understand the study and 
follow the study rules.
2. Patients whose written consent (signature or printed name and personal seal on 
informed consent form) can be obtained before any study procedures are performed.
3. Japanese male patients 20 or more years of age at the time of informed consent.
4. Patients who, if they have a female partner who could become pregnant, agree to 
practice appropriate means of contraception from the time of informed consent 
throughout the entire study treatment period and for 4 months after the last dose of 
study drug.
5. Patients in stable medical condition, including the absence of acute exacerbations of 
chronic illnesses, serious infections, or major surgery within 4 weeks (28 days) prior 
to study treatment initiation.
6. Patients with histologically or cytologically confirmed prostate cancer.
7. Patients whose clinical diagnosis is T1-4 N0 M0, or Tx N0 M0 for patients who have 
undergone radical prostatectomy.
8. Patients who are considered eligible for hormone therapy for prostate cancer.
9. Patients who have not received hormone therapy (eg, GnRH agonist, GnRH 
antagonist, steroidal antiandrogen, non-steroidal androgen) for prostate cancer.
10. Patients who have not undergone surgical castration.
11. Patients with serum testosterone at screening > 150 ng/dL.
12. Patients meeting either of the following criteria for PSA at screening.
Untreated prostate cancer:
PSA at screening > 4.0 ng/mL
Treated* prostate cancer:
PSA at screening > 0.2 ng/mL
*: Patients who have undergone prostatectomy or either or both of high intensity focused ultrasound 
therapy or radiotherapy (excluding 125I-brachytherapy) prior to the start of this study.
13. Eastern Cooperative Oncology Group (ECOG) performance status [17] of 0 or 1 
(Appendix G)
14. Body mass index (BMI*) at screening ≥ 18.0 kg/m2
*: BMI will be calculated by the investigational site using the following formula: BMI = Body weight 
(kg)/(height (m))2


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Body weight will be measured in kilograms to the first decimal point, height will be measured in 
centimeters using integers only, and the results obtained for BMI will be rounded off to the first decimal 
point.
Example: Weight = 79.2 (kg), height = 176 (cm) = 1.76 (m); BMI = 79.2/1.762 = 25.6 (kg/m2)
7.2
Exclusion Criteria
Patients meeting any of the following criteria will be excluded from the study.
1.
Patients exhibiting symptoms judged related to prostate cancer by the investigator 
(eg, bone pain, pelvic pain, ureteral obstruction) who urgently require hormone 
therapy such as GnRH agonist, GnRH antagonist, or combined androgen blockade
(CAB)/ maximum androgen blockade (MAB) therapy, chemotherapy, or 
radiotherapy.
2.
Patients who have received 5-alpha reductase inhibitors (except for patients who 
have been treated for male-pattern alopecias).
3.
Patients who have received chemotherapy for prostate cancer (including 
estramustine).
4.
Patients who have received 125I-brachytherapy.
5.
Patients who received radiotherapy (except for 125I-brachytherapy) within 16 weeks 
(112 days) before study treatment initiation.
6.
Patients who underwent prostatectomy within 16 weeks (112 days before study 
treatment initiation.
7.
Treatment with any investigational compound within the 4 weeks (28 days) prior to 
the first dose of study drug or ongoing participation in another experimental trial 
related to the treatment of prostate cancer.
8.
Diagnosis or treatment for another systemic malignancy within 2 years before study 
treatment initiation, or who had received a diagnosis of another malignancy before 
that and have evidence of residual disease. Patients with non-melanoma skin cancer 
or carcinoma in situ who have undergone complete resection will not be excluded 
from the study.
9.
Patients taking drugs with moderate to strong CYP3A4 inhibitory or inducing 
effects, or any medications, supplements, or food products with P-gp inhibitory
effects, in the 2 weeks (14 days) prior to study treatment initiation.
10. Patients who have received TAK-385 in a past clinical study.
11. Patients for whom it would be difficult to collect blood from a peripheral vein.
12. Patients with uncontrolled and clinically significant nervous, circulatory, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, urogenital, or endocrine disorders, or other 
abnormalities (except for the targeted disease) that could affect study participation or 
the study results. Also, patients meeting any of criteria a through c below.


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a. Patients with uncontrolled diabetes (HbA1c > 8% at screening). However, 
patients whose HbA1c is brought under control with diabetes medications may be 
rescreened.
b. Patients with uncontrolled hypertension (systolic blood pressure > 150 mmHg and 
diastolic blood pressure > 90 mmHg at 2 separate measurements taken no more 
than 60 minutes apart at screening). Patients whose blood pressure is brought 
under control by antihypertensive medication may be rescreened.
c. Patients with myocardial infarction, unstable symptomatic ischemic heart disease, 
arrhythmias of CTCAE Grade > 2, thromboembolism (deep vein thrombosis, 
pulmonary embolism, or symptomatic cerebrovascular events), or other heart 
diseases (eg, pericardial effusion, restrictive cardiomyopathy). However, chronic 
stable atrial fibrillation controlled by stable anticoagulant therapy will be allowed.
13. Patients with bilateral hydronephrosis or bladder neck outlet obstruction.
14. Known hypersensitivity to TAK-385, TAK-385 excipients, or GnRH antagonists.
15. Patients with a past history of gastrointestinal tract treatments (including 
gastrectomy) or gastrointestinal disease that could affect the drug absorption or 
tolerability (malabsorption, esophageal reflux, peptic ulcer, erosive esophagitis).
16. Patients positive for hepatitis B surface antigens (HBsAg), hepatitis C virus (HCV) 
antibodies, human immunodeficiency virus (HIV) antibodies, or serologic test for 
syphilis, or with life-threatening disease other than cancer, at screening.
17. Clinically relevant ECG abnormalities, or the following ECG abnormalities, at 
screening.
a. Q-wave infarction, unless identified 6 or more months prior to TAK-385 
treatment initiation
b. QTcF interval > 450 msec (when calculating the QTc interval, Fridericia’s 
equation [QT/RR0.33] will be used)
18. Patients with congenital QT prolongation.
19. Current use of Class 1A or Class 3 antiarrhythmic medications.
20. New York Heart Association [18] Class III or IV heart failure (Appendix H).
21. Patients with clinical laboratory abnormalities suggesting clinically relevant 
underlying disease, or with any of the following abnormal results, at screening.
•
Serum creatinine ≥ 2.0 mg/dL
•
ALT or AST ≥ 1.5 ULN for the investigational site
•
Total bilirubin ≥ 2 ULN for the investigational site
•
Neutrophil count < 1,500/mm3, platelet count < 100,000/μL, hemoglobin 
< 10.0 g/dL


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•
Results of heart-related tests (creatine kinase MB [CK-MB] and cardiac troponin 
T) exceeding the investigational sites reference value.
22. Patients found to have clinical problems on the basis of examination findings, ECG 
findings, or chest X-ray findings at screening.
23. Patients considered unlikely by investigators to be able to follow the study protocol 
or considered ineligible for the study by investigators for other reasons.
7.3
Prohibited Concomitant Medications, Therapies, and Foods
7.3.1
Prohibited Concomitant Medications
The concomitant use of the following medications will be prohibited during the treatment 
period out of concern for the effects on safety, PK, and pharmacodynamics. 
Furthermore, in Part A, the prohibited concomitant medications may not be used until the 
end of the post-treatment observation period.

GnRH agonists

GnRH antagonists

Steroidal antiandrogens

Nonsteroidal antiandrogens

Drugs that include corticosteroids (except for topical drugs)

Male sex hormone preparations

Female sex hormone preparations

5α reductase inhibitors

Docetaxel

Other chemotherapy drugs indicated for prostate cancer

Drugs with moderately powerful to strongly powerful CYP3A4 inhibitory or inducing 
effects

Drugs with P-gp inhibitory effects
7.3.2
Prohibited Concomitant Therapies
The following therapies for prostate cancer will be prohibited from study treatment 
initiation until the end of safety follow-up.

Surgical castration

Prostatectomy

High-intensity focused ultrasound therapy

Radiotherapy


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7.3.3
Food
From study treatment initiation and during the treatment period (in Part A, until the end 
of the post-treatment observation period), the use of nutritional supplements and the 
consumption of grapefruit and related beverages/foods will be prohibited unless judged 
necessary by the investigator.
7.4
Subject Management
1. Inpatient/outpatient status
Subjects will be admitted to the investigational site from one day before treatment 
initiation in each cohort (Day -1) until Day 15 in Part A. As a rule, from Day 16 on, 
the study will be conducted on an outpatient basis until the safety follow-up. 
However, from Day 27 on, if a subject lives far from the hospital and it would be 
difficult for the subject to come to the hospital at the scheduled times, or if the subject 
desires admission, the study may be conducted on an inpatient basis from Day 27 
until Day 35 at the latest. While subjects are inpatients in Part A, they will eat meals 
(breakfast, lunch, and dinner) at specified times. After being discharged as well, 
subjects will be instructed to avoid eating or drinking excessively until the end of 
safety follow-up. When subjects are coming in for visits on an outpatient basis, they 
will be instructed to be sure to eat dinner on the day before the day of a visit at which 
a blood sample will be collected for laboratory testing, and they will be instructed to 
return to the hospital on the following day without eating for blood collection and 
testing, after which they will receive TAK-385 and then eat breakfast at least 30 
minutes later.
If a subject desires to return home temporarily during the inpatient period, and it 
would not interfere with study treatment, observations, or tests, then the investigator 
may allow the subject to return home temporarily, after carefully checking to be sure 
that the subject’s condition is stable, on the basis of the data that have been collected 
during the study to that point.
Unless there is a special reason, Part B will as a rule be conducted on an outpatient 
basis. Subjects will be instructed to observe the scheduled visit times and undergo 
the examinations and the specified tests. Subjects will also be instructed to inform 
the investigator promptly if they are not able to come in for a scheduled visit.
2. Study treatment
Investigators will instruct subjects to take the study drug 30 minutes before breakfast 
on each day, and to make sure that the time they take the study drug is the same on 
each day, to the extent possible.
If a subject forgets to take the study drug 30 minutes before breakfast, the subject 
should take the drug 30 minutes before lunch on the same day. If a subject forgets to
take the study drug both 30 minutes before breakfast and 30 minutes before lunch, the 
subject should take the study drug 30 minutes before dinner on the same day. It will 
be explained to subjects that they should not take any study drug that they have 
forgotten to take on a later day together with the study drug for that day. Subjects will 


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also be instructed to be sure to note in the patient diary the time they took the study 
drug as well as whether or not they took the study drug 30 minutes before breakfast.
On scheduled outpatient visit days, subjects will be asked to come to the 
investigational site in the morning without taking the study drug, and the scheduled 
tests will be performed.
3. Drinks, etc.
On days on which study drug is to be taken, subjects will be prohibited from drinking 
anything from 1 hour before dosing until 30 minutes after, other than one cup of 
water when they take the study drug.
4. Other
Investigators will instruct subjects that, if a subjective symptom emerges, it should be 
reported, along with the date of onset, severity, outcome, and date of outcome, when 
the subject next visits the investigational site.
Investigators will instruct subjects not to take any drugs, including over-the-counter 
drugs, other than the drugs that they are instructed to take, without consulting the 
investigator in advance.
Subjects will be instructed that, if they are treated at another medical institution in the
time between the treatment period and the safety follow-up, they are to report the 
background for and nature of said treatment to the investigator, and to inform the 
medical institution in question that they are participating in a clinical study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Investigators will enter into the electronic case report form (eCRF) the primary reason for 
discontinuation or withdrawal of the subject from the study, classified into one of the 
following categories. See Section 9.1.23 for subjects discontinuing before the study 
treatment initiation (in the case of Part A) or before randomization (in the case of Part B).
1.
Pretreatment event or adverse event
This will be considered the primary reason if the subject has experienced a PTE or 
AE that requires early termination because continued participation imposes an 
unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the PTE or AE; if a serious AE occurs, the subject temporarily stops 
taking the study drug, and the AE recurs following study treatment resumption, or 
does not resolve event after 2 weeks of treatment interruption; or if toxicity that is 
considered DLT occurs in Part A.
Liver function test abnormalities
If a LFT abnormality meeting any of the following criteria occurs during study 
treatment, study drug administration will be discontinued immediately, and 
appropriate follow-up tests will be performed until the subject’s clinical laboratory 
profile returns to normal, to the level of the first test value obtained after informed 


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consent (in the case of a PTE), or to baseline (in the case of an AE) (see Section 
9.1.8).
-
ALT or AST > 3 ULN; AND total bilirubin > 2 ULN or PT-INR > 1.5
2.
Major protocol deviation
This will be considered the primary reason for study withdrawal if it is discovered 
after the first dose of study treatment (in the case of Part A) or after randomization 
(in the case of Part B) that the subject does not meet the enrollment criteria specified 
in the study protocol, or has not followed the study protocol, and that continuing the 
study would pose an unacceptable risk to the subject's health.
3.
Lost to Follow-up
This will be considered the primary reason for study withdrawal if a subject fails a 
study visit and cannot be contacted. In this case, the fact that contact was attempted 
will be noted in the source documents.
4.
Voluntary withdrawal
This will be considered the primary reason for withdrawal if the subject wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded 
in the eCRF.
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(ie, withdrawal due to an AE or lack of efficacy should not be recorded in the 
“voluntary withdrawal” category).
5.
Study termination
This will be considered the primary reason for withdrawal if the sponsor, IRB, or 
regulatory authorities decide to terminate the study.
6.
Lack of efficacy
This will be considered the primary reason for withdrawal if the expected level of 
efficacy is not obtained because of disease progression assessed by PSA level or 
evaluation of soft tissue or bone lesions by diagnostic imaging (according to the 
Prostate Cancer Handling Guidelines, Fourth Edition [16]), or if the decrease in 
serum testosterone meets any of the following criteria.
1) If, in Part A, serum testosterone does not drop below 50 ng/dL at 2 or more time 
points at least 7 days apart following treatment initiation, and it is determined as 
a result that the patient must be switched to some other therapy.
2) If, in Part B, serum testosterone does not drop below 50 ng/dL by 4 weeks after 
uptitration based on the uptitration criteria (see Section 8.1.3.1).
3) If, in Part B, serum testosterone exceeds 50 ng/dL on 2 consecutive occasions, or 
on 3 occasions in total, whether consecutive or not, by 9 weeks (57 days) after 
the start of treatment following uptitration in accordance with the uptitration 
guidelines (see Section 8.1.3.1).


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7.6
Procedures for Discontinuation or Withdrawal of a Subject
If a subject meets the criteria described in Section 7.5, the investigator will withdraw the 
subject from the study. Furthermore, subjects may withdraw from the study without 
providing a reason at any time during the study. If a subject withdraws from the study, 
the investigator will enter the primary reason for withdrawal in the eCRF, and will 
perform all procedures scheduled for the Early Termination Visit.


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8.0
STUDY DRUG MANAGEMENT
This section contains information regarding all study drugs provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Drug
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Investigational Drug
(1) Investigational drug name: TAK-385
(2) Chemical name
N-(4-{1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-3-
(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl}phenyl)-N'-
methoxyurea
(3) Dosage forms and doses
TAK-385 40 mg tablets: Each tablet contains 40 mg as TAK-385
TAK-385 80 mg tablets: Each tablet contains 80 mg as TAK-385
There are two types of study drug, described above; both are light red, film-coated 
tablets.
(4) Packaging and labeling
Each dosage form comes packaged 40 tablets to a bottle. The label clearly states that 
the drug is for use in a clinical study, and also bears the drug name, protocol number, 
name and address of the study sponsor (or company that manufactured the drug), 
manufacturing number, and storage method (Figure 8.a).


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For Use in a Clinical Study
TAK-385  40 mg Tablets (or 80 mg Tablets)
For oral administration
Contains 40 tablets
Protocol number: TAK-385/TB-AK160108
Manufacturing number: 
Storage method: Room temperature (1-30C)
Expiration date: See the study drug control procedures
Unused study drug and used bottles will be collected by the study 
sponsor; do not discard.
Takeda Pharmaceutical Company
4-1-1 Doshomachi, Chuo-ku, Osaka
Figure 8.a
Sample TAK-385 Bottle Label
8.1.1.2
Drugs not Provided by the Study Sponsor
No drugs will be provided other than the study drug and drugs such as GnRH agonists 
and/or GnRH antagonists following the completion (or discontinuation) of TAK-385 
administration.
8.1.2
Storage
TAK-385 will be stored at room temperature (1-30C).
Investigational drug must be stored in an appropriate, limited-access, secure place until 
they are used or until they are returned to the sponsor or a designee for destruction.
Investigational drug must be stored under the conditions specified on the label, and must 
remain in their original containers until dispensed. The daily temperature log of the drug 
storage area must be maintained every working day.
8.1.3
Dose and Regimen
Table 8.a shows the dosage and number of tablets in Part A (by cohort), and Table 8.b
shows the dosage and number of tablets in Part B (by treatment group).


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Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A)
Cohort
Dosage/Number of Tablets
1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Days 2 to 28): One 80 mg tablet per day
2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
3
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 160 mg (Days 2 to 28): One 80 mg tablet and two 40 mg tablets per day
4
TAK-385 360 mg (Day 1): Three 80 mg tablets and three 40 mg tablet per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
Additional 
cohort*1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Days 2 to 28): One 40 mg tablet per day
*1: Added if tolerability is not confirmed in Cohort 2
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B)
Treatment 
Group
Dosage/Number of Tablets
80 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Day 2 to Week 48*3): Two 40 mg tablets per day
120 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Day 2 to Week 48*3): One 80 mg tablet and one 40 mg tablet per day
40 mg*2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Day 2 to Week 48*3): One 40 mg tablet per day
At uptitration
One TAK-385 40 mg tablet per day will be added
*2: If no problems with tolerability are found in the additional cohort in Part A
*3: Treatment may be continued for up to 96 weeks in total
The specified dose of TAK-385 will be taken once a day orally with 1 cup of water at 
least 30 minutes before breakfast. Except for when various tests are being performed or 
an AE occurs, an effort will be made to ensure that subjects rest for 2 hours after 
receiving the dose.
The investigator or study support staff will check to make sure that all specified study 
drug has been taken.
8.1.3.1
Criteria for Upward Dose Adjustments
Part A: The dose of TAK-385 will not be increased even if inadequate testosterone 
suppression occurs (< 50 ng/dL). If after treatment initiation the serum testosterone level 
does not drop below 50 ng/dL at 2 or more time points separated by at least 7 days and 
the investigator or sub-investigator determines that the patient needs to be switched to 
some other treatment, then TAK-385 treatment will be stopped and the patient withdrawn 
from the study.


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Part B: If the following conditions are met, the dose may be adjusted, taking efficacy and 
safety into consideration. Dose adjustment will be performed when the subject is 
examined by the investigator or sub-investigator.
If the serum testosterone level in an individual patient exceeds 50 ng/dL at Week 5 (Day 
29), Week 9 (Day 57), or Week 13 (Day 85), following review of compliance, a one-time 
upward dose modification (increment of 40 mg daily) will be allowed. After Week 13, 
the dose will not be increased even if the serum testosterone level exceeds 50 ng/dL.
The dose will not be increased in the 120 mg group before the DLT evaluations have 
been completed for Cohort 3 in Part A, or if the dose has not been found to be tolerable. 
Similarly, if tolerability is not found in Cohort 2 in Part A and a 40 mg group is therefore 
going to be used instead of a 120 mg group, then the dose in the 80 mg group will not be 
increased.
8.1.3.2
Criteria for Dose Holds and Dose Reduction
Part A: If a treatment-related AE occurs, or if it would be difficult to continue with TAK-
385 treatment, then the dose of TAK-385 will not be reduced, and study treatment will be
interrupted if necessary.
Part B: If a treatment-related AE occurs or if it would be difficult to continue with TAK-
385 treatment, then study treatment will be interrupted if necessary. Subjects who 
experience serious AEs requiring study treatment interruption within 12 weeks (84 days) 
following treatment initiation may have their doses reduced by one dose level – 40 mg –
following a 2-week treatment interruption period. If the AE continues even after dose 
reduction, or the subject’s serum testosterone level exceeds 50 ng/dL for 4 to 6 weeks 
following dose reduction, then TAK-385 treatment will be discontinued so that the 
subject may receive some other therapy. If a serious AE requiring study treatment 
interruption occurs on or after Week 13 (Day 85) following treatment initiation, and the 
subject’s treatment has not been interrupted prior to that, then the subject’s treatment may 
be interrupted for 2 weeks and then resumed. However, if the AE recurs following study 
treatment resumption, or if the AE does not resolve even after 2 weeks of treatment 
interruption, then the subject will be withdrawn from the study.
Even if the dose has been increased in accordance with Section 8.1.3.1, when reducing 
the dose, it will be reduced by one dose level. Dose reduction will not be performed for 
subjects in the 40 mg group. In addition, if the dose is reduced in accordance with this 
section, then the dose may not be increased as described in Section 8.1.3.1.
Furthermore, if a LFT abnormality is found, it will be handled as shown in Table 8.c.


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Table 8.c
Guidelines for Handling Liver Function Test Abnormalities
Category ALT, AST, and Total 
Bilirubin
Study Drug
ALT and AST Tests Treatment 
Interruption
Dose 
Adjustment
A
ALT or AST ≥ 1.5 ULN 
to < 3 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week for 2 weeks, 
and then every 2 
weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
B
ALT or AST ≥ 3 ULN to 
< 5 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week, and then every 
2 weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
C
ALT or AST ≥ 5 ULN to 
< 8 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests in the 
first week, then every 
week for 2 weeks, 
and then every 2 
weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg
D
ALT or AST ≥8 ULN to 
< 20 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests a 
week for the first 2 
weeks, and then every 
2 weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg*2
E
ALT or AST ≥ 3ULN
AND
Total bilirubin > 2 ULN
(Hy’s law)
Permanently 
discontinue 
treatment
Perform 2 tests a 
week until the test 
values drop, and then 
every week until 
stable*1
N/A
N/A
*1: Stable means ALT and AST both CTCAE Grade 1 (> ULN to 3 ULN)
*2: The study sponsor should be consulted before resuming treatment.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the eCRF, in order to capture this important safety information 
consistently in the database. Cases of overdose without manifested signs or symptoms are 
not considered AEs. AEs associated with an overdose will be documented on AE CRF(s) 
according to Section 10.0.
Serious AEs associated with overdose should be reported according to the procedures 
outlined in Section 10.2.2.
In the event of a study drug overdose, the investigator will treat the subject 
symptomatically.


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8.2
Study Drug Allocation and Prescribing Procedures
In Part A, in order to confirm eligibility for study participation based on the screening 
tests, the investigator or a person designated by the investigator will contact the 
registration center by fax. The investigator will prescribe study drug to the subject after 
confirming that the subject is eligible for the study based on a fax received from the 
registration center.
In Part B, the investigator or a person designated by the investigator will contact the 
registration center by fax to confirm the subject’s eligibility at the start of the treatment 
period.  After confirming, on the basis of a fax received from the registration center, that 
the subject is eligible, the investigator will prescribe the subject the study drug for the 
group to which the subject has been assigned. The investigator or a person designated by 
the investigator will enter the group to which the subject has been assigned in the eCRF.
Subjects will be assigned a 4-digit number, with the first signifying the Part and Cohort, 
the second signifying the investigational site, and the last two digits constituting a series 
number within the cohort at the investigational site. This 4-digit number will be used by 
the investigational sites to identify the specimens that will be used to assess the PK and 
pharmacodynamics. These numbers will be noted on the specimen tubes that are 
provided for measurement, and will be used instead of the subject identification numbers 
for reporting the measurement results. These numbers will not be replaced by the last 3 
digits of the subject identification numbers.
8.3
Randomization Code Creation and Storage
The randomization manager (or a person designated by the study sponsor) will prepare a 
randomization table. The randomization information will be stored in a safe location, and 
will only be accessible to authorized personnel.
8.4
Control and Disposal of Drugs Provided by the Study Sponsor
The study drug controller will receive the written procedures prepared by the study 
sponsor specifying the handling, storage, and control of study drug, and will 
appropriately control the drugs provided by the study sponsor in accordance with these 
written procedures. The investigators will also receive these procedures from the study 
sponsor. These procedures will describe the procedures that will have to be followed to 
ensure that the receipt, handling, storage, control, and prescribing of the study drugs 
provided by the study sponsor, as well as the recovery of unused drugs from subjects and 
their return to the study sponsor, or their disposal, are carried out appropriately and 
reliably.
The study drug controlled will promptly return to the study sponsor any unused drugs 
once the study has been completed at the investigational site in question.


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9.0
STUDY PLAN 
9.1
Study Proceduress
The following sections describe the study procedures and data to be collected. In 
principle, the same investigator will perform examinations and testing, observations, and 
evaluations of subjects. The Schedule of Study Procedures is shown in Appendix A to 
Appendix E.
9.1.1
Informed Consent
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained from the subject before any protocol-directed 
procedures are performed.
A unique subject identification number will be assigned to each subject at the time that 
informed consent is explained. The same subject number will be used throughout the 
study.
Informed Consent for Pharmacogenomics
Informed consent for the storage and banking of the blood sample for pharmacogenomics 
(PGx) testing in this study must be obtained separately before collection. The provision 
of consent to collect and analyze the PGx sample is independent of consent to the other 
aspects of the study.
9.1.2
Demographics, Medical History, and Treatment History
Demographic data will include date of birth, sex, and smoking history at screening. The 
items listed below will be checked with regard to prostate cancer [16]. The findings will 
be input to the eCRF.

Date of diagnosis and diagnostic method used

Gleason classification (pattern 1 to 5 and score) at most recent assessment and date of 
assessment

Tissue type and extent of differentiation

Treatment history (including medication history)

TNM classification (at time of diagnosis)

Prostatectomy yes/no, total resection yes/no, date of surgery

High intensity focused ultrasound yes/no, completion date

Radiation therapy yes/no, completion date

History of other therapy yes/no, mode of therapy, start date, completion date
The medical history will include clinically relevant diseases or conditions associated with 
the targeted disease that disappeared or ended within the past 1 year from the date of 


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informed consent. If a symptom or disease is still present, it will be considered a 
comorbidity (concurrent medical condition) (see Section 9.1.18).
Previous therapeutic drugs used (medication history) will include all drugs that were 
discontinued within 28 days before the date of informed consent and are relevant to the 
eligibility criteria.
9.1.3
Physical Examination
A physical examination will be conducted for the parts of the body listed below 
(interview, visual inspection, auscultation, palpation, percussion, etc.).
(1) eyes, (2) ears, nose, and throat, (3) cardiovascular system, (4) respiratory organs, 
(5) digestive organs, (6) skin, (7) extremities, (8) musculoskeletal system, (9) nervous 
system, (10) lymph nodes, (11) urogenital organs, (12) other
The investigator will evaluate abnormal findings discovered in the pre-administration 
physical examination for clinical relevance and record the results in the source data. 
Findings and changes considered to be clinically relevant will be input as PTEs or 
comorbidities at the proper locations in the source data and eCRF as described in 
Sections 10.0 and 9.1.18.
9.1.4
Weight, Height, and ECOG Performance Status
Weight and height will be measured. Weight will be measured in kilograms to the first 
decimal place, and height will be measured in centimeters to the closest integer. In 
addition, the ECOG performance status will be measured in accordance with Appendix 
G.
9.1.5
Vital Signs
Measurement of vital signs will include temperature (axillary), seated blood pressure 
(systolic and diastolic after resting at least 5 min) and heart rate (bpm). Measurements 
will be taken after the subject has been sitting for 5 min.
9.1.6
Electrocardiogram
A 12-lead ECG will be performed. Measurements will be taken after the subject has been 
in supine position for 5 min. The investigator (or a specialist at the medical institution)
will assess the results by the following categories: Normal range ("Within Normal 
Limits"), Abnormal but not clinically significant ("Abnormal, Not Clinically Significant
"), or Abnormal and clinically significant ("Clinically Significant ").
The following parameters will be transferred from the subject's ECG recording to the 
eCRF: heart rate, QT interval, PR interval, QRS duration, and RR interval.
In determining the QTc value, Bazett corrected QT (QTcB) and QTcF will be calculated 
using the Bazett formula (QT/RR0.5) and Fridericia formula (QT/RR0.33), respectively.


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9.1.7
Imaging Assessment
CT or MRI (thoracic, abdominal, and pelvic regions) and bone scintigraphy will be 
performed during screening to verify that there are no distant metastatic lesions. If 
measurements were taken within 28 days before the start of study drug administration, 
the results of diagnostic imaging and tests conducted before obtaining informed consent 
can be used. CT or MRI and bone scintigraphy will also be performed on the days 
stipulated in the clinical trial schedule (Appendix A to Appendix C) to check for new 
lesions. Disease progression will be determined by the presence or absence of new 
lesions based on the items evaluated in diagnostic imaging. Diagnostic imaging will also 
be performed as needed in Part A if abnormal findings appear in other tests and 
examinations during administration of the study drug.
9.1.8
Clinical Laboratory Tests
Specimens will be handled according to the procedures described in a separate document. 
A general guideline for the total amount of blood to be collected in this study is shown in 
Section 9.5.
Samples for clinical laboratory tests will be collected after at least 10 hours of fasting on 
the days stipulated in the Schedule of Study Procedures (Appendix A to Appendix E). 
Samples to be collected for each laboratory test are shown in Table 9.a.
Table 9.a
Clinical Laboratory Tests
Hematology
Chemistry
Metabolic Panel
Urinalysis
RBC
WBC
Hemoglobin
Hematocrit
Platelet count
Differential WBC 
(neutrophils [including 
absolute count], 
basophils, eosinophils, 
lymphocytes, 
monocytes)
Total protein
Albumin
Glucose
Creatinine
BUN
Uric acid
Total bilirubin
ALT
AST
LDH
-GTP
ALP
CK(CPK)
Na
K
Cl
Ca
P
PT-INR
Triglycerides
Total cholesterol
HDL cholesterol
LDL cholesterol
TSH
HbA1c
pH
Specific gravity
Protein (qualitative)
Glucose (qualitative) 
Occult blood 
(qualitative)
Ketones (qualitative)
Urobilinogen 
(qualitative)
Bilirubin (qualitative)
Tests to be conducted when determining eligibility


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(to be performed only when deemed necessary)
HIV test; hepatititis tests including HBsAg and anti-HCV; serologic test for syphilis
The above clinical laboratory tests will be performed at the medical institution. The 
investigator will evaluate and archive reported clinical laboratory test findings.
When the ALT or AST levels are > 3 ULN, retesting (at least ALP, ALT, AST, total 
bilirubin, γ-GTP, and PT-INR) will be performed within 48 to 72 hours (within 7 days at 
the latest).
(See Section 7.5 for the criteria for the withdrawal from the study.  See Section 10.2.3 for 
the reporting of LFT abnormalities in cases where the ALT or AST level exceeds 3 
ULN, and the total bilirubin level exceeds 2 ULN or the PT-INR exceeds 1.5.)
The investigator will archive the reference ranges for the clinical laboratory tests, 
including the history.
All clinically relevant, abnormal laboratory test values will be input in the source data 
and eCRF of the subject as AEs, etc. All clinically relevant, abnormal laboratory test 
values verified by retesting will be followed up in all subjects until the abnormal value 
returns to an acceptable level or there is a sufficient explanation for the observed change.
9.1.9
Cardiac Tests
CK-MB and cardiac troponin T will be measured at the institution during screening. 
These measurements will also be performed as needed when abnormal findings appear in 
other tests and examinations during administration of the study drug.
9.1.10
Tumor Marker
PSA will be measured by a third-party organization according to a separately prepared 
written procedure. Progression of disease as indicated by PSA (based on the Prostate 
Cancer Handling Guidelines, 4th Edition [16]) is defined as an increase of at least 25% in 
the PSA value measured at least 4 weeks after the minimum PSA value measured during 
the study period (at least 12 weeks if the minimum value was recorded during screening). 
In such a case, the amount of increase must be at least 2 ng/mL. The date this condition 
is met will be considered the disease progression date.
9.1.11
Collection of Pharmacogenomic Sample
After the start of study drug administration (Part A) or after randomization (Part B), one 
sample for PGx testing will be collected as early as possible during the administration 
period. A sample of 5 mL of whole blood for DNA extraction will be collected in an 
EDTA-treated polypropylene tube from each subject who has given consent. The sample 
will be sent to the sample storage facility.
Details of collection, handling, and storage of the sample for PGx testing will be carried 
out according to a separately prepared written procedure.


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9.1.12
Bone Mineral Density (Part B Only)
Bone mineral density will be measured by dual-energy X-ray absorptiometry (DXA). 
Throughout the study period the same subject will be measured on the same model of 
equipment using the same scanning mode. The investigator will input the equipment 
model, date of measurement, and results for the following measurement parameters into 
the eCRF.
Measurement sites: Lumbar 2 to 4 (L2 to L4) and hip (femoral neck, femoral 
trochanteric, femoral intertrochanteric, Ward's triangle, and total)
Measurement parameters: Bone mineral content (BMC, g), bone area (Area, cm2), and 
bone mineral density (BMD, g/cm2) of L2, L3, and L4, femoral neck, femoral 
trochanteric, and femoral intertrochanteric regions, and Ward's triangle; and total bone 
mineral content (BMC, g) (combined), bone area (Area, cm2) (combined), and bone 
mineral density (BMD g/cm2) (Mean) of L2 to L4 and hip.
9.1.13
Ophthalmological Examination (Part B Only)
The examination will be carried out in a darkened room. A slit lamp microscope will be 
used to examine the anterior of the eye, and the results will be classified as follows: 
Normal range, Abnormal but not clinically significant, or Abnormal and clinically 
significant.
9.1.14
BMP Concentrations (Part B Only)
BMP will be measured in serum and urine samples by a third-party organization 
according to a separately prepared written procedure. Sequential BMP testing will not be 
performed, and the measurements will be summarized after a fixed time period.  
Measurements will be conducted when there are clinical findings suggesting an 
association with phospholipidosis or there is a report of an association between 
comparable GnRH antagonists and phospholipidosis.
9.1.15
QOL Assessment (Part B Only)
QOL will be assessed using AMS, EORTC-QLQ-C30, and EPIC scores. After arriving 
at the hospital each subject will personally fill in the form provided by the sponsor before 
other tests are conducted and before the study drug is administered. The scoring of QOL 
will be carried out in the order: AMS, EORTC-QLQ-C30, and EPIC.
9.1.16
Concomitant Medications
The term concomitant medication is refers to any drug given in addition to the study 
drug. These may be prescribed by a physician or obtained by the subject over the 
counter. At each study visit, subjects will be asked whether they have taken any 
medication other than the study drug (used from signing of informed consent through
safety follow-up), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF.


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9.1.17
Concomitant Therapies
The term concomitant therapy refers to a medical act carried out for a therapeutic 
purpose. At each study visit, subjects will be asked whether they have received any 
therapeutic procedures (performed from signing of informed consent through safety 
follow-up).
9.1.18
Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent. This includes clinically significant laboratory, 
ECG, or physical examination abnormalities noted at screening examinations. The 
details of the condition (ie., diagnosis) should be recorded in the eCRF.
9.1.19
Contraception
Male subjects with female partners who may become pregnant will use a barrier-type 
contraceptive device (eg, condom and spermicidal cream or jelly) from the time of 
informed consent until 4 months after the final dose of the study drug. Furthermore, the 
subject will be instructed not to donate sperm during this time frame.
9.1.20
Pregnancy
If the subject's female partner becomes pregnant, the investigator, with the female 
partner's consent, will inform her attending physician (obstetrician) that the subject was 
participating in a clinical study when she became pregnant and reveal the details of the 
study drug.
If a pregnancy is reported for any subject, the investigator, with the subject's consent, will 
carry out a follow-up investigation until delivery, including premature delivery, and make 
a report to the sponsor using the designated follow-up form. The investigator will also 
conduct a postnatal evaluation.
9.1.21
Pharmacokinetic Assessments
The plasma concentrations will be measured at each blood sample collection time point 
(see Appendix D and Appendix E) in accordance with separately prepared written 
procedures.
The 3 time points for TAK-385 dosing that immediately precede blood sample collection, 
and the time points for the collection of blood samples for pharmacokinetic assessment, 
will be entered into the eCRF.
9.1.22
Pharmacodynamic Assessments
Serum testosterone, LH, FSH, DHT, and SHBG will be measured by an external 
measurement facility in accordance with separately prepared written procedures. Serum 
testosterone will be measured along with other highly sensitive measurements at 
specified time points (see Appendix B). Detailed information about the treatment and 
shipment of samples will be provided in the aforementioned written procedures as well.


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9.1.23
Documentation of Subjects Withdrawing From the Study Prior to Study 
Treatment Initiation or Prior to Randomization
The principal investigators will be responsible for all subjects who sign informed 
consent. Investigators will prepare eCRFs for all subjects who withdraw from the study 
prior to study treatment initiation or randomization.
The primary reason for withdrawal from the study prior to study treatment initiation (in 
the case of Part A) or prior to randomization (in the case of Part B) will be entered into 
the eCRF based on the following categories.
PTE / AE
Does not meet inclusion criteria or meets exclusion criteria < The reason will be 
entered. >
Major deviation from the study protocol
Follow-up impossible
Spontaneous withdrawal < The reason will be entered. >
Entire study discontinued
Other < The reason will be entered. >
The subject identification numbers of subjects withdrawing from the study will not be 
reused.
9.1.24
Documentation of Study Enrollment/Randomization
In Part A, only subjects who meet all of the inclusion criteria and do not meet any of the 
exclusion criteria will be enrolled in the treatment period. If a subject cannot proceed to 
the treatment period, the investigator will enter the primary reason for this in the eCRF.
In Part B, only subjects who meet all of the inclusion criteria and do not meet any of the 
exclusion criteria will be randomized. If a subject cannot be randomized, the investigator 
will enter the primary reason for this in the eCRF.
9.2
Monitoring Subject Treatment Compliance
During the inpatient period in Part A, the investigator or a person designated by the 
investigator will give the subject the study drug, confirm that the subject has taken it, and 
record this in the source documents. For study drug administration following discharge 
from the investigational site, subjects will be instructed to take the drug appropriately.
On the day of the first dose in Part B, the investigator or a person designated by the 
investigator will administer the study drug to the subject, confirm that the subject has 
taken the drug, and record this in the source documents. For study drug administration 
from Day 2 on, subjects will be instructed to take the drug appropriately.
The day of treatment initiation, the day of treatment completion, the dose, the actions 
taken with respect to the dose, and the reasons for any changes will be entered in both the 
source documents and the eCRF.


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Subjects will be instructed to bring their study drug (bottles) in with them at each 
outpatient visit. If it is found that a subject has not complied with the study treatment in 
the time since the previous visit (eg, if 20% [6 doses] or more of the specified doses have 
not been taken), then the subject may be withdrawn from the study. If the subject is 
given instructions about treatment noncompliance, then this will be recorded in the 
source documents.
9.3
Schedule of Observations and Procedures
Appendix A through Appendix E show the schedules for all tests, observations, and 
assessments. Investigators will perform the tests, observations, and assessments shown 
below at the specified time points.
9.3.1
Screening
Observations and tests will be performed within 28 days prior to the first dose of study 
drug to confirm subject eligibility for study participation based on the inclusion and 
exclusion criteria presented in Section 7.0. See Section 9.1.23 for the preparation of 
records for subjects withdrawing from the study during screening.
The following tests, observations, and assessments will be performed at screening.
Informed consent
Demographics, medical history, concurrent medical condition, treatment history
Physical examination
Vital signs
Weight, height, and BMI
ECOG performance status
HBsAg, HCV, and HIV antibody and serologic test for syphilis
If the institutional review board judges it necessary, these tests will be performed only for subjects determined 
by the investigator to be at high risk for hepatitis B or C or HIV infection.
12-lead ECG
Chest X-ray examination
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Cardiac tests
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
PTEs


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The following tests will be performed only in Part B.
Ophthalmological examinations
Bone mineral density
QOL assessments
9.3.2
Study Enrollment/Randomization
In Part A, subjects will be enrolled into each cohort by the day before study treatment 
initiation on the basis of the results of the aforementioned screening.
In Part B, subjects will be randomized by the day before study treatment initiation on the 
basis of the results of the aforementioned screening.
Subject who meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be enrolled or randomized in accordance with Section 8.2. As described in 
Section 9.2, subjects will receive their first dose of study drug at the investigational site 
under the supervision of the investigator or a person designated by the investigator.
9.3.3
Day of Study Treatment Initiation
The following tests, observations, and assessments will be performed before study drug is 
administered on the day of study treatment initiation. If 12-lead ECG or clinical 
laboratory tests were performed at screening up to 3 days prior to treatment initiation, 
then they may be used as the tests performed prior to treatment initiation.
Physical examination
Vital signs
Weight
12-lead ECG
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacokinetic assessments
The following tests will be performed only in Part B
Pharmacodynamic assessments (only serum testosterone by high-sensitivity 
measurement)
BMP concentrations
QOL assessments
9.3.4
Study Drug Treatment Period (Except for the Day of Study Treatment 
Initiation)
During the study treatment period, physical examinations and tests will be performed at 
scheduled inpatient and outpatient time points. The following tests, observations, and 
assessments will be performed during the treatment period.


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Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
PGx sample collection
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Pharmacokinetic assessments
The following tests will be performed only in Part B
Ophthalmological examinations
Bone mineral density
BMP concentrations
QOL assessments
9.3.5
Post-treatment Observation Period (Performed Only in Part A)
In Part A, the following tests, observations, and assessments will be performed as post-
treatment observations for 7 days following the last dose of study drug, and the results 
will be entered in the eCRF. Even if the subject withdraws from the study during Part A, 
the same post-treatment observations may be performed, depending on the subject’s 
treatment status. If a subject withdraws from the study, this will be reported to the study 
sponsor, which will be consulted about what actions should be taken.
Physical examination
Pharmacodynamic assessments
Pharmacokinetic assessments
Concomitant medications
Concomitant therapies
AEs


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9.3.6
Continuation Treatment Period
In Part B, if a subject continues receiving the study drug after 48 weeks, the following 
tests, observations, and assessments will be performed every 12, 24, or 48 weeks.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Bone mineral density
QOL assessments
9.3.7
At Study Withdrawal
If a subject withdraws from the study, the reason for withdrawal will be entered in the 
source documents and the eCRF, and the following tests, observations, and assessments 
will be performed within 8 days, including the day of withdrawal. In Part B, if a subject 
withdraws from the study (before Week 96), these same tests, observations, and 
assessments will be performed. The status of completion of the study will be entered in 
the eCRF for all subjects who received study drug in Part A, and for all subjects 
randomized in Part B. Furthermore, in Part B, if a subject completes 48 weeks of 
treatment, but does not subsequently continue receiving study drug, then the subject’s 
status of study completion (including the reason treatment was not continued) will be 
entered in the eCRF.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG


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Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Pharmacokinetic assessments (depending on the time of withdrawal)
The following tests will be performed only in Part B.
Ophthalmological examination (except for subjects who withdraw from the study 
after advancing to the continuation treatment period)
Bone mineral density
BMP concentrations (except for subjects who withdraw from the study after 
advancing to the treatment continuation period)
QOL assessments
9.3.8
Safety Follow-up
The following tests, observations, and assessments will be performed as safety follow-up 
30 to 40 days after the day of the last dose of study drug, and will be the final 
observations performed.
These same tests, observations, and assessments will be performed 30 to 40 days after the 
last dose of study drug for subjects who withdraw from the study as well.
The status of study completion will be entered into the eCRF for all subjects who receive 
study drug in Part A, and for all subjects who are randomized in Part B.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Concomitant medications
Concomitant therapies
AEs


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The following tests will be performed only in Part B.
QOL assessments
9.3.9
Handling After the End of the Study
Study drug will not be supplied to subjects who have completed the study treatment 
period and the continuation treatment period (Part B).
9.4
Biological Sample Storage and Disposal
The 5 mL samples of whole blood collected for PGx research will be stored frozen at the 
sample storage facility (Protocol Annex 1).
The storage period will be 20 years from the day the samples for PGx research were 
initially collected in this study.
During the sample storage period, if a subject wants his samples destroyed, the 
investigational site will ask, via the study sponsor, and in accordance with the specified 
procedures, the sample storage facility to destroy the subject’s samples. The sample 
storage facility will destroy the samples in questions in accordance with the procedures, 
and will inform the investigational site and the study sponsor that the samples have been 
destroyed. However, if the data that allow the subject to be identified (eg, medical 
records) have been destroyed once the study has been completed, and it is therefore no 
longer possible to link the subject to his samples, then the samples will not be destroyed.
Even if the samples can be tied to the subject, if the PGx investigation has already been 
performed, the remaining samples will be destroyed, but the anonymized results of the 
PGx investigation will be retained by the study sponsor.
The study sponsor will construct the administrative structure necessary to protect 
subjects’ personal information, and will stipulate in advance criteria for handling sample 
collection, storage, and disposal, as well as prepare the necessary written procedures.
9.5
Blood Sample Volumes and Numbers of Samples Collected
Table 9.b, Table 9.c, and Table 9.d present guidelines for the volumes of blood samples 
to be collected for each subject.


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Table 9.b
Blood Sample Volumes and Numbers of Samples Collected (Part A)
Type of Sample
Volume of Blood 
Collected Per Sample 
(mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
7
84
Chemistry tests
9.2
7
64.4
Metabolic panel tests
5.6
4
22.4
Cardiac tests
4.4
1
4.4
Tumor marker
2.0
2
4
HIV, etc. tests*1
5.6
1
5.6
Pharmacodynamic assessments
7.0
9
63
PGx sample collection
5
1
5
PK assessments
3
37
111
Total Volume of Blood Collected
363.8
*1: Will be performed only when judged necessary
Table 9.c
Blood Sample Volumes and Numbers of Samples Collected 
(Part B – Screening Through Week 48, Safety Follow-up)
Type of Sample
Volume of Blood 
Collected Per 
Sample (mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
9
108
Chemistry tests
9.2
15
138
Metabolic panel tests
5.6
8
44.8
Cardiac tests
4.4
1
4.4
Tumor marker
2.0
9
18
BMP concentrations
2
5
10
HIV, etc. tests*1
5.6
1
5.6
Pharmacodynamic assessments
7.0
13
91
Serum testosterone (high-sensitivity 
measurement)
5
11
55
PGx sample collection
5
1
5
PK assessments
3
15
45
Total Volume of Blood Collected
524.8
*1: Will be performed only when judged necessary


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Table 9.d
Blood Sample Volumes and Numbers of Samples Collected 
(Part B – Weeks 49 to 96)
Type of Sample
Volume of Blood 
Collected Per Sample 
(mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
4
48
Chemistry tests
9.2
4
36.8
Metabolic panel
5.6
4
22.4
Tumor marker
2.0
4
8
Pharmacodynamic assessments
7.0
4
28
Total Volume of Blood Collected
143.2


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definition
10.1.1
Pretreatment Events
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation.
10.1.2
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug (including study drug); it does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug whether or not it is considered related to the drug.
10.1.3
Additional Points to Consider for Pretreatment Events and Adverse Events
An untoward findings generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition.
(Intermittent events for pre-existing conditions underlying disease should not be 
considered PTEs or AEs.)

Require therapeutic intervention

Require an invasive diagnostic procedure

Require discontinuation or a change in dose of study drug or concomitant medication

Be considered unfavorable by the investigator for any reason.
Diagnosis vs signs and symptoms:
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) and/or symptom(s) should 
be recorded appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:
Change in laboratory value or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie., if some action or intervention is required, 
or if the investigators judges the change to be beyond the normal physiological 
fluctuation). A laboratory re-test and/or continued monitoring of an abnormal value are
not considered an intervention. In addition, repeated or additional noninvasive testing for 
verification, evaluation, or monitoring of an abnormality is not considered an 
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If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal impairment), the diagnosis 
only should be reported appropriately as a PTE or as an AE.
Pre-existing conditions (disease or symptoms existing before informed consent is 
obtained):
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Abnormalities found in initial tests and observations (eg, laboratory tests, ECG, and 
radiology) after informed consent should NOT be recorded as PTEs unless related to 
study procedures, except that abnormalities occurring as a result of initial test or 
observation procedures (such as internal bleeding during blood draw) will be recorded as 
PTEs in the eCRF. If the subject experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded appropriately as 
a PTE (worsening or complication occurs before start of study drug) or an AE (worsening 
or complication occurs after start of study drug). Investigators should ensure that the 
event term recorded captures the change in the condition (eg, "worsening of 
hypertension").
If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) that increase in 
frequency or become serious or severe should be recorded as PTEs/AEs. Symptoms that 
worsen more than expected in subjects with chronic disease (eg, cataracts, rheumatoid 
arthritis) should also be recorded as PTEs/AEs. Investigators should ensure that the AE 
term recorded captures the changes in the condition from Baseline (eg, "worsening of 
XX").
Worsening of PTEs or AEs:
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug or experiences signs/symptoms that occur secondarily to 
PTEs, the worsening or complication should be recorded appropriately as an AEs in the 
eCRF. Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, "worsening of XX").
If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE in the eCRF. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, "worsening of XX").
Underlying disease:
In this study, worsening of the underlying disease will not be handled as an AE. The 
onset or worsening of symptoms associated with progression of the underlying disease 
will be handled as an AE.
Planned surgeries or procedures:
Preplanned procedures (surgelies or therapies) that were scheduled prior to signing of 
informed consent were not considered PTEs or AEs, except that any conditions and 
events associated with the worsening of pre-existing conditions requiring those 
procedures to be undertaken on an emergency basis should be captured appropriately as a 


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PTE or an AE. Complications resulting from any planned surgery should be reported as 
AEs.
Elective surgeries or procedures:
Elective procedures performed where there is no change in the subject's medical 
condition should not be recorded as PTEs or AEs, but should be documented in the 
subject's source documents. Complications resulting from an elective surgery should be 
reported as AEs.
Insufficient clinical response (lack of efficacy):
Insufficient clinical response, efficacy, or pharmacological effect should NOT be 
recorded as an AE. Investigators must make a distinction between worsening of 
pre-existing symptoms and lack of efficacy.
Overdose:
Cases of overdose with any medication without manifested side effects are NOT 
considered PTEs or AEs, but overdoses will be recorded on an overdose page of the 
eCRF.  Any manifested side effects will be considered AEs and will be recorded on the 
AE page of the eCRF.
10.1.4
Serious Adverse Events
A serious AE is defined as any untoward medical occurrence that at any dose:
1.
Results in DEATH.
2.
Is LIFE-THREATENING*.
3.
Requires inpatient HOSPITALIZATION or prolongation of existing 
hospitalization.
4.
Results in persistent or significant DISABILITY/INCAPACITY.
5.
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6.
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in the Takeda Medically Significant 
AE List (Table 10.a).
* The term "life threatening" refers to an event in which the subject is at risk of death at the time of the 
event; it does not refer to an event that hypothetically might have caused death if it was more severe.


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Table 10.a
Takeda Medically Significant AE List
Acute respiratory failure/acute respiratory distress 
syndrome
Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia
Malignant hypertension
Convulsive seizures (such as convulsions and 
epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/oculomucocutaenous 
syndrome (Stevens-Johnson syndrome)
Hepatic necrosis
Acute hepatic failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (including interstitial lung 
disease)
Neuroleptic malignant syndrome/malignant 
hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious 
agent by drugs
Confirmed or suspected endotoxic shock
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported by the same procedures as for SAEs (see Sections 10.2.2 and 
10.3).
10.1.5
Special Interest Adverse Events
A special interest AE (whether serious or not) is one of specific and medical concern 
specific to the study drug or program. Investigators will monitor subjects on an ongoing 
basis for such events, and the sponsor will be notified immediately of any that occur. 
Further investigation may sometimes be necessary to establish assessment of these 
events. Refer to Section 10.2.1.3 for the methods and deadlines for reports to the sponsor 
by investigators.
10.1.5.1
Liver Function Test Abnormalities
LFT abnormalities were identified as specific AEs because nonclinical studies in 
monkeys revealed LFT abnormalities and because clinical studies on oral GnRH 
antagonists with the same backbone structure as TAK-385 have revealed elevated AST 
and ALT as common treatment-related AEs.
The management of LFT abnormality AEs is presented in Table 8.c of the protocol.
When ALT or AST levels are > 3 ULN, retesting will be performed within 48 to 72 
hours (within 7 days at the latest). As soon as they become aware that ALT or AST 
levels are > 3 ULN, investigators will discuss detailed information on affected subjects 
and other potential causes with the sponsor to review whether the administration of study 
drug should be discontinued immediately.
If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN or the PT-
INR is > 1.5, and investigators conclude that the levels cannot be explained by any factor 
other that study drug based on the results of retesting, then they will be handled as serious 
AEs.


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When LFT abnormalities correspond to the criteria in Section 7.5, investigators will 
immediately discontinue administration of study drug and will perform appropriate 
follow-up.
10.1.6
Severity of Pretreatment Events and Adverse Events
The severity of AEs, including laboratory abnormalities, will be determined according to 
the CTCAE. Events not covered in the CTCAE will be classified and defined as follows.
Grade 1
Mild;*1 asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*2
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limited self care ADL*3
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
*1: A semi-colon indicates 'or' within the description of the grade.
*2: Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
*3: Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
AEs that undergo a change in severity for the worse will be individually recorded in the 
eCRF as separate AEs.
Clarification should be made between a serious AE and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. 
The term "severe" is often used to describe the intensity (severity) of a specific event, but 
the event itself may be of relatively minor medical significance (such as a Grade 3 
headache). This is NOT the same as "serious." For example, a white blood cell count of 
1000 to 2000/mm3 is considered Grade 3 (severe) but may not necessarily be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations.
10.1.7
Causality of Adverse Events
The relationships of each AEs to study drug will be assessed using the following 
categories:
Related
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug can 
be argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concomitant therapies, may also be responsible.
Not related
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concomitant therapies.


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10.1.8
Relationship to Study Procedures
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the 
relationship should be assessed as Not Related.
10.1.9
Date of Onset
The date of AE onset (the start date of the AE/PTE) will be determined based on the 
following criteria.
AEs
Date of onset
Signs, symptoms, disease (diagnosis)
The date on which the subject or investigators first notice the signs 
or symptoms of an AE will be recorded.
Asymptomatic disease
The date on which a diagnostic test is conducted and the diagnosis 
is confirmed will be recorded.
The date on which diagnosis is confirmed will be recorded even 
when test findings belatedly reveal older findings or when the time 
of onset can be generally estimated.
Worsening of complications or PTEs
The date on which the subject or investigators first notice 
worsening of signs or symptoms will be recorded.
When initial test results after 
informed consent are normal but 
subsequent test results are abnormal 
(PTE)
When test results turn abnormal after 
start of study drug treatment (AEs)
The date on which laboratory abnormalities considered clinically 
significant are found will be recorded.
When test results after informed 
consent are initially normal but then 
worsen (PTE)
When test results at start of study 
drug treatment are abnormal and then 
worsen (AE)
The date of tests on which laboratory profiles reveal clear increases 
or decreases based on clinical judgment.
10.1.10 Date Resolved
The date resolved (the stop date of the AE/PTE) is the date on which AEs resolve 
(including resolved with sequelae). When AEs result in death, the date of death will be 
used. When an AE is recorded as a separate AE in the eCRF due to worsening of 
severity, the day before the date on which worsening was confirmed will be recorded as 
the date of resolution. Cases in which resolution cannot be confirmed at the end of the 
study will be assessed as ongoing.
10.1.11 Frequency
When an AE that apparently resolves and occurs repeatedly (such as constipation, 
diarrhea, and vomiting) is determined by investigators to be a series of occurrences 
constituting a single event over the period of time from initial onset to ultimate 
resolution, the incidence will be considered "intermittent." All other cases will be 
handled as "continuous."


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10.1.12 Action Taken for Study Drug
Actions taken for study drug will be classified and defined as follows.
Drug Withdrawn
A study drug is terminated due to the particular AE (including when subjects 
themselves decide to discontinue).
Dose not Changed
The particular AE did not require any dose change of study drug.
Discontinuation of study drug, dose reduction, or dose escalation due to AE other 
than the AE in question will be handled as "dose not changed."
Discontinuation of study drug or dose reduction for reasons other than action taken 
for the AE, such as subject carelessness, will be handled as "dose not changed."
Unknown
When subjects cannot be contacted and the course after the date of onset cannot be 
ascertained, etc.
Not Applicable
When study drug treatment has already been completed or discontinued at the time 
that the AE occurs
Dose Reduced
A reduction in study drug dose as action taken for the AE will be handled as "dose 
reduced"(the dose cannot be reduced at the subject's discretion)
Dose Increased
An escalation in study drug dose as action taken for the AE will be handled as "dose 
increased"(the dose cannot be escalated at the subject's discretion)
Dose Interrupted
A temporary discontinuation (suspension) of study drug as action taken for the AE
followed by the resumption of dosing on a later date (including when subjects 
themselves decide to temporarily discontinue) will be handled as a "dose 
interrupted."
10.1.13 Outcome
The outcome of AEs will be classified as follows:
Classification
Criteria
Recovered/
Resolved
Symptoms or findings resolve or recover
Test results normalize or return to levels at baseline (AEs) or to levels at informed 
consent (PTEs)
When an event is recorded as a separate AE due to worsening severity in the eCRF
Recovering/
Resolving
Severity decreases at least 1 grade
Symptoms and findings are nearly resolved
Test results are improved, but have not normalized or returned to levels at baseline 
(AEs) or to levels at informed consent (PTEs)

The subject died from a cause other than the particular AE/PTE with the condition 
remaining “recovering/resolving”. (the date of death does not need to be recorded in 
such cases)
Not 
Recovered/
Not Resolved
No change in symptoms, findings, or test results
Symptoms, findings, or test results on last observable day are worse than at onset
Irreversible congenital anomaly/birth defect

The subject died from a cause other than the particular AE/PTE with the particular 
AE/PTE state remaining “Not recovered/not resolved”. (the date of death does not 
need to be recorded in such cases)
Resolved, with 
Sequelae
Occurrence of dysfunction interfering with ADL


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Classification
Criteria
Fatal
Death immediately related to AEs
"Immediately related" indicates that the AEs caused death or were clearly involved in 
the death.
Outcomes such as for AEs that are not determined (concluded, assumed) to have been 
the immediate cause of death in the same subject will not be handled as death.
The date of death will be recorded when the outcome is death.
Unknown
Follow-up of the event cannot be performed as specified in the protocol because of 
transfer to another hospital, change in residence, or the like
10.2
Procedures
10.2.1
Collection and Reporting of Adverse Events
10.2.1.1
Collection Period of Pretreatment Events and Adverse Events
Pretreatment events will be recorded continuously from when informed consent is 
obtained until the first dose of study drug (Day 1). If it is decided that a subject should be 
withdrawn before the first dose of study drug, PTEs will be recorded until that point in 
time.
AEs will be recorded continuously from the start of study drug administration to subjects 
(Day 1) until the safety follow-up.
10.2.1.2
Reporting of Adverse Events
Investigators will check for subjective symptoms whenever subjects visit. Investigators 
will ask subjects about AEs that may have occurred since the last visit by asking 
questions such as "How have you been since the last visit?"
Any subjects who experience a PTE that meets the criteria for seriousness will be 
followed up by investigators until symptoms resolve or until medically significant 
laboratory abnormalities return to initial levels after informed consent, or else (in the case 
of a permanent or irreversible PTE) until the observed change can be satisfactorily 
explained. No protocol follow-up will be required for PTEs that do not meet the criteria 
for seriousness, regardless of the causal relationship to study procedure.
Any subjects who experience an AE will be followed up by investigators until symptoms 
resolve or until medically significant laboratory abnormalities return to initial levels after 
informed consent, or else (in the case of a permanent or irreversible AE) until the 
observed change can be satisfactorily explained, regardless of the causal relationship to 
study drug. All AEs will be recorded in the eCRF. The following information will be 
documented for each event: event term, start and stop dates, frequency, severity
(intensity), causal relationship to study drug (related, not related), action taken on study 
drug, outcome, causal relationship to study procedures (and procedure considered the 
cause if causally related), and seriousness.
AEs, and PTEs meeting the criteria for seriousness, will be followed up until the 
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10.2.1.3
Reporting of Special Interest Adverse Events
When an AE of special interest that occurs during the period for recording AEs is 
determined to be medically significant based on the following criteria, investigators will 
report the event to the sponsor (see attachment for contact information) within 24 hours 
of the onset of the AE of special interest or within 24 hours after learning of the event 
from the subject. The principal investigator will also prepare a report of LFT 
abnormalities (same report form as for SAEs) within 10 business days, and submit it with 
a signature or printed name and personal seal to the contact identified in the attachment. 
The "Liver Function Test Abnormality Reporting Checklist (Appendix I)" will be used as 
reference to assist in the preparation of the report.
The criteria for LFT abnormalities are given below:
• ALT or AST > 3 ULN
If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN or the PT-
INR is > 1.5, and investigators conclude that the levels cannot be explained by any factor 
other that study drug based on the results of retesting (for procedures, see Section 
10.1.5.1), then they will be handled as serious AEs, and information will be recorded and 
reported by the procedures noted in Section 10.2.2.
AEs of special interest will be recorded as AEs in the eCRF. Related information (such as 
photographs, results of additional diagnostic tests, and records of consultations with 
specialists) will also be submitted to the sponsor.
10.2.2
Collection and Reporting of Serious Adverse Events
SAEs that occur in the period for recording AEs will be reported by the following 
procedures. PTEs meeting the criteria for seriousness noted in Section 10.1.4 will be 
reported by the same procedure as SAEs.
All SAEs that occur from the start of study drug administration in subjects until the safety 
follow-up will be reported by the principal investigator to the sponsor within 24 hours of 
confirming or being notified of the event. The initial report of an SAE and all revised or 
additional information will be recorded in an "SAE Report" to be submitted to the 
sponsor. Copies of related source documentation on medical treatment of subjects will be 
submitted to the sponsor as soon as possible. In cases of death, a copy of the autopsy 
report will be submitted, if possible.
Even after the end of the study, treatment-related SAEs will be reported to the sponsor 
within 24 hours of confirming or being notified of the event.
SAEs leading to withdrawal from the study or discontinuation of study drug will be 
recorded in initial or subsequent "SAE Reports" and in the eCRF.
As a general rule, the initial report of an SAE will be faxed to the Safety Information 
Emergency Response Center using the prescribed "Report of an SAE [Initial Report]" 
form. After faxing the form, the principal investigator will submit the original to the 
monitors.


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After the initial report of the SAE, the principal investigator will report detailed 
information to the sponsor within 10 calendar days. As a general rule, the detailed 
information will be faxed to the Safety Information Emergency Response Center using 
the prescribed "Report of SAEs (Detailed Information)" form. After faxing the form, the 
principal investigator will submit the original to the monitors. Any modifications of the 
contents of the report will be similarly reported.
Safety Information Emergency Response Center (24 hours a day, 365 days a year)
FAX：
TEL：
When the Safety Information Emergency Response Center cannot be contacted, the 
information will, as a general rule, be reported to the monitors using the prescribed 
"Report of an SAE [Initial Report]" form or "Report of SAEs (Detailed Information)" 
form.
All SAEs occurring onsite will be reported by the principal investigator to the head of the 
investigational site by the established procedures in force at the investigational site and to 
the sponsor in accordance with this protocol.
The expectedness of SAEs will be determined on the basis of the Investigator's Brochure 
(including information on AEs reported to investigational site).
10.2.3
Reporting of Drug-Induced LFT Abnormalities Potentially Leading to 
Severe Liver Disorders
Investigators will report ALT or AST levels > 3 ULN to the sponsor and will promptly 
investigate detailed subject information and potential causes other than study drug 
(presence or absence of acute viral hepatitis type A or B, or other acute liver diseases, 
medical history, and complications). Retesting will also be performed (see Section 
10.1.5). If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN 
or the PT-INR is > 1.5, and investigators conclude that the levels cannot be explained by 
any factor other that study drug, the information will be reported by the same procedure 
for SAEs (see Section 10.2.1.3).
10.3
Follow-up of Serious Adverse Events
If information not reported in the detailed report becomes available at a later date, 
investigators will record the information on a copy of the SAE report or will prepare a 
separate document, and one or the other will be submitted to the contact identified in the 
attachment. Investigational site-related data (such as ECG findings, laboratory findings, 
summary of report of discharge from hospital, and results of autopsy) will be submitted 
upon request to the sponsor or the IRB.
Investigators will follow-up all SAEs until they resolve or until the final outcome is 
determined.


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10.3.1
Reporting of Serious Adverse Events to Principal Investigators, IRB, and 
Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and other SAEs subject to expedited reporting to the regulatory 
authorities, principal investigators, and the IRBs/head of the investigational site in 
accordance with the local regulations of the counties in which the study is being 
conducted. The sponsor or the sponsor's CRO will submit an expedited report of fatal or 
life-threatening SUSARs within 7 days, and of any other serious events within 15 days, 
of first learning of or obtaining additional information on the event to the regulatory 
authorities. The sponsor will also submit an expedited report of other safety issues
potentially having a significant effect on the benefit-risk assessment of study drug, 
continuation of study drug treatment, or continuation of the study. The investigational 
site also will forward a copy of all expedited reports to his or her IRB.


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11.0
STUDY SPECIFIC COMMITTEES
A SMC will be established in this study. The principal duties of the SMC will be to 
decide when cohorts can progress to the next Part or to make the necessary decisions 
when it is difficult to judge whether or not DLTs have occurred. This is described in 
detail in separately prepared procedures.


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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent medical conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will 
be coded using the World Health Organization (WHO) Drug Dictionary [generic term] 
and the Japanese Drug Dictionary.
12.1
Electronic Case Report Form
Completed eCRFs are required for each subject who signs informed consent.
The sponsor or its designee will supply the investigational site with access to the eCRF 
system. The sponsor will make arrangements to train the investigators and appropriate 
study support staff in use of the eCRF system. The eCRFs will be used to transmit the 
information collected during the study to the sponsor and regulatory authorities. The 
eCRF must be completed in English. Data will be directly recorded onto eCRF.
The following will be recorded as an audit trail when changes or revisions are made in 
the eCRF: the original and changed/revised information, person making the change or 
revision, and the date and reasons for the change or revision.
The principal investigator must review the eCRFs for completeness and accuracy, and 
must electronically sign the appropriate page of the eCRF. The principal investigator 
bears full responsibility for the accuracy and reliability of all data recorded in the eCRFs.
The following data will not be directly recorded in the eCRF.
1)
Tumor marker, BMP concentration, and pharmacodynamic parameters (except for 
SHBG) measured by an external measurement facilities.
2)
Plasma drug concentration results
Investigators will use the eCRF change and revision record (Data Clarification Form) 
provided by the sponsor when changing or revising recorded entries in the eCRF after the 
clinical trial database has been locked. The principal investigator must review the data 
change for accuracy and completeness, and must provide a signature or printed name and 
personal seal, and the date.
The sponsor or its designee will check the accuracy and completeness of the eCRF when 
visiting the investigational site. The sponsor or its designee will be permitted to review 
subject's medical and hospital records related to the study to ensure the accuracy of the 
eCRFs. Completed eCRFs are the property of the sponsor, and should not be made 
available in any form to third parties other than regulatory authorities without the written 
permission of the sponsor.
12.2
Record Retention
The principal investigator or head of the investigational site will keep the following 
records, including the records and study-specific documents specified in Section 12.1.  
These materials will include the identification log of all participating subjects, medical 
records, source worksheets, all original signed and dated informed consent forms, 


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electronic copies of the eCRFs including audit trail, and drug accountability log. The 
essential relevant documents that are to be archived must also be kept by the principal 
investigator and head of the investigational site until the day specified as 1) or 2) below, 
whichever comes later, unless the sponsor requires records to be kept for longer periods 
of time than this, in which case the head of the investigational site will reach agreement 
on the retention period and record keeping methods with the sponsor.
1)
The day on which marketing approval of the investigational drug is obtained (or the 
day 3 years after the date of notification in the case that the investigation is 
discontinued.)
2)
The day 3 years after the date of early termination or completion of the clinical 
study.
The principal investigator and head of the investigational site will also keep the essential 
relevant documents that are to be archived until notified by the sponsor that the records 
no longer need to be kept.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
Analysts will prepare and finalize the Statistical Analysis Plan before database lock. The 
Statistical Analysis Plan will describe in detail the definitions of the endpoints and 
analytical methods in order to meet all study objectives.
Data review will take place before database lock. The accuracy and completeness of the 
study data, the evaluability of subjects, and the appropriateness of the planned analysis 
will be assessed during data review.
13.1.1
Analysis Sets
Four populations for analysis will be established in this study: the full analysis set, the 
safety analysis set, the DLT analysis set, and the pharmacokinetic analysis set. The 
safety analysis set will be defined as all subjects who receive at least 1 dose of any study 
drug. The DLT analysis set will be defined as all subjects who can be evaluated for 
DLTs (see Section 6.1.2.3). The analysis sets will be defined in detail in the separately 
prepared "Rules for Handling Analytical Data."
Before database lock, the sponsor will consult the medical expert as needed to check on 
the appropriateness of the analysis set definitions and rules for handling the analysis of 
the case data in the sets, and will finalize the "The Rules for Handling Analytical Data" 
after deciding how to handle problematic issues not specified at the planning stage.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
The primary subject characteristics in the safety analysis set will be tabulated. 
Descriptive statistics (number of subjects, mean, median, standard deviation, maximum, 
minimum, and quartiles [same below]) will be calculated for continuous data, and 
frequency tabulations of discrete data will be prepared.
13.1.3
Efficacy Analysis
[Secondary endpoint]
PSA (Part B)
[Analytical method]
The full analysis set will be analyzed as follows.
1)
PSA
Descriptive statistics and the two-sided 95% confidence interval of the mean for PSA in 
Part B will be calculated at each assessment time point specified in the protocol, and the 
changes over time (individual and mean/SD) will be graphed by dose. The changes from 
baseline will also be similarly analyzed. Waterfall plots of the change from baseline at 
Week 13 Day 1 (LOCF) and the change from baseline for the minimum value after the 
start of study drug treatment will be prepared by dose.


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2)
Data conversion and handling of missing data
PSA levels below the lower limit of quantification will be handled as the LLOQ. Test 
data that is not assessed or that is missing, or that is not used per the "Rules for Handling 
Analytical Data," will be excluded from the analysis of assessment.
[Other endpoints]

PSA (Part A)

Disease progression as assessed on the basis of PSA, disease progression as assessed 
on the basis of image assessment (Part B)
13.1.4
Pharmacokinetic Analysis
[Secondary endpoint]
Plasma concentration of unchanged TAK-385
[Analytical method]
The pharmacokinetic profile (such as Cmax and AUC) will be calculated by model-free 
analysis of the plasma concentration profiles of unchanged TAK-385 in the 
pharmacokinetic analysis set. Descriptive statistics of each parameter will be calculated 
by Part and by dose. Descriptive statistics for the plasma concentration of TAK-385 at 
each blood sampling time point specified in the protocol will also be calculated by dose, 
and the changes over time (individual and mean) will be graphed by dose. The plasma 
concentration profiles of TAK-385 will also be analyzed using a compartment model as 
needed.
13.1.5
Pharmacodynamic Analysis
[Secondary endpoint]
Serum testosterone concentration
[Analytical method]
The full analysis set will be analyzed as follows.
1)
Serum testosterone concentration
Descriptive statistics and the two-sided 95% confidence interval of the mean for serum 
testosterone concentration will be calculated by Part and by dose at each assessment time 
point specified in the protocol, and the changes over time (individual and mean/SD) will 
be graphed by Part and by dose.
2)
Data conversion and handling of missing data
Test parameters below the lower limit of quantification will be handled as the LLOQ. 
Test data that is not assessed or that is missing, or that is not used per the "Rules for 
Handling Analytical Data," will be excluded from the analysis of assessment.
[Other endpoints]
Serum concentrations of LH, FSH, DHT, and SHBG


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13.1.6
Other Analysis
[Other endpoints]
QOL assessment based on AMS, EORTC-QLQ-C30, and EPIC (Part B)
13.1.7
Safety Analysis
[Primary endpoints]
DLTs, AEs, clinical laboratory tests, vital signs, and 12-lead ECG
[Analytical methods]
1)
Adverse events
The following analysis will be performed for the safety analysis set.
A treatment-emergent adverse event (TEAE) refers to an event that occurs after the start 
of study drug administration.
The following TEAE will be tabulated by Part and by dose. TEAEs will be coded
according to MedDRA and summarized by System Organ Class (SOC) and Preferred 
Term (PT).

Frequency tabulations of all TEAEs

Frequency tabulations of treatment-related TEAEs

Frequency tabulations of all TEAEs by severity

Frequency tabulations of treatment-related TEAEs by severity

Frequency tabulations of TEAEs for which the study drug action taken was 
"treatment discontinuation"

Frequency tabulations of serious TEAEs

Frequency tabulations of all TEAEs by time of onset
2)
DLT
The following analysis will be performed for the DLT analysis set.
Frequency tabulations of TEAEs determined to be DLTs in Part A will be tabulated by 
PT and by dose.
3)
Clinical laboratory tests, vital signs, and 12-lead ECG
The following analysis will be performed for the safety analysis set.
For continuous data, descriptive statistics for observed values at baseline and at each 
assessment time point as well as for the change from baseline will be calculated by part 
and by dose.
Cross tables for the results of the assessment of each test parameter based on discrete data 
and reference values before and after study drug treatment (such as the determination of 


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whether results are normal or abnormal, or qualitative laboratory values) will be prepared 
by part and by dose.
[Other endpoints]

Bone mineral density
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Planned Sample Size
[Part A]
Each cohort will have 3 or 6 subjects, based on the guidelines on the clinical evaluation 
of antineoplastics.
[Part B]
In order to detect less frequent AEs, 15 subjects per group (total of 30 subjects) were 
established as the number of cases enabling an approximately 80% chance of detecting 
AEs characterized by a true incidence of 10%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Monitoring of Investigational Site
Monitoring visits to the investigational site will be made periodically during the study to 
ensure that all aspects of the protocol are followed. Source documents will be reviewed 
for verification of data recorded on the eCRFs. Source documents are defined as original 
documents, data, and records. The investigator and institution guarantee access to source 
documents by the sponsor or its designee and by the IRB.
The sponsor or its designee will access the principal investigator's files, medication, 
medical records of subjects, and records such as the informed consent form to ensure that 
the study is being properly conducted in compliance with the protocol. They will also 
confirm the consistency of the eCRFs with related source documents. Investigators and 
other study support staff members will take the time to accommodate monitors when they 
visit the investigational site for monitoring purposes.
14.2
Protocol Deviations
Investigators may deviate from or modify the protocol without the prior written 
agreement of the sponsor or prior approval of the IRB for medically unavoidable 
circumstances, such as to avoid immediate hazards to subjects. On such occasions, the 
principal investigator will inform the sponsor and head of the investigational site in 
writing of the details of and reasons for the deviation or change, will keep copies of the 
notification, and will reach agreement with the sponsor on protocol revisions as needed.  
If the protocol is to be revised, a draft will be submitted as soon as possible to the head of 
the investigational site, and the approval of the IRB will be required.
Investigators should document all deviations from the protocol.
14.3
Quality Assurance Audits and Regulatory Authority Inspections
The sponsor or designee will audit the investigational site as needed. On such occasions, 
an auditor designated by the sponsor will contact the investigational site beforehand to 
schedule the auditing visit. The auditor may ask to visit the facilities where laboratory 
test samples are kept, the facilities where medication is stored and prepared, and other 
facilities used during the study. During this study, inspections may also be carried out by 
regulatory authorities, including overseas agencies (such as the US Food and Drug 
Administration [FDA] and the UK Medicines and Healthcare Products Regulatory 
Agency [MHRA]).  The sponsor will be notified immediately whenever the 
investigational site receives a request for an inspection by the regulatory authorities.  The 
principal investigator and head of the investigational site will ensure that the auditor has 
access to all study-related documentation set forth in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This trial will be conducted with the highest respect for the individual participants (ie, 
subjects) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and International Conference on Harmonisation (ICH) 
Guidelines for GCP. Investigators will conduct the study in accordance with regional 
regulatory requirements and the "Responsibilities of the Principal Investigator" in
Appendix F.
15.1
IRB Approval
The IRB must be will be constituted according to the applicable local regulations in 
regions participating in the study. The sponsor or designee will obtain documentation of 
the names and affiliations of the IRB members. When IRB members directly participate 
in the study, documentation that they are not involved in the review and decision-making 
process must be obtained.
The sponsor or designee will submit related documents to the IRB for review and 
approval of the protocol. In addition to the study protocol, Investigator's Brochure and 
copies of the informed consent as well as materials and advertising related to the 
recruitment of subjects, if needed, and other documents required by local regulations 
must also be submitted to central or local IRBs for approval. The sponsor or designee 
will obtain documented approval of the protocol and informed consent form by the IRB 
before the start of the study (ie., before shipment of the sponsor-supplied drug or study 
specific screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (eg, 
informed consent form) reviewed; and state the approval date. The sponsor will ship drug
after confirming the appropriateness of the documented regulations of the investigational 
site. Until the site receives drug, no protocol activities, including screening may occur.
The investigational site will follow all requirements specified by the IRB. This includes 
notifications to the IRB regarding protocol amendments, updates to the informed consent 
form, revisions of materials related to subject recruitment, reports on safety required by 
local regulatory requirements, periodic reports on the conduct of the study as stipulated 
by the IRB, and the study completion report. The sponsor or designee will obtain all 
documented IRB approval of the above and related materials.
Financial compensation paid to subjects should be kept to a level that will not provide 
undue incentive to participate in the study. Financial relief must be approved by the IRB 
and sponsor.
PGx analysis of collected and stored samples will perform at the time when the details 
have been decided. At that time, the sponsor will prepare a PGx protocol, and the
protocol will require prior approval of the sponsor.
15.2
Patient Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form will describe the 


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planned and permitted use (either in Japan or abroad: submission to third parties) and 
disclosure of the personal information and personal medical information of subjects in 
this study. The informed consent form will further explain the nature of the study, 
objectives, and of the potential risks and benefits. The informed consent form will also 
detail the requirements of the participant and the fact that he or she is free to withdraw at 
any time without giving a reason and without prejudice to his or her further medical care.
The principal investigator is responsible for the preparation and contents of the informed 
consent form, and for obtaining the approval of the IRB. The informed consent form 
must be approved by the IRB before being used.
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. Investigators will be responsible for providing subjects with a 
detailed explanation of the contents of the informed consent form. Information should be 
provided verbally and in writing by a method deemed suitable by the IRB whenever 
possible.
Investigators will give subjects (1) a chance to ask questions about the study and 
(2) enough time to decide whether to participate in the study. Subjects who decide to 
participate in the study will personally sign and date the informed consent form before 
participating in the study. Investigators will ask subjects to use a black or blue ball point 
pen to sign the form using their full legal names. Investigators will also sign and date the 
informed consent form before the subject can participate in the study.
Investigators will keep the signed original informed consent form. The date on which 
subjects sign the informed consent form will be recorded by investigators in the medical 
records of the subjects. Subjects will be given a copy of the signed informed consent 
form.
If the informed consent form is revised, investigators will again obtain the informed 
consent of the subjects using the same procedures that were used to obtain initial consent. 
The date on which informed consent is again obtained will be recorded in the medical 
records of the subjects, and subjects will be given a copy of the revised informed consent 
form.
Subjects who have received an explanation of the study based on the informed consent 
form will be given an explanation of PGx analysis based on the "Informed Consent Form 
for PGx Analysis in the TAK-385 Study." Specimens for PGx analysis will be obtained 
from subjects who sign both the informed consent for the study and the informed consent 
for PGx analysis.
The procedure in Section 9.4 will be followed whenever subjects would prefer their 
stored samples to be disposed of.
15.3
Subject Confidentiality
The sponsor or designee affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data 
will only be linked to the sponsor’s clinical study database or documentation via a unique 
subject identification number. As permitted by all applicable laws and regulations, 


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limited subject attributes, such as sex, age, or date of birth, and subject initials may be 
used to verify the subject and accuracy of the subject identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (such as the FDA, MHRA, and PMDA), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the subject’s 
original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a subject’s study participation, and autopsy reports. 
Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (ie., the subject's name, address, and 
other identifier fields not collected on the subject's eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The principal investigator is obliged to provide the sponsor with complete test results and 
all data derived by the investigator from the study. During the study, except when 
required by laws or regulations, only the sponsor may disclose study information to other 
investigators or regulatory authorities. Except where otherwise permitted by the Clinical 
Study Agreement, any public disclosure of the protocol and study results (including 
public websites) is the responsibility of the sponsor.
The sponsor may publish any data or information obtained from the study (including data 
and information provided by the principal investigator) without the consent of the 
principal investigator.
Investigators need to obtain the prior written permission of the sponsor to publish any 
information obtained from the study, such as to a professional associations.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner 
and to comply with applicable laws, regulations and guidance, Takeda will, at a minimum 
register interventional clinical trials it sponsors anywhere in the world on a public 
website (JAPIC-CTI) before the start of the clinical trial. The sponsor's contact 
information will be registered for general access along with the city, state (in the USA), 
and country where the trial is being conducted as well as subject recruitment status.
For some registries, Takeda will assist callers in locating trial sites closest to their homes 
by providing the investigator name, address, and phone number to the callers requesting 
trial information. Once subjects receive investigator contact information, they may call 
the site requesting enrollment into the trial. The investigative sites are encouraged to 
handle the trial inquiries according to their established subject screening process. If the 


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caller asks additional questions beyond the topic of trial enrollment, they should be 
referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must 
provide Takeda with a written notice requesting that their information not be listed on the 
registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on a public website (JAPIC-CTI), as required 
by applicable laws and/or regulations, regardless of the results.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to 
the site where the subject is participating. If a local underwriter is required, then the 
sponsor or its designee will obtain clinical study insurance against the risk of injury to 
clinical study subjects.
Refer to the Clinical Study Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or its designee.


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16.0
REFERENCES
1. Jemal A, Bray F, Melissa M, et al. Global Cancer Statistics. CA Cancer J Clin. 2011; 
61(2): 69-90.
2. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health 
Syst Pharm 1996;53(4):381-96; quiz 446-8.
3. Cancer Statistics in Japan-2013. Foundation for Promotion of Cancer Research. 
November 2013.
4. Prostate Cancer Treatment Guidelines (2012 Edition). Japanese Urological 
Association.
5. Most recent version of the TAK-385 Investigator’s Brochure.
6. Nagata S. Showa Ikaishi Vol. 48, No. 2. 2007. 134-140.
7. Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM. The Aging 
Males' Symptoms scale (AMS) as outcome measure for treatment of androgen 
deficiency. Eur Urol 2004;46(1):80-7.
8. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a qualityof 
life instrument for use in international clinical trials in oncology. Journal of the 
National Cancer Institute 1993;85(5):365-76
9. Fayers P, Bottomley A, EORTC Quality of Life Group, Quality of Life Unit. Quality 
of life research within the EORTC-the EORTC QLQ-C30. European Organisation for 
Research and Treatment of Cancer. European Journal of Cancer 2002;38 Suppl 
4:S125-33.
10. Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. 
EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: EORTC; 2001
11. Takegami M. Journal of the Japanese Urological Association. 2005; 96:657-69.
12. Kakehi Y, Takegami M, Suzukamo Y, Namiki S, Arai Y, Kamoto T, Ogawa O and 
Fukuhara S. Health related quality of life in Japanese men with localized prostate 
cancer treated with current multiple modalities assessed by a newly developed 
Japanese version of the Expanded Prostate Cancer Index Composite. The Journal of 
Urology, 2007; 177: 1856-61.
13. U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010
14. Tengstrand E, Miwa G, and Hsieh F. Bis(monoacylglycerol)phosphate as a non-
invasive biomarker to monitor the onset and time-course of phospholipidosis with 
drug-induced toxicities. Expert Opin. Drug Metab. Toxicol. 2010 6(5):555-570
15. Tengstrand-Baronas E, Lee JW, Alden C, Hsieh F. Biomarkers to monitor drug-
induced phospholipidosis. Toxicology and Applied Pharmacology 2007;218:72-78


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16. Prostate Cancer Handling Guidelines (December 2010, Fourth Edition). Edited by the 
Japanese Urological Association/Japanese Society of Pathology/Japan Radiological 
Society.
17. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982 (5) :649-655
18. Circulatory Disease Diagnosis and Treatment Guidelines (2010 Joint Research Team 
Report) – Acute Cardiac Failure Treatment Guidelines (2011 Revised Edition).


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Appendix A
Schedule of Study Procedures (Part A)
Procedurea
Subject consentb
Screening
Treatment Periodc
Post-treatment 
Observation Periodd
Withdrawale
SFU
Inpatientf
Outpatient
30 to 40 
days after 
the last dose
Before 
treatment 
initiation
D -28 to D -1g
D1h
D2
D3
D7
D12
D13
D14
D15
D21
D28
D29
D30
D31
D35i
Allowable visit window
0
± 1
0
0
+ 3
+ 3
0
+ 7
Confirmation of eligibility
X
Subject backgroundj
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
X
Weight/heightl
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
12-lead ECGm
X
Xo
X
X
X
X
Chest X-ray examination
X
Imaging assessmentn
X
Measure as appropriate
Hematology tests
X
Xo
X
X
X
X
X
X
Blood biochemistry tests
X
Xo
X
X
X
X
X
X
Blood lipid, sugar, etc. tests
X
Xo
X
X
X
Urinalysis
X
Xo
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
X
X
X
X
X
X
X
X
X
Tumor marker
X
X
X
Pharmacokinetic 
assessmentsp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xq
PGx sample collection
X (during the treatment period)
Concomitant medications/ 
therapies
Collected from the time of informed consent until 30 to 40 days after the last dose
Adverse events, etc.
PTEsr
Information collected from study treatment initiation until 30 to 40 days after the last dose
Study treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: D = Day; ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; SFU = safety follow-up


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a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Except for procedures that are normally part of a physical examination, subjects must sign the informed consent form before any study-related procedures are performed.
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
d Days 27 to 35 are performed either on an outpatient or an inpatient basis.
e Unnecessary if the subject withdraws between Day 29 and Day 35.
f Day 1: Day of treatment initiation. As a rule, subjects will not be allowed to leave the investigational site or return home during the inpatient period. However, the 
investigator or sub-investigator may allow the subject to return home temporarily.
g Day -1: Day before treatment initiation
h Day 1: Day of treatment initiation
i If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
j Including past and current medical history and previous therapeutic medications
k Measurements will be taken after the subject has been sitting down for 5 minutes.
l Height will be measured only at screening.
m 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
n Performed at screening only if imaging assessments were not performed within 28 days prior to treatment initiation, or if no usable images are available for the subject.
o Results of tests performed up to 3 days before treatment initiation may be used at the D1 test results.
p See Appendix D for detailed collection times.
q As a rule, blood samples will be collected at subject withdrawal as well, but the blood samples corresponding to the post-treatment observation period will not be necessary.
r Collected from consent acquisition until study treatment initiation.


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Appendix B
Schedule of Study Procedures (Part B – Screening to Week 48, SFU)
Procedurea
Informed consentb
Screening
Treatment Periodcd
Withdra
wal
SFU
Visit Day
Before 
treatment 
initiatione
D -28 to D -
1f
WK
1
WK
1
WK
1
WK
2
WK
3
WK
5
WK
9
WK
13
WK
17
WK
21
WK
25
WK
29
WK
33
WK
37
WK
41
WK
45
WK
49g
30 to 40 
days after 
the last dose
D1h
D2
D4
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Allowable visit 
window
0
0
0
±1
±1
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
+7
Confirmation of 
eligibility
X
Subject backgroundi
X
Physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
X
X
X
X
X
Weight/heightk
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
12-lead ECGl
X
Xn
X
X
X
X
X
X
Chest X-ray 
examination
X
Ophthalmology tests
X
X
X
X
Imaging assessmentm
X
X
X
Bone density (DXA 
method)
X
X
X
X
Hematology tests
X
Xn
X
X
X
X
X
X
X
X
Blood biochemistry 
tests
X
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood lipid, sugar, 
etc. tests
X
Xn
X
X
X
X
X
X
X
Urinalysis
X
Xn
X
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
Xo
X
X
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
X
Tumor marker
X
X
X
X
X
X
X
X
X
X
BMP concentrationp
X
X
X
X
X
X
Pharmacokinetic 
assessmentsq
X
X
X
X
X
X
X
X
X
X
X
X
X
Xr


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PGx sample 
collection
X (randomization through the treatment period)
QOL assessments
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/ 
therapies
Collected from the time of informed consent until 30 to 40 days after the last dose
Adverse events, etc.
PTEss
Information collected from study treatment initiation until 30 to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: WK = Week; D = Day;  ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; QOL = quality of life; SFU = safety follow-up
                                               
a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Except for procedures that are normally part of a physical examination, subjects must sign the informed consent form before any study-related procedures are performed.
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
d Except for pharmacokinetic assessments, if the assessment and test results can be obtained, then the assessments will be performed before study treatment initiation.
e Randomization will be performed by Day -1 (1 day before treatment initiation)
f Day -1: Day before treatment initiation
g If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
h Day 1: Day of treatment initiation
i Including past and current medical history and previous therapeutic medications
j Measurements will be taken after the subject has been sitting down for 5 minutes.
k Height will be measured only at screening.
l 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
m Performed at screening only if imaging assessments were not performed within 28 days prior to treatment initiation, or if no usable images are available for the subject.
n Results of tests performed up to 3 days before treatment initiaion may be used as the D1 test results.
o Blood samples will also be collected for the serum testosterone high sensitivity measurements.  However, at WK1D1, only the high-sensitivity measurements will be 
performed.
p Blood and urine sample collection
q See Appendix E for detailed sample collection times
r As a rule, blood samples will also be collected at withdrawal from the study.
s Information will be collected from consent acquisition until treatment initiation.


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Appendix C
Schedule of Study Procedures (Part B – Weeks 49 to 96)
Procedurea
Continuation Treatment Periodb
Withdrawal
SFU
Scheduled Day
WK49 (WK48)
D1 (D8)
WK61
D1
WK73
D1
WK85
D1
WK97c
D1
30 to 40 days 
after the last dose
Visit Day Allowable Window
±7
±7
±7
±7
±7
+7
Physical examination
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
X
Imaging assessment
X
X
X
Bone density (DXA method)
X
X
X
X
Hematology tests
X
X
X
X
X
X
X
Blood biochemistry tests
X
X
X
X
X
X
X
Blood lipid, sugar, etc. tests
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Pharmacodynamic assessments
X
X
X
X
X
X
Tumor marker
X
X
X
X
X
X
QOL assessments
X
X
X
X
X
X
X
Concomitant medications/ 
therapies
Information collected until 30 to 40 days after the last dose
Adverse events, etc.
Information collected until 30 to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfastf
Abbreviations: WK = Week; D = Day; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; SFU = safety follow-up
                                               
a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
c If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
d Measurements will be taken after the subject has been sitting down for 5 minutes.
e Measurements will be taken after the subject has been lying down for 5 minutes.
f Study drug will not be taken at WK97D1.


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Appendix D
Schedule of Blood Samples Collection for Pharmacokinetic Analysis (Part A)
Time Pointa
Dosing Time Pointb
D1
D2
D3
D7
D12
D13
D14
D15
D21
D28
D29
D30
D31
D35
Before dosingc
X
X
X
X
X
X
X
X
X
X
Xd
Xe
Xf
Xg
0.5 hour (± 10 min) postdose
X
X
1 hour (± 15 min) postdose
X
X
X
1.5 hours (± 15 min) postdose
X
X
2 hours (± 20 min) postdose
X
X
X
X
X
4 hours (± 20 min) postdose
X
X
X
6 hours (± 30 min) postdose
X
X
8 hours (± 30 min) postdose
X
X
X
12 hours (± 1 hour) postdose
X
X
X
Abbreviations: D = day
                                               
a If a blood sample is going to be collected on an outpatient basis, then the subject will come in for the visit without taking the study drug.
b As a rule, a blood sample will be collected at discontinuation as well, but the blood sample for the post-treatment observation period will not have to be collected.
c Blood samples for PK analysis will be collected within 1 hour before dosing.
d 24 hours (± 1 hour) after dosing on D28
e 48 hours (± 4 hours) after dosing on D28
f 72 hours (± 4 hours) after dosing on D28
g Collected before starting the next treatment


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Appendix E
Schedule of Blood Samples Collection for Pharmacokinetic Analysis (Part B)
Time Pointa
Dosing Time Pointb
WK1
WK2
WK3
WK5
WK9
WK13
WK17
WK21
WK25
WK37
WK49
D1c
D2
D4
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Before dosingd
X
X
X
X
X
X
X
X
X
X
X
X
X
2 hours postdose
(± 20 min)
X
X
Abbreviations: WK = week; D = day
                                               
a If a blood sample is going to be collected on an outpatient basis, then the subject will come in for the visit without taking the study drug.
b As a rule, blood samples will be collected at discontinuation as well.
c Blood samples will be collected after the subjects have taken the first dose of study drug at the hospital, and then eaten after an interval of at least 30 minutes, and then after 
another 2 hours have passed.
d Blood samples for PK analysis will be collected within 1 hour before dosing.


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Appendix F
Responsibilities of Principal Investigator
1.
Conduct the appropriate study in accordance with the protocol and GCP considering 
the rights, safety and wellbeing of human subjects.
2.
When a part of the important activities related to the study are delegated to the sub-
investigator or the study support staff, prepare the lists of activities to be delegated 
and responsible personnel, submit the lists to the head of the site in advance to get 
them accepted.
3.
Prepare a written informed consent form and other written information, and update as 
appropriate.
4.
Confirm the contents of the Clinical Study Agreement.
5.
Provide necessary information on the protocol, drugs and responsibilities of 
individual personnel to the sub-investigator and study support staff, and provide 
guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide the explanation 
of the study in writing and obtain the written consent.
7.
Assume responsibility for all the medical judgement related to the study.
8.
Ensure in collaboration with the head of the site that sufficient information on all 
clinicaly significant advesrse events related to the study are provided to subjects 
throughout and beyond the period when subjects participate in the study.
9.
If a subject consult other medical institution or other department, notify the physician 
of the medical institution or department of the subject's participation in the study, as 
well as the end and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the head of the site and the 
sponsor in writing.
11. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic 
signature.
12. Check and confirm the contents of eCRFs prepared by the sub-investigator or 
transcribed from the souce data by the study support staff, and submit them to the 
sponsor with electronic signature.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the head of the site of the end of the study in writing.


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Appendix G
ECOG Performance Status
Score
Activity Level
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Dead.


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Appendix H
New York Heart Association (NYHA) Functional Classification
Class
Patient Symptoms
I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased.


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Appendix I
Liver Function Test Abnormality Reporting Checklist
AS MUCH INFORMATION AS POSSIBLE WILL BE OBTAINED ABOUT THE 
FOLLOWING PARAMETERS
RELATED MEDICAL HISTORY/SYMPTOMS
Viral hepatitis
Auto-immune disorders
Alcohol use
Biliary disorders
Heart disorders, particularly right heart failure or hypotension
Recent viral diseases
Recent travel
Blood transfusions
Allergies
Recent anesthesia/surgical procedures
Drug abuse
Exposure to toxins
Recent tattoos
Family history of liver disease
EVENT INFORMATION
Signs and symptoms
NOTEWORTHY CLINICAL TEST DATA AND TEST RESULTS
Hepatic enzymes (ALT, AST, total bilirubin, ALP, GGT)
Coagulation system parameters
Albumin
Virus serum tests
Auto-immune markers
Liver imaging tests (ultrasound, CT, MRI)
Endoscopic retrograde cholangiopancreatography (ERCP)
Liver biopsy
Eosinophil count


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Appendix J
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment 
No.2.
Page 8, Section 2.0 STUDY SUMMARY
Existing Text
Study Design:
•••
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, and Cohort 3 
will receive a loading dose of 320 mg and a maintenance dose of 160 mg.
•••
Revised Text
Study Design:
•••
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, Cohort 3 will 
receive a loading dose of 320 mg and a maintenance dose of 160 mg, and Cohort 4 will 
receive a loading dose of 360 mg and a maintenance dose of 120 mg.
•••
Rationale for Amendment
Addition of Cohort 4 (loading dose of 360 mg and maintenance dose of 120 mg) to Part 
A for the purpose of evaluating the tolerability of 360 mg as loading dose in Japanese.
Page 9, Section 2.0 STUDY SUMMARY
Existing Text
Numbers of Subjects:
Part A: 3 to 6 subjects in each cohort (3 to 18 subjects in total)
Part B: 15 subjects in each group (30 subjects in total)
Revised Text
Numbers of Subjects:
Part A: 3 to 6 subjects in each cohort (3 to 24 subjects in total)
Part B: 15 subjects in each group (30 subjects in total)


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Rationale for Amendment
Change based on the addition of Part A, Cohort 4.
Page 9, Section 2.0 STUDY SUMMARY
Existing Text
Dosage:
Part A
Cohort 1: Loading dose of 320 mg and maintenance dose of 80 mg
Cohort 2: Loading dose of 320 mg and maintenance dose of 120 mg
Cohort 3: Loading dose of 320 mg and maintenance dose of 160 mg
(Additional cohort: Loading dose of 320 mg and maintenance dose of 40 mg)
Revised Text
Dosage:
Part A
Cohort 1: Loading dose of 320 mg and maintenance dose of 80 mg
Cohort 2: Loading dose of 320 mg and maintenance dose of 120 mg
Cohort 3: Loading dose of 320 mg and maintenance dose of 160 mg
Cohort 4: Loading dose of 360 mg and maintenance dose of 120 mg
(Additional cohort: Loading dose of 320 mg and maintenance dose of 40 mg)
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.
Page 25, Section 4.1.2 Clinical Studies
Existing Text
Not applicable
Revised Text
4.1.2.6 Overseas Thorough QTc Study in Healthy Adults (
)
 is a double-blind (open-label moxifloxacin), randomized study 
that evaluated the effect of single doses of TAK-385 on QT/QTc intervals in healthy 
adults.
 
 


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[5].
Rationale for Amendment
Insertion of results from a completed clinical study.
Page 28, Section 6.1 Study Design
Existing Text
•••
TAK-385 will be taken once a day for 28 days at the doses assigned to each cohort.  
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, and Cohort 3 
will receive a loading dose of 320 mg and a maintenance dose of 160 mg. The doses will 
be taken orally at least 30 minutes before breakfast.
•••
However, if tolerability is not confirmed in Cohort 2, then a cohort will be added that will 
receive a loading dose of TAK-385 320 mg and a maintenance dose of 40 mg.
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 
320 mg and maintenance dose of either 80 mg or 120 mg – equal numbers of subjects 
will be randomized to 80 mg and 120 mg) once a day orally to evaluate safety.
•••
Revised Text
•••
TAK-385 will be taken once a day for 28 days at the doses assigned to each cohort.  
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, Cohort 3 will 
receive a loading dose of 320 mg and a maintenance dose of 160 mg, and Cohort 4 will 
receive a loading dose of 360 mg and a maintenance dose of 120 mg.  The doses will 
be taken orally at least 30 minutes before breakfast.
•••
However, if tolerability is not confirmed in Cohort 2, then a cohort will be added that will 
receive a loading dose of TAK-385 320 mg and a maintenance dose of 40 mg.
Cohort 4 will be conducted after tolerability is confirmed in Cohort 2. Cohort 4 will 
be conducted for the purpose of evaluating the tolerability of 360 mg as loading dose 


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CONFIDENTIAL
in Japanese. 360 mg has been found tolerable in single dosing in the overseas phase 
1 single-/multiple-dose study (TAK-385_C27001)
 
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 
320 mg and maintenance dose of either 80 mg or 120 mg – equal numbers of subjects 
will be randomized to 80 mg and 120 mg) once a day orally to evaluate safety.
•••
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.
Page 29, Section 6.1 Study Design
Existing Text
Figure 6.a.
Study Design and Treatment Schema (Part A)
Evaluation of Transition
Cohort 2 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)
Evaluation of Transition
*1
Cohort 3 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 160 mg (Days 2-28)
Evaluation of Transition
*2
Part B (Expansion phase)
Part A (Dose-rising phase)
Cohort 1 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Days 2-28)


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Revised Text
Figure 6.a.
Study Design and Treatment Schema (Part A)
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.
Page 30, Section 6.1 Study Design
Existing Text
Figure 6.a and Figure 6.b show an overview of the study schedule.  See Appendix A 
through Appendix D for a more detailed schedule of the study tests, observations, and 
assessments.
Revised Text
Figure 6.a and Figure 6.b show an overview of the study schedule.  See Appendix A 
through Appendix E for a more detailed schedule of the study tests, observations, and 
assessments.
Rationale for Amendment
Correction of typographical error.
Evaluation of Transition
Evaluation of Transition
Cohort 2 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)
Evaluation of Transition*1
Cohort 3 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 160 mg (Days 2-28)
Evaluation of Transition*2
Part B (Expansion phase)
Part A (Dose-rising phase)
Cohort 1 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Days 2-28)
Cohort 4 (n = 3-6)
TAK-385
Loading dose 360 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)


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Page 31 to 32, Section 6.1.1 Cohort/Part Advancement Criteria
Existing Text
•••
Whether or not the study will proceed to Cohort 3 and Part B will be determined by the 
study sponsor after consulting the SMC based on a comprehensive evaluation of the 
tolerability and safety data from Cohort 2 of Part A.
•••
Because assessment of the MTD is not the objective of this study, additional subjects will 
not be enrolled if TAK-385 is found to be tolerable in an evaluation of the 3 subjects in 
Cohort 3, nor will additional subjects be enrolled at lower dose levels if TAK-385 is not 
found to be tolerable at the dose level initially investigated.
Revised Text
•••
Cohort 3, Cohort 4 and Part B will be conducted after tolerability is confirmed in 
Cohort 2. Whether or not the study will proceed to Part B will be determined by the 
study sponsor after consulting the SMC based on a comprehensive evaluation of the 
tolerability and safety data from Cohort 2 of Part A.
•••
Because assessment of the MTD is not the objective of this study, additional subjects will 
not be enrolled if TAK-385 is found to be tolerable in an evaluation of the 3 subjects in 
Cohort 3 or Cohort 4, nor will additional subjects be enrolled at lower dose levels if 
TAK-385 is not found to be tolerable at the dose level initially investigated.
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.


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Page 32, Section 6.1.1 Cohort/Part Advancement Criteria
Existing Text
Table 6.c
Cohort/Part Advancement Criteria
Number of Subjects With 
DLT
(DLT evaluable subjects)
Cohort
Procedure
0/3
1
Proceed to Cohort 2
2
Proceed to Cohort 3 and Part B
3
Stop
1/3
1 to 3
Add 3 subjects in the same cohort
2/3 or 3/3
1
Stop
2
Add a cohort*1
3
Stop
1/6
1
Proceed to Cohort 2
2
Proceed to Cohort 3 and Part B
3
Stop
≥ 2/6
1
Stop
2
Add a cohort*1
3
Stop
Revised Text
Table 6.c
Cohort/Part Advancement Criteria
Number of Subjects With 
DLT
(DLT evaluable subjects)
Cohort
Procedure
0/3
1
Proceed to Cohort 2
2
Proceed to Cohort 3, Cohort 4 and Part B
3, 4
Stop
1/3
1 to 4
Add 3 subjects in the same cohort
2/3 or 3/3
1
Stop
2
Add a cohort*1
3, 4
Stop
1/6
1
Proceed to Cohort 2
2
Proceed to Cohort 3, Cohort 4 and Part B
3, 4
Stop
≥ 2/6
1
Stop
2
Add a cohort*1
3, 4
Stop
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.


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Page 34, Section 6.2 Rationale for Study Design, Dosage, and Endpoints
Existing Text
(1) Rationale for the target patient population and the study design
•••
The treatment period in Part B was made 48 weeks long in order to investigate safety and 
efficacy over a longer period, in light of the fact that the safety and efficacy of TAK-385 
in multiple dosing for 28 days will have been confirmed in Part A. If the investigator
determines after 48 weeks that there are no safety problems and that TAK-385 treatment 
may be continued, then treatment may be continued for up to a total of 96 weeks.
•••
Revised Text
(1) Rationale for the target patient population and the study design
•••
The treatment period in Part B was made 48 weeks long in order to investigate safety and 
efficacy over a longer period, in light of the fact that the safety and efficacy of TAK-385 
in multiple dosing for 28 days will have been confirmed in Part A. If the investigator or 
sub-investigator determines after 48 weeks that there are no safety problems and that 
TAK-385 treatment may be continued, then treatment may be continued for up to a total 
of 96 weeks.
•••
Rationale for Amendment
Revised to better fit the actual situation at investigational sites.
Page 35, Section 6.2 Rationale for Study Design, Dosage, and Endpoints
Existing Text
(3) Rationale for endpoints
•••
Revised Text
(3) Rationale for dosage in Part A, Cohort 4
19.320 mg or 360 mg may be selected as the loading dose in the planned phase 3 
multinational study. Based on this situation, a new cohort, Cohort 4, was added 
to Part A in Amendment 2 of the study protocol, designed to evaluate the 
tolerability of loading dose of 360 mg in Japanese patients before joining the 
phase 3 multinational study.  As for the maintenance dose, the same dose as 
Part A, Cohort 2 (120 mg) was selected, since this dose is expected to keep 
serum testosterone at castration levels and maintain this effect.


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20.As described in the section above, the tolerability of single doses of 360 mg and 
multiple doses as high as 160 mg (for 28 days) has been confirmed in a phase 1 
study in healthy adult males that was conducted in Europe (TAK-385_C27001).
 
  Based on the fact that there are no major 
differences between Japanese and Americans in the pharmacokinetic or 
pharmacodynamic profiles of TAK-385, and that there are no major differences 
between the pharmacokinetic profiles obtained in healthy adult men and 
women, there are no safety concerns in using the loading dose of 360 mg and 
maintenance dose of 120 mg in Part A, Cohort 4.
(4) Rationale for endpoints
•••
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.
Page 47, Section 8.1.3 Dose and Regimen
Existing Text
Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A)
Cohort
Dosage/Number of Tablets
1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Days 2 to 28): One 80 mg tablet per day
2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
3
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 160 mg (Days 2 to 28): One 80 mg tablet and two 40 mg tablets per day
Additional 
cohort*1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Days 2 to 28): One 40 mg tablet per day


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Revised Text
Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A)
Cohort
Dosage/Number of Tablets
1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Days 2 to 28): One 80 mg tablet per day
2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
3
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 160 mg (Days 2 to 28): One 80 mg tablet and two 40 mg tablets per day
4
TAK-385 360 mg (Day 1): Three 80 mg tablets and three 40 mg tablet per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
Additional 
cohort*1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Days 2 to 28): One 40 mg tablet per day
Rationale for Amendment
Change based on the addition of Part A, Cohort 4.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6806d2799
A Phase 1, Open-label, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and
Pharmacodynamics of TAK-385 Alone in Hormone Treatment-naive Japanese Patients With Non-metastatic
Prostate Cancer
Clinical Approval
03-Oct-2017 10:10 UTC


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CLINICAL STUDY PROTOCOL
Study Title: A Phase 1, Open-label, Multicenter Study to Evaluate the Tolerability, Safety, 
Pharmacokinetics, and Pharmacodynamics of TAK-385 Alone in Hormone Treatment-
naive Japanese Patients With Non-metastatic Prostate Cancer
Short Title: A Phase 1 Study of TAK-385 in Hormone
Treatment-naive Patients With Prostate Cancer
Sponsor:
Takeda Pharmaceutical Company Limited
1-1 Doshomachi 4-chome, Chuo-ku, Osaka
Study Number:
TB-AK160108
Version
Amendment 1
IND Number:
NA
EudraCT 
Number:
NA
Study Drug:
TAK-385
Date:
23 January 2015
CONFIDENTIAL PROPERTY
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered. Furthermore, the information is only meant for review and 
compliance by the recipient, his or her staff, and applicable institutional review committee and regulatory 
agencies to enable conduct of the study.


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1.0
STUDY ADMINISTRATION INFORMATION
1.1
Contacts and Responsibilities for Study-Related Activities
A separate contact information list will be provided to each site.
1.2
Principles of Clinical Studies
This study will be conducted with the highest respect for the individual participants in 
accordance with requirements of this clinical study protocol and also in accordance with 
the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws,
clinical trial disclosure laws, and regulations.
1.3
Protocol Amendment Summary of Changes
The primary purpose of this amendment is to make changes to the protocol so that the 
study procedures match the situation at the investigational sites.  Minor grammatical and 
editorial changes are also included. Full details on changes of text are given in Appendix 
J.


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TABLE OF CONTENTS
1.0
STUDY ADMINISTRATION INFORMATION .................................................. 2
1.1
Contacts and Responsibilities for Study-Related Activities............................. 2
1.2
Principles of Clinical Studies ......................................................................... 2
1.3
Protocol Amendment Summary of Changes................................................... 2
2.0
STUDY SUMMARY........................................................................................... 8
3.0
LIST OF ABBREVIATIONS............................................................................. 12
4.0
INTRODUCTION............................................................................................. 14
4.1
Summary ..................................................................................................... 14
4.1.1
Nonclinical Summary...................................................................... 15
4.1.2
Clinical Studies............................................................................... 19
4.2
Rationale for the Proposed Study................................................................. 25
5.0
STUDY OBJECTIVES AND ENDPOINTS...................................................... 26
5.1
Objectives.................................................................................................... 26
5.1.1
Primary Objectives.......................................................................... 26
5.1.2
Secondary Objectives...................................................................... 26
5.2
Endpoints..................................................................................................... 26
5.2.1
Primary Endpoints .......................................................................... 26
5.2.2
Secondary Endpoints....................................................................... 26
5.2.3
Additional Endpoints ...................................................................... 27
6.0
STUDY DESIGN AND DESCRIPTION........................................................... 28
6.1
Study Design ............................................................................................... 28
6.1.1
Cohort/Part Advancement Criteria................................................... 31
6.1.2
DLT ................................................................................................ 32
6.2
Rationale for Study Design, Dosage, and Endpoints..................................... 33
6.3
Premature Termination or Suspension of Study or Investigational Site ......... 36
6.3.1
Criteria for Premature Termination or Suspension of the Study ....... 36
6.3.2
Criteria for Premature Termination or Suspension of 
Investigational Sites ........................................................................ 36
6.3.3
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s)................................... 36
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ... 37
7.1
Inclusion Criteria ......................................................................................... 37
7.2
Exclusion Criteria ........................................................................................ 38
7.3
Prohibited Concomitant Medications, Therapies, and Foods ........................ 40
7.3.1
Prohibited Concomitant Medications............................................... 40
7.3.2
Prohibited Concomitant Therapies .................................................. 40


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7.3.3
Food ............................................................................................... 41
7.4
Subject Management.................................................................................... 41
7.5
Criteria for Discontinuation or Withdrawal of a Subject ............................... 42
7.6
Procedures for Discontinuation or Withdrawal of a Subject.......................... 44
8.0
STUDY DRUG MANAGEMENT..................................................................... 45
8.1
Study Drug .................................................................................................. 45
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling.................. 45
8.1.2
Storage............................................................................................ 46
8.1.3
Dose and Regimen .......................................................................... 46
8.1.4
Overdose......................................................................................... 49
8.2
Study Drug Allocation and Prescribing Procedures ...................................... 50
8.3
Randomization Code Creation and Storage .................................................. 50
8.4
Control and Disposal of Drugs Provided by the Study Sponsor .................... 50
9.0
STUDY PLAN .................................................................................................. 51
9.1
Study Proceduress........................................................................................ 51
9.1.1
Informed Consent............................................................................ 51
9.1.2
Demographics, Medical History, and Treatment History.................. 51
9.1.3
Physical Examination...................................................................... 52
9.1.4
Weight, Height, and ECOG Performance Status.............................. 52
9.1.5
Vital Signs ...................................................................................... 52
9.1.6
Electrocardiogram........................................................................... 52
9.1.7
Imaging Assessment........................................................................ 52
9.1.8
Clinical Laboratory Tests ................................................................ 53
9.1.9
Cardiac Tests................................................................................... 54
9.1.10
Tumor Marker................................................................................. 54
9.1.11
Collection of Pharmacogenomic Sample ......................................... 54
9.1.12
Bone Mineral Density (Part B Only) ............................................... 55
9.1.13
Ophthalmological Examination (Part B Only) ................................. 55
9.1.14
BMP Concentrations (Part B Only) ................................................. 55
9.1.15
QOL Assessment (Part B Only)....................................................... 55
9.1.16
Concomitant Medications................................................................ 55
9.1.17
Concomitant Therapies ................................................................... 56
9.1.18
Concurrent Medical Conditions....................................................... 56
9.1.19
Contraception.................................................................................. 56
9.1.20
Pregnancy ....................................................................................... 56
9.1.21
Pharmacokinetic Assessments ......................................................... 56
9.1.22
Pharmacodynamic Assessments ...................................................... 56


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9.1.23
Documentation of Subjects Withdrawing From the Study Prior to 
Study Treatment Initiation or Prior to Randomization...................... 57
9.1.24
Documentation of Study Enrollment/Randomization....................... 57
9.2
Monitoring Subject Treatment Compliance.................................................. 57
9.3
Schedule of Observations and Procedures.................................................... 58
9.3.1
Screening........................................................................................ 58
9.3.2
Study Enrollment/Randomization.................................................... 59
9.3.3
Day of Study Treatment Initiation ................................................... 59
9.3.4
Study Drug Treatment Period (Except for the Day of Study 
Treatment Initiation) ....................................................................... 59
9.3.5
Post-treatment Observation Period (Performed Only in Part A) ....... 60
9.3.6
Continuation Treatment Period........................................................ 61
9.3.7
At Study Withdrawal....................................................................... 61
9.3.8
Safety Follow-up............................................................................. 62
9.3.9
Handling After the End of the Study................................................ 63
9.4
Biological Sample Storage and Disposal...................................................... 63
9.5
Blood Sample Volumes and Numbers of Samples Collected......................... 63
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS................................. 66
10.1
Definition .................................................................................................... 66
10.1.1
Pretreatment Events ........................................................................ 66
10.1.2
Adverse Events ............................................................................... 66
10.1.3
Additional Points to Consider for Pretreatment Events and 
Adverse Events ............................................................................... 66
10.1.4
Serious Adverse Events................................................................... 68
10.1.5
Special Interest Adverse Events....................................................... 69
10.1.6
Severity of Pretreatment Events and Adverse Events....................... 70
10.1.7
Causality of Adverse Events............................................................ 70
10.1.8
Relationship to Study Procedures.................................................... 71
10.1.9
Date of Onset.................................................................................. 71
10.1.10
Date Resolved................................................................................. 71
10.1.11
Frequency ....................................................................................... 71
10.1.12
Action Taken for Study Drug........................................................... 72
10.1.13
Outcome ......................................................................................... 72
10.2
Procedures................................................................................................... 73
10.2.1
Collection and Reporting of Adverse Events ................................... 73
10.2.2
Collection and Reporting of Serious Adverse Events....................... 74
10.2.3
Reporting of Drug-Induced LFT Abnormalities Potentially 
Leading to Severe Liver Disorders .................................................. 75


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10.3
Follow-up of Serious Adverse Events .......................................................... 75
10.3.1
Reporting of Serious Adverse Events to Principal Investigators, 
IRB, and Regulatory Authorities ..................................................... 76
11.0
STUDY SPECIFIC COMMITTEES.................................................................. 77
12.0
DATA HANDLING AND RECORDKEEPING................................................. 78
12.1
Electronic Case Report Form....................................................................... 78
12.2
Record Retention ......................................................................................... 78
13.0
STATISTICAL METHODS............................................................................... 80
13.1
Statistical and Analytical Plans .................................................................... 80
13.1.1
Analysis Sets................................................................................... 80
13.1.2
Analysis of Demographics and Other Baseline Characteristics ........ 80
13.1.3
Efficacy Analysis ............................................................................ 80
13.1.4
Pharmacokinetic Analysis ............................................................... 81
13.1.5
Pharmacodynamic Analysis............................................................. 81
13.1.6
Other Analysis ................................................................................ 82
13.1.7
Safety Analysis ............................................................................... 82
13.2
Interim Analysis and Criteria for Early Termination..................................... 83
13.3
Determination of Planned Sample Size ........................................................ 83
14.0
QUALITY CONTROL AND QUALITY ASSURANCE ................................... 84
14.1
Monitoring of Investigational Site................................................................ 84
14.2
Protocol Deviations...................................................................................... 84
14.3
Quality Assurance Audits and Regulatory Authority Inspections .................. 84
15.0
ETHICAL ASPECTS OF THE STUDY ............................................................ 85
15.1
IRB Approval .............................................................................................. 85
15.2
Patient Information, Informed Consent, and Subject Authorization .............. 85
15.3
Subject Confidentiality ................................................................................ 86
15.4
Publication, Disclosure, and Clinical Trial Registration Policy..................... 87
15.4.1
Publication and Disclosure.............................................................. 87
15.4.2
Clinical Trial Registration ............................................................... 87
15.4.3
Clinical Trial Results Disclosure ..................................................... 88
15.5
Insurance and Compensation for Injury........................................................ 88
16.0
REFERENCES.................................................................................................. 89
LIST OF TABLES IN THE PROTOCOL
Table 4.a
............................................ 18
Table 4.b
................................................ 19
Table 6.a
Study Schedule (Part A)......................................................................... 30


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Table 6.b
Study Schedule (Part B)......................................................................... 31
Table 6.c
Cohort/Part Advancement Criteria.......................................................... 32
Table 6.d
Criteria for Advancing From an Additional Cohort to Part B.................. 32
Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A) ............................... 47
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B) ............... 47
Table 8.c
Guidelines for Handling Liver Function Test Abnormalities................... 49
Table 9.a
Clinical Laboratory Tests ....................................................................... 53
Table 9.b
Blood Sample Volumes and Numbers of Samples Collected (Part A) ..... 64
Table 9.c
Blood Sample Volumes and Numbers of Samples Collected  (Part B –
Screening Through Week 48, Safety Follow-up) .................................... 64
Table 9.d
Blood Sample Volumes and Numbers of Samples Collected  (Part B –
Weeks 49 to 96) ..................................................................................... 65
Table 10.a
Takeda Medically Significant AE List .................................................... 69
LIST OF FIGURES IN THE PROTOCOL
Figure 6.a.
Study Design and Treatment Schema (Part A)........................................ 29
Figure 6.b
Study Design and Treatment Schema (Part B)........................................ 30
Figure 8.a
Sample TAK-385 Bottle Label ............................................................... 46
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures (Part A)................................................... 91
Appendix B
Schedule of Study Procedures (Part B – Screening to Week 48, SFU) .... 93
Appendix C
Schedule of Study Procedures (Part B – Weeks 49 to 96) ....................... 95
Appendix D
Schedule of Blood Samples Collection for Pharmacokinetic Analysis 
(Part A).................................................................................................. 96
Appendix E
Schedule of Blood Samples Collection for Pharmacokinetic Analysis 
(Part B).................................................................................................. 97
Appendix F
Responsibilities of Principal Investigator ............................................... 98
Appendix G
ECOG Performance Status..................................................................... 99
Appendix H
New York Heart Association (NYHA) Functional Classification .......... 100
Appendix I
Liver Function Test Abnormality Reporting Checklist.......................... 101
Appendix J
Detailed Description of Amendments to Text ....................................... 102


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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Study Drug:
TAK-385
Study Title: A Phase 1, Open-label, Multicenter Study 
to Evaluate the Tolerability, Safety, Pharmacokinetics, 
and Pharmacodynamics of TAK-385 Alone in Hormone 
Treatment-naive Japanese Patients With Non-metastatic 
Prostate Cancer
IND Number:
NA
EudraCT Number:
NA
Study Number: TB-AK160108
Phase: 1
Study Design:
This study consists of two parts: Part A, a dose-rising phase, and Part B, an expansion phase.
In Part A, three to six patients will be enrolled in each cohort. Whether or not the study will proceed to the
next cohort or Part B will be determined through assessment of tolerability at the dose in question, based on 
the incidence of dose-limiting toxicity (DLT) in the evaluation period. TAK-385 will be taken once a day 
for 28 days at the doses assigned to each cohort. Cohort 1 will receive a loading dose of 320 mg and a 
maintenance dose of 80 mg, Cohort 2 will receive a loading dose of 320 mg and a maintenance dose of 
120 mg, and Cohort 3 will receive a loading dose of 320 mg and a maintenance dose of 160 mg. Patients 
being switched to a gonadotropin-releasing hormone (GnRH) agonist (eg, leuprorelin) or a GnRH 
antagonist (eg, degarelix) following the completion of TAK-385 treatment in Part A will first pass through 
a 1-week observation period (except for study withdrawals). Whether or not the study will proceed to Part 
B will be determined by the study sponsor after consulting the study monitoring committee (SMC) based 
on a comprehensive evaluation of the tolerability and safety data from Cohort 2 of Part A.
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 320 mg and 
maintenance dose of either 80 mg or 120 mg – equal numbers of subjects will be randomized to 80 mg and 
120 mg) once a day orally to evaluate safety. In addition to the safety assessments, efficacy assessments 
will also be performed according to the study schedule, and study drug will be administered until the 
discontinuation criteria (Section 7.5) are met for each individual subject. After completing 48 weeks of 
treatment, subject may, at the discretion of the investigator, and depending on the wishes of the subject, 
continue receiving study drug (for a maximum of 96 weeks), or they may complete the study and be 
switched to a GnRH agonist or a GnHR antagonist, starting from the day after the day of the last dose of 
TAK-385.
All subjects who receive study drug will undergo safety follow-up 30 to 40 days after the last dose of 
TAK-385.
Part A (Dose-rising phase)
Primary Objectives:
To evaluate the tolerability and safety of TAK-385 in hormone treatment-naive patients with non-
metastatic prostate cancer.
Secondary Objectives:
To evaluate the pharmacokinetics (PK) and the effects on serum testosterone of TAK-385 in hormone 
treatment-naive patients with non-metastatic prostate cancer.
Part B (Expansion phase)
Primary Objectives:
To evaluate the safety of TAK-385 in hormone treatment-naive patients with non-metastatic prostate 
cancer.
Secondary Objectives:
To evaluate the change over time in the prostate-specific antigen (PSA) levels and the PK and effects on 
serum testosterone of TAK-385 in hormone treatment-naive patients with non-metastatic prostate cancer.


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Subject Population: Japanese patients with hormone treatment-naive non-metastatic prostate cancer
Numbers of Subjects
Part A: 3 to 6 subjects in each cohort (3 to 18 
subjects in total)
Part B: 15 subjects in each group (30 subjects in 
total)
Number of Sites
Part A: 2 to 3 sites
Part B: Approximately 7 sites (some of the sites will 
be the same as the sites in Part A)
Dosage
Dosage: TAK-385 once a day orally at least 30 
minutes before breakfast
Part A
Cohort 1: Loading dose of 320 mg and maintenance 
dose of 80 mg
Cohort 2: Loading dose of 320 mg and maintenance 
dose of 120 mg
Cohort 3: Loading dose of 320 mg and maintenance 
dose of 160 mg
(Additional cohort: Loading dose of 320 mg and 
maintenance dose of 40 mg)
Part B
80 mg group: Loading dose of 320 mg and 
maintenance dose of 80 mg
120 mg group: Loading dose of 320 mg and 
maintenance dose of 120 mg
(If there is an additional cohort in Part A, then 
instead of a 120 mg group, there will be a 40 mg 
group, which will received a loading dose of 
320 mg and a maintenance dose of 40 mg.)
Route of Administration
Oral
Duration of Treatment
Part A: 28 days
Part B: 48 weeks (may be continued for up to a total 
of 96 weeks maximum)
Period of Evaluation
Part A: Approximately 2 months
Part B: Approximately 1 year (approx. 2 years if 
therapy is continued)
Main Criteria for Inclusion
1.
Patients with histologically or cytologically confirmed prostate cancer
2.
Patients whose clinical diagnosis is T1-4 N0 M0, or Tx N0 M0 for patients who have undergone 
radical prostatectomy
3.
Patients who have not received hormone therapy (eg, GnRH agonist, GnRH antagonist, steroidal 
antiandrogen, non-steroidal androgen) for prostate cancer
4.
Patients with serum testosterone at screening > 150 ng/dL
5.
Patients meeting either of the following criteria for PSA at screening
Untreated prostate cancer:
PSA at screening > 4.0 ng/mL
Treated prostate cancer:
PSA at screening > 0.2 ng/mL
6.
Eastern Cooperative Oncology Group (ECOG) performance status  of 0 or 1


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Main Criteria for Exclusion
1.
Patients exhibiting symptoms judged related to prostate cancer by the investigator (eg, bone pain, 
pelvic pain, ureteral obstruction) who urgently require hormone therapy such as GnRH agonist, GnRH 
antagonist, or combined androgen blockade (CAB)/maximum androgen blockade (MAB) therapy, 
chemotherapy, or radiotherapy
2.
Patients who have received 5-alpha reductase inhibitors (except for patients who have been treated for 
male-pattern alopecias)
3.
Treatment with any investigational compound within the 4 weeks (28 days) prior to the first dose of 
study drug or ongoing participation in another experimental trial related to the treatment of prostate 
cancer
4.
Known hypersensitivity to TAK-385, TAK-385 excipients, or GnRH antagonists
5.
Clinically relevant ECG abnormalities, or the following ECG abnormalities, at screening

Q-wave infarction, unless identified 6 or more months prior to TAK-385 treatment initiation

Fridericia corrected QT (QTcF) interval > 450 msec (when calculating the QTc interval, 
Fridericia’s equation [QT/RR0.33] will be used)
6.
Patients with congenital QT prolongation
Endpoints
Part A
Primary endpoints

DLTs, adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead ECGs
Secondary endpoints

Plasma concentrations of unchanged TAK-385

Serum testosterone concentrations
Part B
Primary endpoints

AEs, clinical laboratory tests, vital signs, and 12-lead ECGs
Secondary endpoints

PSA levels

Plasma concentrations of unchanged TAK-385

Serum testosterone concentrations
Statistical Consideations
Safety analyses
1)
Incidences of AEs
The following analysis will be performed for the safety analysis set.
Treatment-emergent adverse events (TEAEs) will be tabulated by part and dose. TEAEs will be coded 
according to Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ 
class (SOC) and preferred term (PT).
2)
DLTs
The following analysis will be performed for the DLT analysis set.
The incidences of TEAEs judged to be DLTs in Part A will be tabulated by PT and dose.
3)
Clinical laboratory test value profiles, vital signs, and 12-lead ECGs
The following analyses will be performed for the safety analysis set.
For continuous data, summary statistics will be calculated for the baseline values, the values observed at 
each assessment time point, and the changes from baseline by part and dose.
For categorical data and assessments based on reference values, cross tabulation of the values before and 


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after treatment (eg, normal/abnormal, qualitative clinical laboratory test values) will be performed by part 
and dose for each test parameter.
Pharmacokinetic analyses
Pharmacokinetic parameters (eg, maximum observed plasma concentration [Cmax], area under the plasma 
concentration - time curve [AUC]) will be evaluated using the plasma TAK-385 concentrations, and 
summary statistics will be calculated for the plasma concentrations and each of the pharmacokinetic 
parameters. Figures showing the changes over time in the plasma concentration of TAK-385 will also be 
prepared.
Rationale for the Planned Sample Size
Part A
Each cohort will have 3 or 6 subjects, based on the the guidelines on the clinical evaluation of 
antineoplastics
Part B
In order to detect less frequent AEs, 15 subjects per group (total of 30 subjects) were established as the 
number of cases enabling an approximately 80% chance of detecting AEs characterized by a true incidence 
of 10%.


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
AMS
Aging Male's Symptoms
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BMI
body mass index
BMP
di-docosahexaenoyl (22:6)-bis(monoacylglycerol)
phosphate
CAB
combined androgen blockade 
CK-MB
creatine kinase MB
Cmax
maximum observed plasma concentration
CTCAE
Common Terminology Criteria for Adverse Events
DHT
dihydrotestosterone
DLT
dose-limiting toxicity
eCRF
electronic case report form
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
EPIC
Expanded Prostate Cancer Index Composite
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin-releasing hormone
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
LFT
liver function test
LH
luteinizing hormone
MAB
maximum androgen blockade
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect level
PK
Pharmacokinetics
P-gp
P-glycoprotein
PGx
pharmacogenomics
PSA
prostate-specific antigen
PT-INR
Prothrombin Time-International Normalized Ratio


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PTE
Pretreatment Event
QTc
corrected QT (interval)
QTcB
Bazett corrected QT
QTcF
Fridericia corrected QT
SHBG
sex hormone binding globulin
SMC
study monitoring committee
Tmax
maximum drug concentration time
TEAE
treatment-emergent adverse event
ULN
upper limit of normal


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4.0
INTRODUCTION
4.1
Summary
In 2008 prostate cancer reached approximately 900,000 cases/year worldwide and is now 
the second leading cancer in men, accounting for 13.7% of cancer cases in men [1]. The 
median age of diagnosis is 70, and prostate cancer is rarely diagnosed in men under 40 
[2]. Incidence increases with age and is expected to rise in the future as the population 
ages. In Japan, 2008 statistics show that prostate cancer ranks a high fourth in morbidity 
among cancers in men [3]. Prostate cancer in Japan also occurs more often with age, and 
the incidences increases rapidly in men 60 and older.
It is known that prostate cancer is to responsive to surgical castration and that the 
effectiveness of this therapy results from the elimination of androgen. This knowledge 
led to the understanding that most prostate cancers are growth hormone dependent and 
ever since this discovery, hormone therapy has played an important role in the treatment 
of prostate cancer.
Castration by orchiectomy or a gonadotropin-releasing hormone (GnRH) agonist is the 
main mode of therapy for localized progressive and metastatic cancers, and GnRH 
agonists such as leuprorelin acetate are widely used [4]. When multiple doses of a GnRH 
agonist are administered, a temporary increase in gonadotropin secretion (flare up) occurs. 
That is followed by a decrease in responsiveness (desensitization) in the pituitary gland 
and gonads, which appears to work effectively by inhibiting the secretion of sex 
hormones. The flare up sometimes leads to a temporary worsening of symptoms, and the 
effectiveness of GnRH agonist begins to appear about 3 to 4 weeks after the initial dose.  
In addition, the GnRH is a peptide formulation and is unable to be administered orally. 
Consequently, development of a new medication that is easy to administer and does not 
cause flare ups is needed.
TAK-385 is a non-peptide orally active GnRH antagonist with a novel structure that was 
discovered by Takeda Pharmaceutical Company, Ltd. TAK-385 antagonizes GnRH at the 
GnRH receptors present in the basophils (secreting cells) of the anterior pituitary gland 
and inhibits the GnRH-stimulated secretion of gonadotropin luteinizing hormone (LH) 
and follicle-stimulating hormone (FSH) from those cells. This action lowers the serum 
testosterone concentration in the blood. An antitumor effect is expected in prostate 
cancer patients due to the suppression of serum testosterone production by the testes. 
TAK-385 is also expected to manifest its effects rapidly without causing flare ups like 
GnRH agonists. Moreover, because it is a non-peptide formulation, TAK-385 can be 
administered orally, unlike peptide-based GnRH agonists that must be absorbed 
subcutaneously. The clinical pharmacokinetic and pharmacodynamic profiles may offer 
additional advantages compared with a depot peptide formulations, such as more rapid 
recovery from short term medical castration.
Takeda Pharmaceutical Co., Ltd. decided to develop TAK-385 for the treatment of 
prostate cancer both overseas and in Japan. Moreover, development of TAK-385 in Japan 
and Asia for endometriosis and uterine fibroids is already underway.


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4.1.1
Nonclinical Summary
4.1.1.1
Pharmacology Related to the Proposed Mechanism of Action
A series of in vitro and in vivo pharmacological studies have demonstrated that TAK-385 
acts as a potent and highly selective antagonist for human GnRHR (hGnRHR).
 
 
 
 
 
 
 [5].
4.1.1.2
Safety Pharmacology
In safety pharmacology studies,
 
 
 
 
 
 
 [5].
4.1.1.3
Pharmacokinetics and Product Metabolism in Animals
 
 
 
 
 
 
 
 
 
 


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 [5].
4.1.1.4
Toxicology
TAK-385 has been evaluated for safety in single- and repeat-dose toxicity studies, with 
supportive toxicokinetic analyses, in mice, rats, and monkeys.  Genetic, carcinogenicity, 
reproductive, and phototoxicity studies have also been performed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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[5].


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4.1.2
Clinical Studies
4.1.2.1
Japanese Phase 1 Single- and Multiple-dose Study (
)
A placebo-controlled double-blind single dose study of the safety, pharmacokinetics (PK), 
and pharmacodynamics of TAK-385 was conducted in 72 premenopausal healthy adult 
Japanese women (including 12 in the placebo group). Moreover, a crossover study 
comparing fasted state/postprandial administration, and fasted/preprandial administration 
was conducted in 24 premenopausal healthy women to investigate the effect of meals on 
TAK-385 PK. In addition, a placebo-controlled double-blind, 14-day multiple dose study 
of safety, PK, and pharmacodynamics during of TAK-385 was conducted in 48 
premenopausal healthy adult women (including 12 in the placebo group).
 
 
 
 
 


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[5].


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4.1.2.2
Overseas Phase 1 Single- and Multiple-dose Study (
)
A placebo-controlled double-blind single-dose study of the safety, PK, and 
pharmacodynamics of TAK-385 was conducted in 72 premenopausal healthy adult 
American women (including 12 in the placebo group). Moreover, a crossover study 
comparing fasted with fed (post-breakfast) administration was conducted in 12 
premenopausal healthy women to investigate the effect of food on the PK of TAK-385. 
In addition, a placebo-controlled double-blind, 14-day multiple dose study of safety, PK, 
and pharmacodynamics during of TAK-385 was conducted in 36 premenopausal 
healthyadult women (including 9 in the placebo group).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [5].


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4.1.2.3
Japanese Phase 1 Study of Drug-drug Interactions With Erythromycin 
(
)
A phase 1 open-label drug-drug interaction study was carried out in healthy Japanese
male and female subjects to evaluate the effect of multiple doses (300 mg, q.i.d.) of 
erythromycin (moderate CYP3A4 inhibitor and P-gp inhibitor) on the single-dose PK of 
TAK-385 (20 mg). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[5].
4.1.2.4
Overseas Phase 1 Drug-drug Interaction Study (
)
 
 
 
 
 
 
 


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 [5].
4.1.2.5
Overseas Phase 1 Single- and Multiple-dose Study (TAK-385_C27001)
Study C27001 was a phase 1 study that evaluated the safety, tolerability, PK, and PD of 
TAK-385 in 176 healthy English adult male subjects (128 subjects received TAK-385) 
receiving single doses of TAK-385 up to 360 mg QD and multiple doses of TAK-385 up 
to 180 mg QD for up to 28 days. The study had 4 parts: Part 1 included single-dose 
administration of TAK-385 to 32 subjects across 4 dose cohorts plus placebo and had a 
fed/fasted arm; Part 2 included multiple dose administration of TAK-385 for 14 days to 
40 subjects across 5 dose cohorts plus placebo; and Parts 3 and 4 included multiple dose 
administration of TAK-385 for 28 days to 66 and 38 subjects, respectively, across 2 dose 
cohorts (a total of 4 dose levels), plus placebo.
There were no deaths or SAEs following single-dose or multiple-dose treatment with 
TAK-385 for 14 or 28 days.
Following 28 days of QD dosing, there were 3 discontinuations due to drug-related, 
hepatic AEs: 2 subjects in the 160 mg dose cohort in Part 3 of the study discontinued 
treatment due to Grade 1 AEs of hepatic enzyme increased (ALT and AST); and 1 subject 
in the 60 mg dose cohort in Part 4 of the study discontinued treatment due to a Grade 2 
AE of liver function test (LFT) abnormal (ALT and AST). There was no clear trend 
between dose level and toxicity, although abnormal liver transaminase levels appeared 
more likely to occur within 2 weeks at higher dose levels. All AEs resolved by the end of 
the study.
The majority of subjects had at least 1 AE, but no increase in the incidence of AEs with 
increasing dose of TAK-385 was observed. The most common AEs observed across all 
dose cohorts were bradycardia, hot flush, and headache, and the most common, drug-
related AE was hot flush.
A number of cardiac AEs according to Common Terminology Criteria for Adverse Events 
(CTCAE) were reported, but for these subjects the ECG interpretation was considered to 
be not clinically significant by the investigator. These cardiac AEs included 
electrocardiogram QT prolonged (1 AE in Part 1, 4 AEs in Part 2, and 7 AEs in Part 3) 
and first degree atrioventricular block (2 AEs in Part 1 and 6 AEs in Part 2). Changes in 
mean QTc interval of approximately 15 to 20 msec were noted before administration on 
Day 14 (80 to 180 mg QD) in adult male subjects in this study. The QTc changes were 
independent of drug administration, not correlated to drug levels, and are similar to those 
observed in surgical and medical castration studies with other compounds. No major 


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safety concerns were noted in healthy male subjects receiving single (80 to 360 mg) and 
multiple (20 to 180 mg) doses of TAK-385, and TAK-385 was well tolerated.
Single doses of 80 to 360 mg of TAK-385 administered orally (fasted state) were 
absorbed rapidly in plasma with median Tmax values ranging from 1.75 to 4.00 hours 
after administration across the entire dose range. After attaining Cmax, TAK-385 plasma 
concentrations declined in a multi-exponential manner with a mean T1/2 ranging from 
19.1 to 21.7 hours. The mean Cmax and AUC values for TAK-385 generally increased in 
an approximately dose-proportional manner over the 80 to 360 mg dose range.
When a multiple dose of 20 to 180 mg QD of TAK-385 was administered, the drug was 
readily absorbed in plasma on Days 1 and 14, and Cmax typically occurred within 1 to 2 
hours after dosing. After attaining Cmax, individual PK profiles on Day 14 exhibited a 
multi-exponential elimination phase with a mean elimination phase T1/2 of 
approximately 36 to 65 hours at doses of 20 to 180 mg QD. The trough concentration-
time data (Day 2, and Days 11 to 14) implied that steady-state conditions were attained 
within approximately 10 days.
Similarly, the effect of food was studied in 6 male subjects in the crossover period (Part 
1). Compared to fasting conditions, the absorption of TAK-385 in plasma decreased and 
was delayed following a single 180 mg dose taken 30 minutes after the start of a standard 
FDA high-fat, high-calorie breakfast. Least square mean Cmax and AUC(0-inf) values 
decreased by approximately 52% and 47%, respectively. Furthermore, median Tmax 
increased from 1.75 hours to 5.00 hours under fed conditions. When the dose was 
administered 30 minutes prior to the standardized morning meal (Part 2), systemic 
exposure to TAK-385 appeared to be reduced to a lesser extent (approximately 28% on 
average) and no changes in the absorption rate were observed.
In this study, serum LH, FSH, dihydrotestosterone (DHT), and testosterone 
concentrations were determined following single and multiple oral doses of TAK-385 or 
placebo for up to 28 days. TAK-385 caused an immediate and effective suppression of 
gonadotropins (LH, FSH) and testosterone. While no changes were observed in the 
placebo group, serum testosterone levels were markedly suppressed in all TAK-385 dose 
groups within the first 3 days of administration. Loading doses of 320/240/160 mg for up 
to 3 days and doses of 180 mg or greater led to testosterone levels below the conventional 
castration level within 48 hours. The onset of the testosterone lowering response 
shortened as the loading dose increased. This phenemon was likely a result of higher 
TAK-385concentrations in the blood. Similar dose-dependent suppressive effects were 
observed after a single oral dose. These findings support the principal mechanism of 
action that, as a GnRH antagonist, TAK-385 competitively binds with the pituitary GnRH 
receptors.
In administration over 28 days in Part 3 and 4, both 160 mg and 80 mg QD were effective 
at achieving conventional medical castration levels during the third and fourth weeks of 
multiple administration. Despite the loading dose regimen, however, the 40-mg QD dose 
was ineffective in maintaining castration levels between Days 14 and 28. The results at 
60 mg QD were intermediate to those of 40 and 80 mg QD and suggested that the likely 


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minimal, fully effective maintenance dose for medical castration would be 80 mg QD or 
above [5].
4.2
Rationale for the Proposed Study
The results of the phase 1 study conducted in England (TAK-385_C27001) demonstrate 
the tolerability of multiple doses of TAK-385 (20 to 80 mg) in healthy adult men. 
Moreover, the plasma concentration of TAK-385 increased as the dose increased, and 
rose slightly greater than dose proportionality. The blood concentrations of the measured 
hormones all decreased rapidly with multiple doses of TAK-385 and effective 
suppression of serum testosterone was sustained throughout the adminsitration period.
 
Because prostate cancer is a sex-hormone dependent disease, and an antitumor effect is 
expected as a result of lowering hormone concentrations in the blood through 
administration of TAK-385, it was decided to conduct a phase 1 study in patients with
prostate cancer.
This protocol was prepared in accordance with the Good Clinical Practice (GCP).


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
Part A
To evaluate the tolerability and safety of TAK-385 in hormone treatment-naive patients 
with non-metastatic prostate cancer.
Part B
To evaluate the safety of TAK-385 in hormone treatment-naive patients with non-
metastatic prostate cancer.
5.1.2
Secondary Objectives
Part A
To evaluate the PK and the effects on serum testosterone of TAK-385 in hormone 
treatment-naive patients with non-metastatic prostate cancer.
Part B
To evaluate the change over time in the prostate-specific antigen (PSA) levels and the 
PK and effects on serum testosterone of TAK-385 in hormone treatment-naive patients 
with non-metastatic prostate cancer.
5.2
Endpoints
5.2.1
Primary Endpoints
Part A
Safety: Dose-limiting toxicities (DLTs), AEs, clinical laboratory tests, vital signs, and 
12-lead ECGs
Part B
Safety: AEs, clinical laboratory tests, vital signs, and 12-lead ECGs
5.2.2
Secondary Endpoints
Part A
PK: Plasma concentrations of unchanged TAK-385
Pharmacodynamics: Serum testosterone concentrations
Part B
Efficacy: PSA levels
PK: Plasma concentrations of unchanged TAK-385
Pharmacodynamics: Serum testosterone concentrations


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5.2.3
Additional Endpoints
Part A
Efficacy: PSA levels
Pharmacodynamics: LH, FSH, DHT, and sex hormone binding globulin (SHBG) 
serum concentrations
Part B
Safety: Bone density [6]
Efficacy: Disease progression assessed by PSA, disease progression assessed by 
imaging
Pharmacodynamics: LH, FSH, DHT, and SHBG serum concentrations
Other: QOL assessments based on the Aging Male's Symptoms (AMS) [7], European 
Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 [8, 9, 10], 
and the Expanded Prostate Cancer Index Composite (EPIC) [11, 12]


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a multicenter phase 1, open-label, dose range-finding study to evaluate the 
tolerability, safety, PK, and pharmacodynamics of TAK-385 alone in hormone treatment-
naive Japanese patients with non-metastatic prostate cancer.
This study consists of two parts: Part A, a dose-rising phase, and Part B, an expansion 
phase. The designs of Part A and Part B are shown in “Study Design and Treatment 
Schema” (Figure 6.a and Figure 6.b).
In Part A, three to six patients will be enrolled in each cohort. Whether or not the study 
will proceed to the next cohort or Part B will be determined through assessment of 
tolerability at the dose in question, based on the incidence of DLT in the evaluation
period (treatment initiation to Day 28).
TAK-385 will be taken once a day for 28 days at the doses assigned to each cohort. 
Cohort 1 will receive a loading dose of 320 mg and a maintenance dose of 80 mg, Cohort 
2 will receive a loading dose of 320 mg and a maintenance dose of 120 mg, and Cohort 3 
will receive a loading dose of 320 mg and a maintenance dose of 160 mg. The doses will 
be taken orally at least 30 minutes before breakfast. Patients being switched to a GnRH 
agonist (eg, leuprorelin) or a GnRH antagonist (eg, degarelix) following the completion 
of TAK-385 treatment in Part A will first pass through a 1-week observation (no-
treatment) period. However, patients whose treatments were discontinued because they 
met the discontinuation criteria (Section 7.5) during the 28-day treatment period will not 
have to pass through this observation period.
If tolerability is confirmed in Cohort 2, then the study will proceed to Cohort 3 and Part B 
simultaneously. The tolerability in Japanese of the maximum dose at which tolerability 
was found in 28-day multiple dosing in the overseas phase 1 single-/multiple-dose study 
(TAK-385_C27001) (160 mg) will be evaluated for the purpose of checking the 
tolerability of dose escalation to 160 mg in Part B as well as the PK. In the overseas 
phase 1 single-/multiple-dose study (TAK-385_C27001), no findings indicative of safety 
problems were obtained in multiple dosing for 28 days with 160 mg. However, if 
tolerability is not confirmed in Cohort 2, then a cohort will be added that will receive a 
loading dose of TAK-385 320 mg and a maintenance dose of 40 mg.
In Part B, subjects will be randomized to receive study drug (TAK-385 loading dose of 
320 mg and maintenance dose of either 80 mg or 120 mg – equal numbers of subjects 
will be randomized to 80 mg and 120 mg) once a day orally to evaluate safety. In 
addition to the safety assessments, efficacy assessments will also be performed according 
to the study schedule, and study drug will be administered until the discontinuation 
criteria (Section 7.5) are met for each individual subject. After completing 48 weeks of 
treatment, subjects may, at the discretion of the investigator, and depending on the wished 
of the subhect, continue receiving study drug (for a maximum of 96 weeks), or they may 
complete the study and be switched to a GnRH agonist (eg, leuprorelin) or a GnHR 
antagonist (eg, degarelix), starting from the day after the day of the last dose of TAK-385.
Subjects withdrawing from the study will not be replaced.


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If no problems with tolerability are found in the additional cohort in Part A, then the 
study will proceed to Part B with a 40 mg group instead of a 120 mg group (TAK-385 
loading dose of 320 mg and maintenance dose of 40 mg).
All subjects who receive study drug, whether in Part A or Part B, will undergo safety 
follow-up 30 to 40 days after the last dose of TAK-385.
*1: If tolerability is not confirmed in Cohort 2, then a cohort will be added which will receive a loading 
dose of 320 mg and a maintenance dose of 40 mg.
*2: If a cohort is added, and the additional cohort continues to the end and no problems with tolerability 
are found, then the study will proceed to Part B.
Figure 6.a.
Study Design and Treatment Schema (Part A)
Evaluation of Transition
Cohort 2 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Days 2-28)
Evaluation of Transition
*1
Cohort 3 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 160 mg (Days 2-28)
Evaluation of Transition
*2
Part B (Expansion phase)
Part A (Dose-rising phase)
Cohort 1 (n = 3-6)
TAK-385
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Days 2-28)


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*1: If a cohort is added in Part A, then in Part B 120 mg group will be replaced to 40 mg group, in which 
subjects will receive loading dose of 320 mg and maintenance dose of 40 mg.
Figure 6.b
Study Design and Treatment Schema (Part B)
Figure 6.a and Figure 6.b show an overview of the study schedule. See Appendix A
through Appendix D for a more detailed schedule of the study tests, observations, and 
assessments.
Table 6.a
Study Schedule (Part A)
Screening
Treatment Period
Post-treatment 
Observation Period
Safety Follow-up
DLT Evaluation Period (treatment initiation to Day 28)
Outpatient
Inpatient
Outpatient
Outpatient/Inpatient
Outpatient
Day -28 to Day -1*1
Day 1*1 to Day 15
Day 16 to Day 28*2
Day 29 to Day 35*2
...
30 to 40 days after 
the last dose
of TAK-385
Assessment of eligibility
Screening tests
Admission
Discharge
Tests/observations
Treatment initiation
Treatment completion
Tests/observations
Initiation of other 
treatment
Tests/observations
Observations
Tests/observations
*1: Day -1 and Day 1 are the day before treatment initiation and the day of treatment initiation, respectively.
*2: Days 27 to 35 are performed either on an outpatient or an inpatient basis.
Part B (Expansion phase)
Eligibility assessment/randomization (1:1)
(performed by the day before treatment initiation)
TAK-385 80 mg
Loading dose 320 mg (Day 1)
Maintenance dose 80 mg (Day 2 on)
TAK-385 120 mg *1
Loading dose 320 mg (Day 1)
Maintenance dose 120 mg (Day 2 on)
Screening
(1 to 28 days before treatment initiation)
Visit at end of TAK-385 treatment
(Safety follow-up 30 to 40 days after the last dose of TAK-385)
End of treatment (Week 48)
TAK-385 continuation treatment
(Up to Week 96 at most)


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Table 6.b
Study Schedule (Part B)
Screening
Treatment Period
Continuation Treatment Period
Safety Follow-up
Outpatient
Days -28 to -1*1
Week 1, Day 1*1 to Week 48, 
Day 7*2
Week 49, Day 1 to Week 96, 
Day 7*2
30 to 40 days after the last dose 
of TAK-385
Assessment of eligibility, 
randomization
Screening tests
Treatment completion
Tests, observations
Treatment initiation
Treatment completion
Tests, observations
Treatment initiation
Tests, observations
Initiation of other treatment
*1: Day -1 and Day 1 are the day before treatment initiation and the day of treatment initiation, respectively.
*2: Other treatments may be initiated starting on the day after the day of the last dose of TAK-385 (Week 48, Day 8 or Week 96, Day 
8).
6.1.1
Cohort/Part Advancement Criteria
Whether or not the study will proceed to the next cohort in Part A will be determined by 
the study sponsor after consulting the study monitoring committee (SMC) and following 
a comprehensive evaluation of the safety data based on the number of subjects 
experiencing DLT in each cohort (Table 6.c). Drug will be administered to the subjects in 
the next cohort after the decision on cohort advancement is made. See the separately 
prepared written procedures for detailed study advancement criteria.
In each cohort, if no DLT occurs in even 1 of the 3 subjects during the DLT evaluation 
period (see Section 6.1.2.2), then the dose will be judged tolerable, and the study will 
proceed to the next cohort. If a DLT occurs in 1 subject in the DLT evaluation period, 
and additional 3 subjects will be enrolled in this cohort, and DLT will be evaluated in a 
total of 6 subjects. If DLT occurs in 1 of these 6 subjects, this dose will be judged 
tolerable, and the study will proceed to the next cohort. If DLT occurs in 2 or more 
subjects, the study will be stopped, but if it is determined, after consulting the SMC, that 
this dose is tolerable, then the study will proceed to the next cohort.
Whether or not the study will proceed to Cohort 3 and Part B will be determined by the 
study sponsor after consulting the SMC based on a comprehensive evaluation of the 
tolerability and safety data from Cohort 2 of Part A.
If the study cannot proceed from Cohort 2 to Cohort 3 and Part B because of a tolerability 
problem, the study will proceed to an additional cohort that will receive a TAK-385 
loading dose of 320 mg and a maintenance dose of 40 mg. In this case, as well, 3 
subjects will be enrolled, and assessed in the same manner as described above. If the 
study proceeds to the additional cohort, and continues until the treatment of the additional 
cohort has been completed, and it is confirmed that no problems with tolerability are 
found, then the study will proceed to Part B.
If DLT occurs in 2 or more subjects in Cohort 3, then whether or not to increase the dose 
to 160 mg in Part B will be determined in consultation with the SMC.


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Because assessment of the MTD is not the objective of this study, additional subjects will 
not be enrolled if TAK-385 is found to be tolerable in an evaluation of the 3 subjects in 
Cohort 3, nor will additional subjects be enrolled at lower dose levels if TAK-385 is not 
found to be tolerable at the dose level initially investigated.
Table 6.c
Cohort/Part Advancement Criteria
Number of Subjects With 
DLT 
(DLT evaluable subjects)
Cohort
Procedure
0/3
1
Proceed to Cohort 2
2
Proceed to Cohort 3 and Part B
3
Stop
1/3
1 to 3
Add 3 subjects in the same cohort
2/3 or 3/3
1
Stop
2
Add a cohort*1
3
Stop
1/6
1
Proceed to Cohort 2
2
Proceed to Cohort 3 and Part B
3
Stop
≥ 2/6
1
Stop
2
Add a cohort*1
3
Stop
*1: TAK-385 loading dose of 320 mg and maintenance dose of 40 mg
Table 6.d
Criteria for Advancing From an Additional Cohort to Part B
Number of Subjects With 
DLT 
(DLT evaluable subjects)
Procedure
0/3
Proceed to Part B
1/3
Add 3 subjects
2/3 or 3/3
Stop
1/6
Proceed to Part B
≥ 2/6
Stop
6.1.2
DLT
6.1.2.1
Definition of DLT
DLTs are defined at treatment-related AEs that occur within the first 28 days of treatment 
and that meet one of the criteria described below based on CTCAE Version 4.03 (issued 
June 14, 2010) [13].


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1.
Grade 3 or higher toxicity
Clinical laboratory abnormalities meet this criterion if they are found at 2 
consecutive time points 7 or more days apart, except for ALT or AST > 3 upper 
limit of normal(ULN), total bilirubin > 2 ULN, or prothrombin time-international 
normalized ratio (PT-INR) > 1.5 at 2 time points 2 or more days apart.
2.
Either of the following ECG findings at 2 time points 7 or more days apart
QT/Fridericia corrected QT (QTcF) > 500 msec after treatment initiation
QT/QTcF interval prolongation > 60 msec postdose
The QTcF interval will be calculated using Fridericia’s equation (QT/RR0.33).
If it is difficult to determine whether or not an event is a DLT and the subject who 
experienced the event should be included in the DLT analysis set, the sponsor will consult 
the SMC before making a final decision on whether or not the event is a DLT.
Study treatment will be continued until the end of the 28-day treatment period unless a 
DLT occurs. If a subject is withdrawn from the study for a reason other than a DLT or if 
treatment compliance is below 80% (23 doses), the subject will be considered ineligible 
for inclusion in the DLT analysis set, and replacement subjects will be added in order to 
obtain 3 or 6 evaluable subjects.
6.1.2.2
DLT Evaluation Period
From treatment initiation until Day 28 in Part A.
6.1.2.3
DLT Evaluable Subjects
Subjects meeting any of the following criteria enrolled in a cohort in Part A.

Subjects who have taken at least 80% of the doses of TAK-385 (23 doses) during the 
DLT evaluation period and for whom the DLT evaluation period observations have 
been completed.

Subjects who experienced DLTs during the DLT evaluation period.
6.2
Rationale for Study Design, Dosage, and Endpoints
(1) Rationale for the target patient population and the study design
The novel GnRH antagonist TAK-385 is expected to compensate for the deficiencies 
of the GnRH agonists that have been widely used in the treatment of prostate cancer 
to date, and is being developed as a novel therapeutic medication for prostate cancer. 
The target patient population for this study was therefore made Japanese patients 
with prostate cancer.
Because this study will be the first time in Japan that TAK-385 will be administered 
to patients with prostate cancer, and the safety and efficacy of TAK-385 for the target 
population have not been sufficiently demonstrated, the TAK-385 treatment period in
Part A was set at 28 days. The treatment period would minimize the inconvenience 


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to subjects with safety concerns or insufficient efficacy. Because TAK-385 will be 
administered alone to hormone treatment-naive patients with prostate cancer, a 
placebo would not be used, and that the study would be conducted as an open-label 
study. It was also decided that if a subject is going to be switched to some other 
therapy after receiving the last dose of TAK-385 in Part A, then the patient would 
have to first pass through a 1-week observation (no-treatment) period because of 
concerns about the safety of the temporary concomitant use of TAK-385 with other 
therapies. However, subjects meeting the discontinuation criteria (Section 7.5) 
during the 28-day treatment period would not need to first pass through a 1-week 
observation period if they need to be switched to some other therapy immediately.
The treatment period in Part B was made 48 weeks long in order to investigate safety 
and efficacy over a longer period, in light of the fact that the safety and efficacy of 
TAK-385 in multiple dosing for 28 days will have been confirmed in Part A. If the 
investigator determines after 48 weeks that there are no safety problems and that 
TAK-385 treatment may be continued, then treatment may be continued for up to a 
total of 96 weeks. Part B was made an open-label phase with randomization to one 
of two doses the tolerability of which will have been confirmed in Part A. An open-
label study design was used because TAK-385 is being administered alone to 
hormone treatment-naive patient with prostate cancer. In addition, if a subject is 
going to be switched to some other treatment after the last dose of TAK-385 then, 
unlike in Part A, and assuming use in the actual clinical setting, it was decided that 
the other therapy could be initiated without any intervening observation period for 
confirming the safety of temporary concomitant use with the other therapy.
Furthermore, TAK-385 has been found to be affected by food, and the results that 
have been obtained suggest that TAK-385 absorption is decreased and delayed when 
a single dose is taken 30 minutes after food compared to when it is taken in a fasted 
condition (TAK-385_C27001). It was therefore decided that TAK-385 should be 
taken at least 30 minutes before breakfast.
Because the company plans to participate in multinational studies in the future, it was 
decided that Part B would be conducted using the same dosage and administration as 
that being used in the phase 2 studies being conducted overseas. Because Part B will 
be conducted using a dosage the tolerability of which will have been confirmed in 
Cohorts 1 and 2 in Part A, it was decided that Part A Cohort 3 and Part B could be 
conducted in parallel.
(2) Rationale for loading dose (Part A, Cohort 1)
In a phase 1 study in healthy adult males that was conducted in Europe 
(TAK-385_C27001), the tolerability of single doses as high as 360 mg and multiple
doses as high as 160 mg was confirmed. In order to keep serum testosterone at 
castration levels and maintain this effect, it was felt that a dose of at least TAK-385 
80 mg a day would be necessary as a maintenance dose. In addition, in study 
TAK-385_C27001, single doses of TAK-385 180 mg and above reduced serum 
testosterone levels to castration levels within 48 hours.


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Based on these existing data on TAK-385 and on the development plan, it was 
decided that the loading dose for Cohort 1 in Part A of this study should be 320 mg, a 
dose that is within the range of doses that have been confirmed to be safe in single 
dosing, and that can be reliably expected to suppress serum testosterone levels within 
48 hours. Given that TAK-385 is going to be used in patients with prostate cancer, 
the company concluded that it would be necessary to use a dose that could be 
expected to be effective from the beginning, and that this dose would be tolerated as 
the loading dose in Japanese. The maintenance dose was set at 80 mg, which can be 
expected to suppress serum testosterone levels.
(3) Rationale for endpoints
1) Rationale for the primary endpoints
The endpoint in Part A is DLT, in order to confirm the tolerability of TAK-385 in 
multiple dosing. AEs, clinical laboratory tests, vital signs, and 12-lead ECGs 
were also made primary endpoints, in order to confirm safety.
In part B, the primary endpoints were made AEs, clinical laboratory tests, vital 
signs, and 12-lead ECGs, in order to confirm the safety of the use of TAK-385 in 
multiple dosing for 48 weeks.
2) Rationale for secondary endpoints
In both Part A and Part B, the plasma concentrations of unchanged TAK-385 will 
be investigated in order to confirm the PK of TAK-385 in multiple dosing. The 
change in serum testosterone levels over time will also be investigated, in order to 
confirm the pharmacodynamics. In addition, in Part B, PSA levels will also be 
evaluated in order to investigate the efficacy of TAK-385 in prostate cancer.
3) Rationale for other endpoints
In Part A, the changes over time in the blood levels of LH, FSH, DHT, and SHBG, 
which are involved in testosterone synthesis, will be investigated. PSA levels will 
also be evaluated, in order to preliminarily investigate the efficacy of TAK-385 in 
prostate cancer.
In Part B, disease progression assessed on the basis of PSA and disease 
progression assessed on the basis of imaging assessments will be evaluated in 
accordance with the Prostate Cancer Handling Guidelines, Fourth Edition [16], in 
order to preliminarily investigate the efficacy of TAK-385 in prostate cancer. In 


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addition, as in Part A, the changes over time in the blood levels of LH, FSH, DHT, 
and SHBG will also be investigated. Moreover, because androgen-deprivation 
therapy is known to promote loss of bone mineral density and increase the 
potential for bone fractures, bone density tests were specified in order to evaluate 
the effects of TAK-385 on bone mineral density. In nonclinical studies, changes 
suggesting systemic phospholipidosis have been found in the organs/tissues of 
animals. Therefore, in order to closely monitor subjects for phospholipidosis, 
ophthalmology tests were specified, as was assessment of the level of di-
docosahexaenoyl (22:6)-bis(monoacylglycero)phosphate (BMP) [14, 15]. 
Furthermore, in order to evaluate the effects of TAK-385 on quality of life in 
patients with prostate cancer, quality of life assessments will be performed using 
the Japanese versions of AMS, EORTC-QLQ-C30, and EPIC, which are widely 
used in clinical studies overseas.
6.3
Premature Termination or Suspension of Study or Investigational Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug
that indicates a change in the known risk/benefit profile for the product, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

The SMC recommends that the study be suspended or terminated.

Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Investigational Sites
An investigational site may be terminated prematurely or suspended if the site (including 
the investigator) is found in significant violation of GCP, protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise 
permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)
In the event that the sponsor, an institutional review board (IRB)/independent ethics 
committee (IEC) or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All inclusion and exclusion criterial, including test results, need to be checked before 
study treatment initiation (Part A) or randomization (Part B).
7.1
Inclusion Criteria
Subject eligibility will be determined based on the following criteria.
1. Patients judged by the investigator to have the capacity to understand the study and 
follow the study rules.
2. Patients whose written consent (signature or printed name and personal seal on 
informed consent form) can be obtained before any study procedures are performed.
3. Japanese male patients 20 or more years of age at the time of informed consent.
4. Patients who, if they have a female partner who could become pregnant, agree to 
practice appropriate means of contraception from the time of informed consent 
throughout the entire study treatment period and for 4 months after the last dose of 
study drug.
5. Patients in stable medical condition, including the absence of acute exacerbations of 
chronic illnesses, serious infections, or major surgery within 4 weeks (28 days) prior 
to study treatment initiation.
6. Patients with histologically or cytologically confirmed prostate cancer.
7. Patients whose clinical diagnosis is T1-4 N0 M0, or Tx N0 M0 for patients who have 
undergone radical prostatectomy.
8. Patients who are considered eligible for hormone therapy for prostate cancer.
9. Patients who have not received hormone therapy (eg, GnRH agonist, GnRH 
antagonist, steroidal antiandrogen, non-steroidal androgen) for prostate cancer.
10. Patients who have not undergone surgical castration.
11. Patients with serum testosterone at screening > 150 ng/dL.
12. Patients meeting either of the following criteria for PSA at screening.
Untreated prostate cancer:
PSA at screening > 4.0 ng/mL
Treated* prostate cancer:
PSA at screening > 0.2 ng/mL
*: Patients who have undergone prostatectomy or either or both of high intensity focused ultrasound 
therapy or radiotherapy (excluding 125I-brachytherapy) prior to the start of this study.
13. Eastern Cooperative Oncology Group (ECOG) performance status [17] of 0 or 1 
(Appendix G)
14. Body mass index (BMI*) at screening ≥18.0 kg/m2
*: BMI will be calculated by the investigational site using the following formula: BMI = Body weight 
(kg)/(height (m))2


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Body weight will be measured in kilograms to the first decimal point, height will be measured in 
centimeters using integers only, and the results obtained for BMI will be rounded off to the first decimal 
point.
Example: Weight = 79.2 (kg), height = 176 (cm) = 1.76 (m); BMI = 79.2/1.762 = 25.6 (kg/m2)
7.2
Exclusion Criteria
Patients meeting any of the following criteria will be excluded from the study.
1.
Patients exhibiting symptoms judged related to prostate cancer by the investigator 
(eg, bone pain, pelvic pain, ureteral obstruction) who urgently require hormone 
therapy such as GnRH agonist, GnRH antagonist, or combined androgen blockade 
(CAB)/ maximum androgen blockade (MAB) therapy, chemotherapy, or 
radiotherapy.
2.
Patients who have received 5-alpha reductase inhibitors (except for patients who 
have been treated for male-pattern alopecias).
3.
Patients who have received chemotherapy for prostate cancer (including 
estramustine).
4.
Patients who have received 125I-brachytherapy.
5.
Patients who received radiotherapy (except for 125I-brachytherapy) within 16 weeks 
(112 days) before study treatment initiation.
6.
Patients who underwent prostatectomy within 16 weeks (112 days before study 
treatment initiation.
7.
Treatment with any investigational compound within the 4 weeks (28 days) prior to 
the first dose of study drug or ongoing participation in another experimental trial 
related to the treatment of prostate cancer.
8.
Diagnosis or treatment for another systemic malignancy within 2 years before study 
treatment initiation, or who had received a diagnosis of another malignancy before 
that and have evidence of residual disease. Patients with non-melanoma skin cancer 
or carcinoma in situ who have undergone complete resection will not be excluded 
from the study.
9.
Patients taking drugs with moderate to strong CYP3A4 inhibitory or inducing 
effects, or any medications, supplements, or food products with P-gp inhibitory 
effects, in the 2 weeks (14 days) prior to study treatment initiation.
10. Patients who have received TAK-385 in a past clinical study.
11. Patients for whom it would be difficult to collect blood from a peripheral vein.
12. Patients with uncontrolled and clinically significant nervous, circulatory, pulmonary, 
hepatic, renal, metabolic, gastrointestinal, urogenital, or endocrine disorders, or other 
abnormalities (except for the targeted disease) that could affect study participation or 
the study results. Also, patients meeting any of criteria a through c below.


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a. Patients with uncontrolled diabetes (HbA1c > 8% at screening). However, 
patients whose HbA1c is brought under control with diabetes medications may be 
rescreened.
b. Patients with uncontrolled hypertension (systolic blood pressure > 150 mmHg and 
diastolic blood pressure > 90 mmHg at 2 separate measurements taken no more 
than 60 minutes apart at screening). Patients whose blood pressure is brought 
under control by antihypertensive medication may be rescreened.
c. Patients with myocardial infarction, unstable symptomatic ischemic heart disease, 
arrhythmias of CTCAE Grade > 2, thromboembolism (deep vein thrombosis, 
pulmonary embolism, or symptomatic cerebrovascular events), or other heart 
diseases (eg, pericardial effusion, restrictive cardiomyopathy). However, chronic 
stable atrial fibrillation controlled by stable anticoagulant therapy will be allowed.
13. Patients with bilateral hydronephrosis or bladder neck outlet obstruction.
14. Known hypersensitivity to TAK-385, TAK-385 excipients, or GnRH antagonists.
15. Patients with a past history of gastrointestinal tract treatments (including 
gastrectomy) or gastrointestinal disease that could affect the drug absorption or 
tolerability (malabsorption, esophageal reflux, peptic ulcer, erosive esophagitis).
16. Patients positive for hepatitis B surface antigens (HBsAg), hepatitis C virus (HCV) 
antibodies, human immunodeficiency virus (HIV) antibodies, or serologic test for 
syphilis, or with life-threatening disease other than cancer, at screening.
17. Clinically relevant ECG abnormalities, or the following ECG abnormalities, at 
screening.
a. Q-wave infarction, unless identified 6 or more months prior to TAK-385 treatment 
initiation
b. QTcF interval > 450 msec (when calculating the QTc interval, Fridericia’s 
equation [QT/RR0.33] will be used)
18. Patients with congenital QT prolongation.
19. Current use of Class 1A or Class 3 antiarrhythmic medications.
20. New York Heart Association [18] Class III or IV heart failure (Appendix H).
21. Patients with clinical laboratory abnormalities suggesting clinically relevant 
underlying disease, or with any of the following abnormal results, at screening.
•
Serum creatinine ≥2.0 mg/dL
•
ALT or AST ≥1.5 ULN for the investigational site
•
Total bilirubin ≥2 ULN for the investigational site
•
Neutrophil count < 1,500/mm3, platelet count < 100,000/μL, hemoglobin 
< 10.0 g/dL


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•
Results of heart-related tests (creatine kinase MB [CK-MB] and cardiac troponin 
T) exceeding the investigational sites reference value.
22. Patients found to have clinical problems on the basis of examination findings, ECG 
findings, or chest X-ray findings at screening.
23. Patients considered unlikely by investigators to be able to follow the study protocol 
or considered ineligible for the study by investigators for other reasons.
7.3
Prohibited Concomitant Medications, Therapies, and Foods
7.3.1
Prohibited Concomitant Medications
The concomitant use of the following medications will be prohibited during the treatment 
period out of concern for the effects on safety, PK, and pharmacodynamics. Furthermore, 
in Part A, the prohibited concomitant medications may not be used until the end of the 
post-treatment observation period.

GnRH agonists

GnRH antagonists

Steroidal antiandrogens

Nonsteroidal antiandrogens

Drugs that include corticosteroids (except for topical drugs)

Male sex hormone preparations

Female sex hormone preparations

5α reductase inhibitors

Docetaxel

Other chemotherapy drugs indicated for prostate cancer

Drugs with moderately powerful to strongly powerful CYP3A4 inhibitory or inducing 
effects

Drugs with P-gp inhibitory effects
7.3.2
Prohibited Concomitant Therapies
The following therapies for prostate cancer will be prohibited from study treatment 
initiation until the end of safety follow-up.

Surgical castration

Prostatectomy

High-intensity focused ultrasound therapy

Radiotherapy


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7.3.3
Food
From study treatment initiation and during the treatment period (in Part A, until the end 
of the post-treatment observation period), the use of nutritional supplements and the 
consumption of grapefruit and related beverages/foods will be prohibited unless judged 
necessary by the investigator.
7.4
Subject Management
1. Inpatient/outpatient status
Subjects will be admitted to the investigational site from one day before treatment 
initiation in each cohort (Day -1) until Day 15 in Part A. As a rule, from Day 16 on, 
the study will be conducted on an outpatient basis until the safety follow-up. 
However, from Day 27 on, if a subject lives far from the hospital and it would be 
difficult for the subject to come to the hospital at the scheduled times, or if the 
subject desires admission, the study may be conducted on an inpatient basis from 
Day 27 until Day 35 at the latest. While subjects are inpatients in Part A, they will eat 
meals (breakfast, lunch, and dinner) at specified times. After being discharged as 
well, subjects will be instructed to avoid eating or drinking excessively until the end 
of safety follow-up. When subjects are coming in for visits on an outpatient basis, 
they will be instructed to be sure to eat dinner on the day before the day of a visit at 
which a blood sample will be collected for laboratory testing, and they will be 
instructed to return to the hospital on the following day without eating for blood 
collection and testing, after which they will receive TAK-385 and then eat breakfast 
at least 30 minutes later.
If a subject desires to return home temporarily during the inpatient period, and it 
would not interfere with study treatment, observations, or tests, then the investigator 
may allow the subject to return home temporarily, after carefully checking to be sure 
that the subject’s condition is stable, on the basis of the data that have been collected 
during the study to that point.
Unless there is a special reason, Part B will as a rule be conducted on an outpatient 
basis. Subjects will be instructed to observe the scheduled visit times and undergo 
the examinations and the specified tests. Subjects will also be instructed to inform 
the investigator promptly if they are not able to come in for a scheduled visit.
2. Study treatment
Investigators will instruct subjects to take the study drug 30 minutes before breakfast 
on each day, and to make sure that the time they take the study drug is the same on 
each day, to the extent possible.
If a subject forgets to take the study drug 30 minutes before breakfast, the subject 
should take the drug 30 minutes before lunch on the same day. If a subject forgets to 
take the study drug both 30 minutes before breakfast and 30 minutes before lunch, 
the subject should take the study drug 30 minutes before dinner on the same day. It 
will be explained to subjects that they should not take any study drug that they have 
forgotten to take on a later day together with the study drug for that day. Subjects 


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will also be instructed to be sure to note in the patient diary the time they took the 
study drug as well as whether or not they took the study drug 30 minutes before 
breakfast.
On scheduled outpatient visit days, subjects will be asked to come to the 
investigational site in the morning without taking the study drug, and the scheduled 
tests will be performed.
3. Drinks, etc.
On days on which study drug is to be taken, subjects will be prohibited from drinking 
anything from 1 hour before dosing until 30 minutes after, other than one cup of 
water when they take the study drug.
4. Other
Investigators will instruct subjects that, if a subjective symptom emerges, it should 
be reported, along with the date of onset, severity, outcome, and date of outcome, 
when the subject next visits the investigational site.
Investigators will instruct subjects not to take any drugs, including over-the-counter 
drugs, other than the drugs that they are instructed to take, without consulting the 
investigator in advance.
Subjects will be instructed that, if they are treated at another medical institution in 
the time between the treatment period and the safety follow-up, they are to report the 
background for and nature of said treatment to the investigator, and to inform the 
medical institution in question that they are participating in a clinical study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Investigators will enter into the electronic case report form (eCRF) the primary reason for 
discontinuation or withdrawal of the subject from the study, classified into one of the 
following categories. See Section 9.1.23 for subjects discontinuing before the study 
treatment initiation (in the case of Part A) or before randomization (in the case of Part B).
1.
Pretreatment event or adverse event
This will be considered the primary reason if the subject has experienced a PTE or 
AE that requires early termination because continued participation imposes an 
unacceptable risk to the subject’s health or the subject is unwilling to continue 
because of the PTE or AE; if a serious AE occurs, the subject temporarily stops 
taking the study drug, and the AE recurs following study treatment resumption, or 
does not resolve event after 2 weeks of treatment interruption; or if toxicity that is 
considered DLT occurs in Part A.
Liver function test abnormalities
If a LFT abnormality meeting any of the following criteria occurs during study 
treatment, study drug administration will be discontinued immediately, and 
appropriate follow-up tests will be performed until the subject’s clinical laboratory 
profile returns to normal, to the level of the first test value obtained after informed 


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consent (in the case of a PTE), or to baseline (in the case of an AE) (see Section 
9.1.8).
-
ALT or AST > 3 ULN; AND total bilirubin > 2 ULN or PT-INR > 1.5
2.
Major protocol deviation
This will be considered the primary reason for study withdrawal if it is discovered 
after the first dose of study treatment (in the case of Part A) or after randomization 
(in the case of Part B) that the subject does not meet the enrollment criteria specified 
in the study protocol, or has not followed the study protocol, and that continuing the
study would pose an unacceptable risk to the subject's health.
3.
Lost to Follow-up
This will be considered the primary reason for study withdrawal if a subject fails a 
study visit and cannot be contacted. In this case, the fact that contact was attempted 
will be noted in the source documents.
4.
Voluntary withdrawal
This will be considered the primary reason for withdrawal if the subject wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded 
in the eCRF.
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(ie, withdrawal due to an AE or lack of efficacy should not be recorded in the 
“voluntary withdrawal” category).
5.
Study termination
This will be considered the primary reason for withdrawal if the sponsor, IRB, or 
regulatory authorities decide to terminate the study.
6.
Lack of efficacy
This will be considered the primary reason for withdrawal if the expected level of 
efficacy is not obtained because of disease progression assessed by PSA level or 
evaluation of soft tissue or bone lesions by diagnostic imaging (according to the 
Prostate Cancer Handling Guidelines, Fourth Edition [16]), or if the decrease in 
serum testosterone meets any of the following criteria.
1) If, in Part A, serum testosterone does not drop below 50 ng/dL at 2 or more time 
points at least 7 days apart following treatment initiation, and it is determined as 
a result that the patient must be switched to some other therapy.
2) If, in Part B, serum testosterone does not drop below 50 ng/dL by 4 weeks after 
uptitration based on the uptitration criteria (see Section 8.1.3.1).
3) If, in Part B, serum testosterone exceeds 50 ng/dL on 2 consecutive occasions, or 
on 3 occasions in total, whether consecutive or not, by 9 weeks (57 days) after 
the start of treatment following uptitration in accordance with the uptitration 
guidelines (see Section 8.1.3.1).


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7.6
Procedures for Discontinuation or Withdrawal of a Subject 
If a subject meets the criteria described in Section 7.5, the investigator will withdraw the 
subject from the study. Furthermore, subjects may withdraw from the study without 
providing a reason at any time during the study. If a subject withdraws from the study, 
the investigator will enter the primary reason for withdrawal in the eCRF, and will 
perform all procedures scheduled for the Early Termination Visit.


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8.0
STUDY DRUG MANAGEMENT
This section contains information regarding all study drugs provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material.
8.1
Study Drug
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Investigational Drug
(1) Investigational drug name: TAK-385
(2) Chemical name
N-(4-{1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-3-
(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl}phenyl)-N'-
methoxyurea
(3) Dosage forms and doses
TAK-385 40 mg tablets: Each tablet contains 40 mg as TAK-385
TAK-385 80 mg tablets: Each tablet contains 80 mg as TAK-385
There are two types of study drug, described above; both are light red, film-coated 
tablets.
(4) Packaging and labeling
Each dosage form comes packaged 40 tablets to a bottle. The label clearly states that 
the drug is for use in a clinical study, and also bears the drug name, protocol number, 
name and address of the study sponsor (or company that manufactured the drug), 
manufacturing number, and storage method (Figure 8.a).


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For Use in a Clinical Study
TAK-385  40 mg Tablets (or 80 mg Tablets)
For oral administration
Contains 40 tablets
Protocol number: TAK-385/TB-AK160108
Manufacturing number: 
Storage method: Room temperature (1-30C)
Expiration date: See the study drug control procedures
Unused study drug and used bottles will be collected by the study 
sponsor; do not discard.
Takeda Pharmaceutical Company
4-1-1 Doshomachi, Chuo-ku, Osaka
Figure 8.a
Sample TAK-385 Bottle Label
8.1.1.2
Drugs not Provided by the Study Sponsor
No drugs will be provided other than the study drug and drugs such as GnRH agonists 
and/or GnRH antagonists following the completion (or discontinuation) of TAK-385 
administration.
8.1.2
Storage
TAK-385 will be stored at room temperature (1-30C).
Investigational drug must be stored in an appropriate, limited-access, secure place until 
they are used or until they are returned to the sponsor or a designee for destruction.
Investigational drug must be stored under the conditions specified on the label, and must 
remain in their original containers until dispensed. The daily temperature log of the drug 
storage area must be maintained every working day.
8.1.3
Dose and Regimen
Table 8.a shows the dosage and number of tablets in Part A (by cohort), and Table 8.b
shows the dosage and number of tablets in Part B (by treatment group).


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Table 8.a
Cohorts, Dosages, and Numbers of Tablets (Part A)
Cohort
Dosage/Number of Tablets
1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Days 2 to 28): One 80 mg tablet per day
2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Days 2 to 28): One 80 mg tablet and one 40 mg tablet per day
3
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 160 mg (Days 2 to 28): One 80 mg tablet and two 40 mg tablets per day
Additional 
cohort*1
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Days 2 to 28): One 40 mg tablet per day
*1: Added if tolerability is not confirmed in Cohort 2
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B)
Treatment 
Group
Dosage/Number of Tablets
80 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Day 2 to Week 48*3): Two 40 mg tablets per day
120 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Day 2 to Week 48*3): One 80 mg tablet and one 40 mg tablet per day
40 mg*2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Day 2 to Week 48*3): One 40 mg tablet per day
At uptitration
One TAK-385 40 mg tablet per day will be added
*2: If no problems with tolerability are found in the additional cohort in Part A
*3: Treatment may be continued for up to 96 weeks in total
The specified dose of TAK-385 will be taken once a day orally with 1 cup of water at 
least 30 minutes before breakfast. Except for when various tests are being performed or 
an AE occurs, an effort will be made to ensure that subjects rest for 2 hours after 
receiving the dose.
The investigator or study support staff will check to make sure that all specified study 
drug has been taken.
8.1.3.1
Criteria for Upward Dose Adjustments
Part A: The dose of TAK-385 will not be increased even if inadequate testosterone 
suppression occurs (< 50 ng/dL). If after treatment initiation the serum testosterone level 
does not drop below 50 ng/dL at 2 or more time points separated by at least 7 days and 
the investigator or sub-investigator determines that the patient needs to be switched to 
some other treatment, then TAK-385 treatment will be stopped and the patient withdrawn 
from the study.


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Part B: If the following conditions are met, the dose may be adjusted, taking efficacy and 
safety into consideration. Dose adjustment will be performed when the subject is 
examined by the investigator or sub-investigator.
If the serum testosterone level in an individual patient exceeds 50 ng/dL at Week 5 (Day 
29), Week 9 (Day 57), or Week 13 (Day 85), following review of compliance, a one-time 
upward dose modification (increment of 40 mg daily) will be allowed. After Week 13, 
the dose will not be increased even if the serum testosterone level exceeds 50 ng/dL.
The dose will not be increased in the 120 mg group before the DLT evaluations have been 
completed for Cohort 3 in Part A, or if the dose has not been found to be tolerable. 
Similarly, if tolerability is not found in Cohort 2 in Part A and a 40 mg group is therefore 
going to be used instead of a 120 mg group, then the dose in the 80 mg group will not be 
increased.
8.1.3.2
Criteria for Dose Holds and Dose Reduction
Part A: If a treatment-related AE occurs, or if it would be difficult to continue with 
TAK-385 treatment, then the dose of TAK-385 will not be reduced, and study treatment 
will be interrupted if necessary.
Part B: If a treatment-related AE occurs or if it would be difficult to continue with 
TAK-385 treatment, then study treatment will be interrupted if necessary. Subjects who 
experience serious AEs requiring study treatment interruption within 12 weeks (84 days) 
following treatment initiation may have their doses reduced by one dose level – 40 mg –
following a 2-week treatment interruption period. If the AE continues even after dose 
reduction, or the subject’s serum testosterone level exceeds 50 ng/dL for 4 to 6 weeks 
following dose reduction, then TAK-385 treatment will be discontinued so that the 
subject may receive some other therapy. If a serious AE requiring study treatment 
interruption occurs on or after Week 13 (Day 85) following treatment initiation, and the 
subject’s treatment has not been interrupted prior to that, then the subject’s treatment may 
be interrupted for 2 weeks and then resumed. However, if the AE recurs following study 
treatment resumption, or if the AE does not resolve even after 2 weeks of treatment 
interruption, then the subject will be withdrawn from the study.
Even if the dose has been increased in accordance with Section 8.1.3.1, when reducing 
the dose, it will be reduced by one dose level. Dose reduction will not be performed for 
subjects in the 40 mg group. In addition, if the dose is reduced in accordance with this 
section, then the dose may not be increased as described in Section 8.1.3.1.
Furthermore, if a LFT abnormality is found, it will be handled as shown in Table 8.c.


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Table 8.c
Guidelines for Handling Liver Function Test Abnormalities
Category ALT, AST, and Total 
Bilirubin
Study Drug
ALT and AST Tests Treatment 
Interruption
Dose 
Adjustment
A
ALT or AST ≥1.5 ULN 
to < 3 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week for 2 weeks, 
and then every 2 
weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
B
ALT or AST ≥3 ULN to 
< 5 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week, and then every 
2 weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
C
ALT or AST ≥5 ULN to 
< 8 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests in the 
first week, then every 
week for 2 weeks, 
and then every 2 
weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg
D
ALT or AST ≥8 ULN to 
< 20 ULN
AND
Total bilirubin <1.5 ULN
Interrupt 
treatment
Perform 2 tests a 
week for the first 2 
weeks, and then every 
2 weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg*2
E
ALT or AST ≥3ULN
AND
Total bilirubin > 2 ULN
(Hy’s law)
Permanently 
discontinue 
treatment
Perform 2 tests a 
week until the test 
values drop, and then 
every week until 
stable*1
N/A
N/A
*1: Stable means ALT and AST both CTCAE Grade 1 (> ULN to 3 ULN)
*2: The study sponsor should be consulted before resuming treatment.
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of 
investigational drug, to or by a study subject, at a dose above that which is assigned to 
that individual subject according to the study protocol.
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the eCRF, in order to capture this important safety information 
consistently in the database. Cases of overdose without manifested signs or symptoms are 
not considered AEs. AEs associated with an overdose will be documented on AE CRF(s) 
according to Section 10.0.
Serious AEs associated with overdose should be reported according to the procedures 
outlined in Section 10.2.2.
In the event of a study drug overdose, the investigator will treat the subject 
symptomatically.


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8.2
Study Drug Allocation and Prescribing Procedures
In Part A, in order to confirm eligibility for study participation based on the screening 
tests, the investigator or a person designated by the investigator will contact the 
registration center by fax. The investigator will prescribe study drug to the subject after 
confirming that the subject is eligible for the study based on a fax received from the 
registration center.
In Part B, the investigator or a person designated by the investigator will contact the 
registration center by fax to confirm the subject’s eligibility at the start of the treatment 
period.  After confirming, on the basis of a fax received from the registration center, that 
the subject is eligible, the investigator will prescribe the subject the study drug for the 
group to which the subject has been assigned. The investigator or a person designated by 
the investigator will enter the group to which the subject has been assigned in the eCRF.
Subjects will be assigned a 4-digit number, with the first signifying the Part and Cohort, 
the second signifying the investigational site, and the last two digits constituting a series 
number within the cohort at the investigational site. This 4-digit number will be used by 
the investigational sites to identify the specimens that will be used to assess the PK and 
pharmacodynamics. These numbers will be noted on the specimen tubes that are 
provided for measurement, and will be used instead of the subject identification numbers 
for reporting the measurement results. These numbers will not be replaced by the last 3 
digits of the subject identification numbers.
8.3
Randomization Code Creation and Storage
The randomization manager (or a person designated by the study sponsor) will prepare a 
randomization table. The randomization information will be stored in a safe location, and 
will only be accessible to authorized personnel.
8.4
Control and Disposal of Drugs Provided by the Study Sponsor
The study drug controller will receive the written procedures prepared by the study 
sponsor specifying the handling, storage, and control of study drug, and will 
appropriately control the drugs provided by the study sponsor in accordance with these 
written procedures. The investigators will also receive these procedures from the study 
sponsor. These procedures will describe the procedures that will have to be followed to 
ensure that the receipt, handling, storage, control, and prescribing of the study drugs 
provided by the study sponsor, as well as the recovery of unused drugs from subjects and 
their return to the study sponsor, or their disposal, are carried out appropriately and 
reliably.
The study drug controlled will promptly return to the study sponsor any unused drugs 
once the study has been completed at the investigational site in question.


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9.0
STUDY PLAN 
9.1
Study Proceduress
The following sections describe the study procedures and data to be collected. In 
principle, the same investigator will perform examinations and testing, observations, and 
evaluations of subjects. The Schedule of Study Procedures is shown in Appendix A to 
Appendix E.
9.1.1
Informed Consent
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained from the subject before any protocol-directed 
procedures are performed.
A unique subject identification number will be assigned to each subject at the time that 
informed consent is explained. The same subject number will be used throughout the 
study.
Informed Consent for Pharmacogenomics
Informed consent for the storage and banking of the blood sample for pharmacogenomics 
(PGx) testing in this study must be obtained separately before collection. The provision 
of consent to collect and analyze the PGx sample is independent of consent to the other 
aspects of the study.
9.1.2
Demographics, Medical History, and Treatment History
Demographic data will include date of birth, sex, and smoking history at screening. The 
items listed below will be checked with regard to prostate cancer [16]. The findings will 
be input to the eCRF.

Date of diagnosis and diagnostic method used

Gleason classification (pattern 1 to 5 and score) at most recent assessment and date of 
assessment

Tissue type and extent of differentiation

Treatment history (including medication history)

TNM classification (at time of diagnosis)

Prostatectomy yes/no, total resection yes/no, date of surgery

High intensity focused ultrasound yes/no, completion date

Radiation therapy yes/no, completion date

History of other therapy yes/no, mode of therapy, start date, completion date
The medical history will include clinically relevant diseases or conditions associated with 
the targeted disease that disappeared or ended within the past 1 year from the date of 


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informed consent. If a symptom or disease is still present, it will be considered a 
comorbidity (concurrent medical condition) (see Section 9.1.18).
Previous therapeutic drugs used (medication history) will include all drugs that were 
discontinued within 28 days before the date of informed consent and are relevant to the 
eligibility criteria.
9.1.3
Physical Examination
A physical examination will be conducted for the parts of the body listed below 
(interview, visual inspection, auscultation, palpation, percussion, etc.).
(1) eyes, (2) ears, nose, and throat, (3) cardiovascular system, (4) respiratory organs, 
(5) digestive organs, (6) skin, (7) extremities, (8) musculoskeletal system, (9) nervous 
system, (10) lymph nodes, (11) urogenital organs, (12) other
The investigator will evaluate abnormal findings discovered in the pre-administration 
physical examination for clinical relevance and record the results in the source data. 
Findings and changes considered to be clinically relevant will be input as PTEs or 
comorbidities at the proper locations in the source data and eCRF as described in 
Sections 10.0 and 9.1.18.
9.1.4
Weight, Height, and ECOG Performance Status
Weight and height will be measured. Weight will be measured in kilograms to the first 
decimal place, and height will be measured in centimeters to the closest integer. In 
addition, the ECOG performance status will be measured in accordance with Appendix G.
9.1.5
Vital Signs
Measurement of vital signs will include temperature (axillary), seated blood pressure 
(systolic and diastolic after resting at least 5 min) and heart rate (bpm). Measurements 
will be taken after the subject has been sitting for 5 min.
9.1.6
Electrocardiogram
A 12-lead ECG will be performed. Measurements will be taken after the subject has been 
in supine position for 5 min. The investigator (or a specialist at the medical institution) 
will assess the results by the following categories: Normal range ("Within Normal 
Limits"), Abnormal but not clinically significant ("Abnormal, Not Clinically Significant
"), or Abnormal and clinically significant ("Clinically Significant ").
The following parameters will be transferred from the subject's ECG recording to the 
eCRF: heart rate, QT interval, PR interval, QRS duration, and RR interval.
In determining the QTc value, Bazett corrected QT (QTcB) and QTcF will be calculated 
using the Bazett formula (QT/RR0.5) and Fridericia formula (QT/RR0.33), respectively.
9.1.7
Imaging Assessment
CT or MRI (thoracic, abdominal, and pelvic regions) and bone scintigraphy will be 
performed during screening to verify that there are no distant metastatic lesions. If 


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measurements were taken within 28 days before the start of study drug administration, 
the results of diagnostic imaging and tests conducted before obtaining informed consent 
can be used. CT or MRI and bone scintigraphy will also be performed on the days 
stipulated in the clinical trial schedule (Appendix A to Appendix C) to check for new 
lesions. Disease progression will be determined by the presence or absence of new 
lesions based on the items evaluated in diagnostic imaging. Diagnostic imaging will also 
be performed as needed in Part A if abnormal findings appear in other tests and 
examinations during administration of the study drug.
9.1.8
Clinical Laboratory Tests
Specimens will be handled according to the procedures described in a separate document. 
A general guideline for the total amount of blood to be collected in this study is shown in 
Section 9.5.
Samples for clinical laboratory tests will be collected after at least 10 hours of fasting on 
the days stipulated in the Schedule of Study Procedures (Appendix A to Appendix E). 
Samples to be collected for each laboratory test are shown in Table 9.a.
Table 9.a
Clinical Laboratory Tests
Hematology
Chemistry
Metabolic Panel
Urinalysis
RBC
WBC
Hemoglobin
Hematocrit
Platelet count
Differential WBC 
(neutrophils [including 
absolute count], 
basophils, eosinophils, 
lymphocytes, 
monocytes)
Total protein
Albumin
Glucose
Creatinine
BUN
Uric acid
Total bilirubin
ALT
AST
LDH
-GTP
ALP
CK (CPK)
Na
K
Cl
Ca
P
PT-INR
Triglycerides
Total cholesterol
HDL cholesterol
LDL cholesterol
TSH
HbA1c
pH
Specific gravity
Protein (qualitative)
Glucose (qualitative) 
Occult blood 
(qualitative)
Ketones (qualitative)
Urobilinogen 
(qualitative)
Bilirubin (qualitative)
Tests to be conducted when determining eligibility
(to be performed only when deemed necessary)
HIV test; hepatititis tests including HBsAg and anti-HCV; serologic test for syphilis


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The above clinical laboratory tests will be performed at the medical institution. The 
investigator will evaluate and archive reported clinical laboratory test findings.
When the ALT or AST levels are > 3 ULN, retesting (at least ALP, ALT, AST, total 
bilirubin, γ-GTP, and PT-INR) will be performed within 48 to 72 hours (within 7 days at 
the latest).
(See Section 7.5 for the criteria for the withdrawal from the study.  See Section 10.2.3 for 
the reporting of LFT abnormalities in cases where the ALT or AST level exceeds 3 
ULN, and the total bilirubin level exceeds 2 ULN or the PT-INR exceeds 1.5.)
The investigator will archive the reference ranges for the clinical laboratory tests, 
including the history.
All clinically relevant, abnormal laboratory test values will be input in the source data 
and eCRF of the subject as AEs, etc. All clinically relevant, abnormal laboratory test 
values verified by retesting will be followed up in all subjects until the abnormal value 
returns to an acceptable level or there is a sufficient explanation for the observed change.
9.1.9
Cardiac Tests
CK-MB and cardiac troponin T will be measured at the institution during screening. 
These measurements will also be performed as needed when abnormal findings appear in 
other tests and examinations during administration of the study drug.
9.1.10
Tumor Marker
PSA will be measured by a third-party organization according to a separately prepared 
written procedure. Progression of disease as indicated by PSA (based on the Prostate 
Cancer Handling Guidelines, 4th Edition [16]) is defined as an increase of at least 25% in 
the PSA value measured at least 4 weeks after the minimum PSA value measured during 
the study period (at least 12 weeks if the minimum value was recorded during screening). 
In such a case, the amount of increase must be at least 2 ng/mL. The date this condition 
is met will be considered the disease progression date.
9.1.11
Collection of Pharmacogenomic Sample
After the start of study drug administration (Part A) or after randomization (Part B), one 
sample for PGx testing will be collected as early as possible during the administration 
period. A sample of 5 mL of whole blood for DNA extraction will be collected in an 
EDTA-treated polypropylene tube from each subject who has given consent. The sample 
will be sent to the sample storage facility.
Details of collection, handling, and storage of the sample for PGx testing will be carried 
out according to a separately prepared written procedure.


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9.1.12
Bone Mineral Density (Part B Only)
Bone mineral density will be measured by dual-energy X-ray absorptiometry (DXA). 
Throughout the study period the same subject will be measured on the same model of 
equipment using the same scanning mode. The investigator will input the equipment 
model, date of measurement, and results for the following measurement parameters into 
the eCRF.
Measurement sites: Lumbar 2 to 4 (L2 to L4) and hip (femoral neck, femoral trochanteric, 
femoral intertrochanteric, Ward's triangle, and total) 
Measurement parameters: Bone mineral content (BMC, g), bone area (Area, cm2), and 
bone mineral density (BMD, g/cm2) of L2, L3, and L4, femoral neck, femoral 
trochanteric, and femoral intertrochanteric regions, and Ward's triangle; and total bone 
mineral content (BMC, g) (combined), bone area (Area, cm2) (combined), and bone 
mineral density (BMD g/cm2) (Mean) of L2 to L4 and hip.
9.1.13
Ophthalmological Examination (Part B Only)
The examination will be carried out in a darkened room. A slit lamp microscope will be 
used to examine the anterior of the eye, and the results will be classified as follows: 
Normal range, Abnormal but not clinically significant, or Abnormal and clinically 
significant.
9.1.14
BMP Concentrations (Part B Only)
BMP will be measured in serum and urine samples by a third-party organization 
according to a separately prepared written procedure. Sequential BMP testing will not be 
performed, and the measurements will be summarized after a fixed time period.  
Measurements will be conducted when there are clinical findings suggesting an 
association with phospholipidosis or there is a report of an association between 
comparable GnRH antagonists and phospholipidosis.
9.1.15
QOL Assessment (Part B Only)
QOL will be assessed using AMS, EORTC-QLQ-C30, and EPIC scores. After arriving at 
the hospital each subject will personally fill in the form provided by the sponsor before 
other tests are conducted and before the study drug is administered. The scoring of QOL 
will be carried out in the order: AMS, EORTC-QLQ-C30, and EPIC.
9.1.16
Concomitant Medications
The term concomitant medication is refers to any drug given in addition to the study drug. 
These may be prescribed by a physician or obtained by the subject over the counter. At 
each study visit, subjects will be asked whether they have taken any medication other 
than the study drug (used from signing of informed consent through safety follow-up), 
and all medication including vitamin supplements, over-the-counter medications, and oral 
herbal preparations, must be recorded in the eCRF.


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9.1.17
Concomitant Therapies
The term concomitant therapy refers to a medical act carried out for a therapeutic purpose.
At each study visit, subjects will be asked whether they have received any therapeutic 
procedures (performed from signing of informed consent through safety follow-up).
9.1.18
Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent. This includes clinically significant laboratory, 
ECG, or physical examination abnormalities noted at screening examinations. The details 
of the condition (ie, diagnosis) should be recorded in the eCRF.
9.1.19
Contraception
Male subjects with female partners who may become pregnant will use a barrier-type 
contraceptive device (eg, condom and spermicidal cream or jelly) from the time of 
informed consent until 4 months after the final dose of the study drug. Furthermore, the 
subject will be instructed not to donate sperm during this time frame.
9.1.20
Pregnancy
If the subject's female partner becomes pregnant, the investigator, with the female 
partner's consent, will inform her attending physician (obstetrician) that the subject was 
participating in a clinical study when she became pregnant and reveal the details of the 
study drug.
If a pregnancy is reported for any subject, the investigator, with the subject's consent, will 
carry out a follow-up investigation until delivery, including premature delivery, and make 
a report to the sponsor using the designated follow-up form. The investigator will also 
conduct a postnatal evaluation.
9.1.21
Pharmacokinetic Assessments
The plasma concentrations will be measured at each blood sample collection time point 
(see Appendix D and Appendix E) in accordance with separately prepared written 
procedures.
The 3 time points for TAK-385 dosing that immediately precede blood sample collection, 
and the time points for the collection of blood samples for pharmacokinetic assessment, 
will be entered into the eCRF.
9.1.22
Pharmacodynamic Assessments
Serum testosterone, LH, FSH, DHT, and SHBG will be measured by an external 
measurement facility in accordance with separately prepared written procedures. Serum 
testosterone will be measured along with other highly sensitive measurements at 
specified time points (see Appendix B). Detailed information about the treatment and 
shipment of samples will be provided in the aforementioned written procedures as well.


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9.1.23
Documentation of Subjects Withdrawing From the Study Prior to Study 
Treatment Initiation or Prior to Randomization
The principal investigators will be responsible for all subjects who sign informed consent. 
Investigators will prepare eCRFs for all subjects who withdraw from the study prior to 
study treatment initiation or randomization.
The primary reason for withdrawal from the study prior to study treatment initiation (in 
the case of Part A) or prior to randomization (in the case of Part B) will be entered into 
the eCRF based on the following categories.
PTE / AE
Does not meet inclusion criteria or meets exclusion criteria < The reason will be 
entered. >
Major deviation from the study protocol
Follow-up impossible
Spontaneous withdrawal < The reason will be entered. >
Entire study discontinued
Other < The reason will be entered. >
The subject identification numbers of subjects withdrawing from the study will not be 
reused.
9.1.24
Documentation of Study Enrollment/Randomization
In Part A, only subjects who meet all of the inclusion criteria and do not meet any of the 
exclusion criteria will be enrolled in the treatment period. If a subject cannot proceed to 
the treatment period, the investigator will enter the primary reason for this in the eCRF.
In Part B, only subjects who meet all of the inclusion criteria and do not meet any of the 
exclusion criteria will be randomized. If a subject cannot be randomized, the investigator 
will enter the primary reason for this in the eCRF.
9.2
Monitoring Subject Treatment Compliance
During the inpatient period in Part A, the investigator or a person designated by the 
investigator will give the subject the study drug, confirm that the subject has taken it, and 
record this in the source documents. For study drug administration following discharge 
from the investigational site, subjects will be instructed to take the drug appropriately.
On the day of the first dose in Part B, the investigator or a person designated by the 
investigator will administer the study drug to the subject, confirm that the subject has 
taken the drug, and record this in the source documents. For study drug administration 
from Day 2 on, subjects will be instructed to take the drug appropriately.
The day of treatment initiation, the day of treatment completion, the dose, the actions 
taken with respect to the dose, and the reasons for any changes will be entered in both the 
source documents and the eCRF.


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Subjects will be instructed to bring their study drug (bottles) in with them at each 
outpatient visit. If it is found that a subject has not complied with the study treatment in 
the time since the previous visit (eg, if 20% [6 doses] or more of the specified doses have 
not been taken), then the subject may be withdrawn from the study. If the subject is 
given instructions about treatment noncompliance, then this will be recorded in the 
source documents.
9.3
Schedule of Observations and Procedures
Appendix A through Appendix E show the schedules for all tests, observations, and 
assessments. Investigators will perform the tests, observations, and assessments shown 
below at the specified time points.
9.3.1
Screening
Observations and tests will be performed within 28 days prior to the first dose of study 
drug to confirm subject eligibility for study participation based on the inclusion and 
exclusion criteria presented in Section 7.0. See Section 9.1.23 for the preparation of 
records for subjects withdrawing from the study during screening.
The following tests, observations, and assessments will be performed at screening.
Informed consent
Demographics, medical history, concurrent medical condition, treatment history
Physical examination
Vital signs
Weight, height, and BMI
ECOG performance status

HBsAg, HCV, and HIV antibody and serologic test for syphilis
If the institutional review board judges it necessary, these tests will be performed only for subjects determined 
by the investigator to be at high risk for hepatitis B or C or HIV infection.
12-lead ECG
Chest X-ray examination
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Cardiac tests
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
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The following tests will be performed only in Part B.
Ophthalmological examinations
Bone mineral density
QOL assessments
9.3.2
Study Enrollment/Randomization
In Part A, subjects will be enrolled into each cohort by the day before study treatment 
initiation on the basis of the results of the aforementioned screening.
In Part B, subjects will be randomized by the day before study treatment initiation on the 
basis of the results of the aforementioned screening.
Subject who meet all of the inclusion criteria and do not meet any of the exclusion 
criteria will be enrolled or randomized in accordance with Section 8.2. As described in 
Section 9.2, subjects will receive their first dose of study drug at the investigational site 
under the supervision of the investigator or a person designated by the investigator.
9.3.3
Day of Study Treatment Initiation
The following tests, observations, and assessments will be performed before study drug is 
administered on the day of study treatment initiation. If 12-lead ECG or clinical 
laboratory tests were performed at screening up to 3 days prior to treatment initiation, 
then they may be used as the tests performed prior to treatment initiation.
Physical examination
Vital signs
Weight
12-lead ECG
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacokinetic assessments
The following tests will be performed only in Part B
Pharmacodynamic assessments (only serum testosterone by high-sensitivity 
measurement)
BMP concentrations
QOL assessments
9.3.4
Study Drug Treatment Period (Except for the Day of Study Treatment 
Initiation)
During the study treatment period, physical examinations and tests will be performed at 
scheduled inpatient and outpatient time points. The following tests, observations, and 
assessments will be performed during the treatment period.


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Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
PGx sample collection
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Pharmacokinetic assessments
The following tests will be performed only in Part B
Ophthalmological examinations
Bone mineral density
BMP concentrations
QOL assessments
9.3.5
Post-treatment Observation Period (Performed Only in Part A)
In Part A, the following tests, observations, and assessments will be performed as post-
treatment observations for 7 days following the last dose of study drug, and the results 
will be entered in the eCRF. Even if the subject withdraws from the study during Part A, 
the same post-treatment observations may be performed, depending on the subject’s 
treatment status. If a subject withdraws from the study, this will be reported to the study 
sponsor, which will be consulted about what actions should be taken.
Physical examination
Pharmacodynamic assessments
Pharmacokinetic assessments
Concomitant medications
Concomitant therapies
AEs


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9.3.6
Continuation Treatment Period
In Part B, if a subject continues receiving the study drug after 48 weeks, the following 
tests, observations, and assessments will be performed every 12, 24, or 48 weeks.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Bone mineral density
QOL assessments
9.3.7
At Study Withdrawal
If a subject withdraws from the study, the reason for withdrawal will be entered in the 
source documents and the eCRF, and the following tests, observations, and assessments 
will be performed within 8 days, including the day of withdrawal. In Part B, if a subject 
withdraws from the study (before Week 96), these same tests, observations, and 
assessments will be performed. The status of completion of the study will be entered in 
the eCRF for all subjects who received study drug in Part A, and for all subjects 
randomized in Part B. Furthermore, in Part B, if a subject completes 48 weeks of 
treatment, but does not subsequently continue receiving study drug, then the subject’s 
status of study completion (including the reason treatment was not continued) will be 
entered in the eCRF.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG


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Imaging assessments
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Pharmacodynamic assessments (serum testosterone, LH, FSH, DHT, and SHBG)
Tumor marker (PSA)
Concomitant medications
Concomitant therapies
AEs
Treatment compliance
Pharmacokinetic assessments (depending on the time of withdrawal)
The following tests will be performed only in Part B.
Ophthalmological examination (except for subjects who withdraw from the study 
after advancing to the continuation treatment period)
Bone mineral density
BMP concentrations (except for subjects who withdraw from the study after 
advancing to the treatment continuation period)
QOL assessments
9.3.8
Safety Follow-up
The following tests, observations, and assessments will be performed as safety follow-up 
30 to 40 days after the day of the last dose of study drug, and will be the final 
observations performed.
These same tests, observations, and assessments will be performed 30 to 40 days after the 
last dose of study drug for subjects who withdraw from the study as well.
The status of study completion will be entered into the eCRF for all subjects who receive 
study drug in Part A, and for all subjects who are randomized in Part B.
Physical examination
Vital signs
Weight
ECOG performance status
12-lead ECG
Clinical laboratory tests (hematology, chemistry, metabolic panel, and urinalysis)
Concomitant medications
Concomitant therapies
AEs


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The following tests will be performed only in Part B.
QOL assessments
9.3.9
Handling After the End of the Study
Study drug will not be supplied to subjects who have completed the study treatment 
period and the continuation treatment period (Part B).
9.4
Biological Sample Storage and Disposal
The 5 mL samples of whole blood collected for PGx research will be stored frozen at the 
sample storage facility (Protocol Annex 1).
The storage period will be 20 years from the day the samples for PGx research were 
initially collected in this study.
During the sample storage period, if a subject wants his samples destroyed, the 
investigational site will ask, via the study sponsor, and in accordance with the specified 
procedures, the sample storage facility to destroy the subject’s samples. The sample 
storage facility will destroy the samples in questions in accordance with the procedures, 
and will inform the investigational site and the study sponsor that the samples have been 
destroyed. However, if the data that allow the subject to be identified (eg, medical 
records) have been destroyed once the study has been completed, and it is therefore no 
longer possible to link the subject to his samples, then the samples will not be destroyed.
Even if the samples can be tied to the subject, if the PGx investigation has already been 
performed, the remaining samples will be destroyed, but the anonymized results of the 
PGx investigation will be retained by the study sponsor.
The study sponsor will construct the administrative structure necessary to protect 
subjects’ personal information, and will stipulate in advance criteria for handling sample 
collection, storage, and disposal, as well as prepare the necessary written procedures.
9.5
Blood Sample Volumes and Numbers of Samples Collected
Table 9.b, Table 9.c, and Table 9.d present guidelines for the volumes of blood samples to 
be collected for each subject.


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Table 9.b
Blood Sample Volumes and Numbers of Samples Collected (Part A)
Type of Sample
Volume of Blood 
Collected Per Sample 
(mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
7
84
Chemistry tests
9.2
7
64.4
Metabolic panel tests
5.6
4
22.4
Cardiac tests
4.4
1
4.4
Tumor marker
2.0
2
4
HIV, etc. tests*1
5.6
1
5.6
Pharmacodynamic assessments
7.0
9
63
PGx sample collection
5
1
5
PK assessments
3
37
111
Total Volume of Blood Collected
363.8
*1: Will be performed only when judged necessary
Table 9.c
Blood Sample Volumes and Numbers of Samples Collected 
(Part B – Screening Through Week 48, Safety Follow-up)
Type of Sample
Volume of Blood 
Collected Per 
Sample (mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
9
108
Chemistry tests
9.2
15
138
Metabolic panel tests
5.6
8
44.8
Cardiac tests
4.4
1
4.4
Tumor marker
2.0
9
18
BMP concentrations
2
5
10
HIV, etc. tests*1
5.6
1
5.6
Pharmacodynamic assessments
7.0
13
91
Serum testosterone (high-sensitivity 
measurement)
5
11
55
PGx sample collection
5
1
5
PK assessments
3
15
45
Total Volume of Blood Collected
524.8
*1: Will be performed only when judged necessary


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Table 9.d
Blood Sample Volumes and Numbers of Samples Collected 
(Part B – Weeks 49 to 96)
Type of Sample
Volume of Blood 
Collected Per Sample 
(mL)
Number of Samples 
(Times) Collected
Total Volume 
(mL)
Hematology tests
12
4
48
Chemistry tests
9.2
4
36.8
Metabolic panel
5.6
4
22.4
Tumor marker
2.0
4
8
Pharmacodynamic assessments
7.0
4
28
Total Volume of Blood Collected
143.2


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definition
10.1.1
Pretreatment Events
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation.
10.1.2
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug (including study drug); it does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug whether or not it is considered related to the drug.
10.1.3
Additional Points to Consider for Pretreatment Events and Adverse Events
An untoward findings generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition.
(Intermittent events for pre existing conditions underlying disease should not be 
considered PTEs or AEs.)

Require therapeutic intervention

Require an invasive diagnostic procedure

Require discontinuation or a change in dose of study drug or concomitant medication

Be considered unfavorable by the investigator for any reason.
Diagnosis vs signs and symptoms:
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) and/or symptom(s) should 
be recorded appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:
Change in laboratory value or ECG parameters are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required, 
or if the investigators judges the change to be beyond the normal physiological 
fluctuation). A laboratory re-test and/or continued monitoring of an abnormal value are
not considered an intervention. In addition, repeated or additional noninvasive testing for 
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If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal impairment), the diagnosis only 
should be reported appropriately as a PTE or as an AE.
Pre-existing conditions (disease or symptoms existing before informed consent is 
obtained):
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Abnormalities found in initial tests and observations (eg, laboratory tests, ECG, and 
radiology) after informed consent should NOT be recorded as PTEs unless related to 
study procedures, except that abnormalities occurring as a result of initial test or 
observation procedures (such as internal bleeding during blood draw) will be recorded as 
PTEs in the eCRF. If the subject experiences a worsening or complication of such a 
concurrent condition, the worsening or complication should be recorded appropriately as 
a PTE (worsening or complication occurs before start of study drug) or an AE (worsening 
or complication occurs after start of study drug). Investigators should ensure that the 
event term recorded captures the change in the condition (eg, "worsening of 
hypertension").
If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) that increase in 
frequency or become serious or severe should be recorded as PTEs/AEs. Symptoms that 
worsen more than expected in subjects with chronic disease (eg, cataracts, rheumatoid 
arthritis) should also be recorded as PTEs/AEs. Investigators should ensure that the AE 
term recorded captures the changes in the condition from Baseline (eg, "worsening of 
XX").
Worsening of PTEs or AEs:
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug or experiences signs/symptoms that occur secondarily to 
PTEs, the worsening or complication should be recorded appropriately as an AEs in the 
eCRF. Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, "worsening of XX").
If the subject experiences a worsening or complication of an AE after any change in study 
drug, the worsening or complication should be recorded as a new AE in the eCRF. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, "worsening of XX").
Underlying disease:
In this study, worsening of the underlying disease will not be handled as an AE. The 
onset or worsening of symptoms associated with progression of the underlying disease 
will be handled as an AE.
Planned surgeries or procedures:
Preplanned procedures (surgelies or therapies) that were scheduled prior to signing of 
informed consent were not considered PTEs or AEs, except that any conditions and 
events associated with the worsening of pre-existing conditions requiring those 
procedures to be undertaken on an emergency basis should be captured appropriately as a 


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PTE or an AE. Complications resulting from any planned surgery should be reported as 
AEs.
Elective surgeries or procedures:
Elective procedures performed where there is no change in the subject's medical 
condition should not be recorded as PTEs or AEs, but should be documented in the 
subject's source documents. Complications resulting from an elective surgery should be 
reported as AEs.
Insufficient clinical response (lack of efficacy):
Insufficient clinical response, efficacy, or pharmacological effect should NOT be 
recorded as an AE. Investigators must make a distinction between worsening of 
preexisting symptoms and lack of efficacy.
Overdose:
Cases of overdose with any medication without manifested side effects are NOT 
considered PTEs or AEs, but overdoses will be recorded on an overdose page of the 
eCRF.  Any manifested side effects will be considered AEs and will be recorded on the 
AE page of the eCRF.
10.1.4
Serious Adverse Events
A serious AE is defined as any untoward medical occurrence that at any dose:
1.
Results in DEATH.
2.
Is LIFE-THREATENING*.
3.
Requires inpatient HOSPITALIZATION or prolongation of existing 
hospitalization.
4.
Results in persistent or significant DISABILITY/INCAPACITY.
5.
Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6.
Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:
•
May require intervention to prevent items 1 through 5 above.
•
May expose the subject to danger, even though the event is not immediately 
life threatening or fatal or does not result in hospitalization.
•
Includes any event or synonym described in the Takeda Medically Significant 
AE List (Table 10.a).
* The term "life threatening" refers to an event in which the subject is at risk of death at the time of the 
event; it does not refer to an event that hypothetically might have caused death if it was more severe.


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Table 10.a
Takeda Medically Significant AE List
Acute respiratory failure/acute respiratory distress 
syndrome
Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia
Malignant hypertension
Convulsive seizures (such as convulsions and 
epilepsy)
Agranulocytosis
Aplastic anemia
Toxic epidermal necrolysis/oculomucocutaenous 
syndrome (Stevens-Johnson syndrome)
Hepatic necrosis
Acute hepatic failure
Anaphylactic shock
Acute renal failure
Pulmonary hypertension
Pulmonary fibrosis (including interstitial lung 
disease)
Neuroleptic malignant syndrome/malignant 
hyperthermia
Spontaneous abortion/stillbirth and fetal death
Confirmed or suspected transmission of infectious 
agent by drugs
Confirmed or suspected endotoxic shock
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported by the same procedures as for SAEs (see Sections 10.2.2 and 
10.3).
10.1.5
Special Interest Adverse Events
A special interest AE (whether serious or not) is one of specific and medical concern 
specific to the study drug or program. Investigators will monitor subjects on an ongoing 
basis for such events, and the sponsor will be notified immediately of any that occur. 
Further investigation may sometimes be necessary to establish assessment of these events.
Refer to Section 10.2.1.3 for the methods and deadlines for reports to the sponsor by 
investigators.
10.1.5.1
Liver Function Test Abnormalities
LFT abnormalities were identified as specific AEs because nonclinical studies in 
monkeys revealed LFT abnormalities and because clinical studies on oral GnRH 
antagonists with the same backbone structure as TAK-385 have revealed elevated AST 
and ALT as common treatment-related AEs.
The management of LFT abnormality AEs is presented in Table 8.c of the protocol.
When ALT or AST levels are > 3 ULN, retesting will be performed within 48 to 72 
hours (within 7 days at the latest). As soon as they become aware that ALT or AST levels 
are > 3 ULN, investigators will discuss detailed information on affected subjects and 
other potential causes with the sponsor to review whether the administration of study 
drug should be discontinued immediately.
If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN or the PT-
INR is > 1.5, and investigators conclude that the levels cannot be explained by any factor 
other that study drug based on the results of retesting, then they will be handled as serious 
AEs.


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When LFT abnormalities correspond to the criteria in Section 7.5, investigators will 
immediately discontinue administration of study drug and will perform appropriate 
follow-up.
10.1.6
Severity of Pretreatment Events and Adverse Events
The severity of AEs, including laboratory abnormalities, will be determined according to 
the CTCAE. Events not covered in the CTCAE will be classified and defined as follows.
Grade 1
Mild;*1 asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*2
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limited self care ADL*3
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
*1: A semi-colon indicates 'or' within the description of the grade.
*2: Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
*3: Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
AEs that undergo a change in severity for the worse will be individually recorded in the 
eCRF as separate AEs.
Clarification should be made between a serious AE and an AE that is considered severe in 
intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
term "severe" is often used to describe the intensity (severity) of a specific event, but the 
event itself may be of relatively minor medical significance (such as a Grade 3 headache). 
This is NOT the same as "serious." For example, a white blood cell count of 1000 to 
2000/mm3 is considered Grade 3 (severe) but may not necessarily be considered serious. 
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations.
10.1.7
Causality of Adverse Events
The relationships of each AEs to study drug will be assessed using the following 
categories:
Related
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug can 
be argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concomitant therapies, may also be responsible.
Not related
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concomitant therapies.


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10.1.8
Relationship to Study Procedures
The relationship should be assessed as Related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the 
relationship should be assessed as Not Related.
10.1.9
Date of Onset
The date of AE onset (the start date of the AE/PTE) will be determined based on the 
following criteria.
AEs
Date of onset
Signs, symptoms, disease (diagnosis)
The date on which the subject or investigators first notice the signs 
or symptoms of an AE will be recorded.
Asymptomatic disease
The date on which a diagnostic test is conducted and the diagnosis 
is confirmed will be recorded.
The date on which diagnosis is confirmed will be recorded even 
when test findings belatedly reveal older findings or when the time 
of onset can be generally estimated.
Worsening of complications or PTEs
The date on which the subject or investigators first notice 
worsening of signs or symptoms will be recorded.
When initial test results after 
informed consent are normal but 
subsequent test results are abnormal 
(PTE)
When test results turn abnormal after 
start of study drug treatment (AEs)
The date on which laboratory abnormalities considered clinically 
significant are found will be recorded.
When test results after informed 
consent are initially normal but then 
worsen (PTE)
When test results at start of study 
drug treatment are abnormal and then 
worsen (AE)
The date of tests on which laboratory profiles reveal clear increases 
or decreases based on clinical judgment.
10.1.10 Date Resolved
The date resolved (the stop date of the AE/PTE) is the date on which AEs resolve 
(including resolved with sequelae). When AEs result in death, the date of death will be 
used. When an AE is recorded as a separate AE in the eCRF due to worsening of severity, 
the day before the date on which worsening was confirmed will be recorded as the date of 
resolution. Cases in which resolution cannot be confirmed at the end of the study will be 
assessed as ongoing.
10.1.11 Frequency
When an AE that apparently resolves and occurs repeatedly (such as constipation, 
diarrhea, and vomiting) is determined by investigators to be a series of occurrences 
constituting a single event over the period of time from initial onset to ultimate resolution, 
the incidence will be considered "intermittent." All other cases will be handled as 
"continuous."


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10.1.12 Action Taken for Study Drug
Actions taken for study drug will be classified and defined as follows.
Drug Withdrawn
A study drug is terminated due to the particular AE (including when subjects 
themselves decide to discontinue).
Dose not Changed
The particular AE did not require any dose change of study drug.
Discontinuation of study drug, dose reduction, or dose escalation due to AE other 
than the AE in question will be handled as "dose not changed."
Discontinuation of study drug or dose reduction for reasons other than action taken 
for the AE, such as subject carelessness, will be handled as "dose not changed."
Unknown
When subjects cannot be contacted and the course after the date of onset cannot be 
ascertained, etc.
Not Applicable
When study drug treatment has already been completed or discontinued at the time 
that the AE occurs
Dose Reduced
A reduction in study drug dose as action taken for the AE will be handled as "dose 
reduced"(the dose cannot be reduced at the subject's discretion)
Dose Increased
An escalation in study drug dose as action taken for the AE will be handled as "dose 
increased"(the dose cannot be escalated at the subject's discretion)
Dose Interrupted
A temporary discontinuation (suspension) of study drug as action taken for the AE
followed by the resumption of dosing on a later date (including when subjects 
themselves decide to temporarily discontinue) will be handled as a "dose 
interrupted."
10.1.13 Outcome
The outcome of AEs will be classified as follows:
Classification
Criteria
Recovered/
Resolved
Symptoms or findings resolve or recover
Test results normalize or return to levels at baseline (AEs) or to levels at informed 
consent (PTEs)
When an event is recorded as a separate AE due to worsening severity in the eCRF
Recovering/
Resolving
Severity decreases at least 1 grade
Symptoms and findings are nearly resolved
Test results are improved, but have not normalized or returned to levels at baseline 
(AEs) or to levels at informed consent (PTEs)

The subject died from a cause other than the particular AE/PTE with the condition 
remaining “recovering/resolving”. (the date of death does not need to be recorded in 
such cases)
Not 
Recovered/
Not Resolved
No change in symptoms, findings, or test results
Symptoms, findings, or test results on last observable day are worse than at onset
Irreversible congenital anomaly/birth defect

The subject died from a cause other than the particular AE/PTE with the particular 
AE/PTE state remaining “Not recovered/not resolved”. (the date of death does not 
need to be recorded in such cases)
Resolved, with 
Sequelae
Occurrence of dysfunction interfering with ADL


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Classification
Criteria
Fatal
Death immediately related to AEs
"Immediately related" indicates that the AEs caused death or were clearly involved in 
the death.
Outcomes such as for AEs that are not determined (concluded, assumed) to have been 
the immediate cause of death in the same subject will not be handled as death.
The date of death will be recorded when the outcome is death.
Unknown
Follow-up of the event cannot be performed as specified in the protocol because of 
transfer to another hospital, change in residence, or the like
10.2
Procedures
10.2.1
Collection and Reporting of Adverse Events
10.2.1.1
Collection Period of Pretreatment Events and Adverse Events
Pretreatment events will be recorded continuously from when informed consent is 
obtained until the first dose of study drug (Day 1). If it is decided that a subject should be 
withdrawn before the first dose of study drug, PTEs will be recorded until that point in 
time.
AEs will be recorded continuously from the start of study drug administration to subjects 
(Day 1) until the safety follow-up.
10.2.1.2
Reporting of Adverse Events
Investigators will check for subjective symptoms whenever subjects visit. Investigators 
will ask subjects about AEs that may have occurred since the last visit by asking 
questions such as "How have you been since the last visit?"
Any subjects who experience a PTE that meets the criteria for seriousness will be 
followed up by investigators until symptoms resolve or until medically significant 
laboratory abnormalities return to initial levels after informed consent, or else (in the case 
of a permanent or irreversible PTE) until the observed change can be satisfactorily 
explained. No protocol follow-up will be required for PTEs that do not meet the criteria 
for seriousness, regardless of the causal relationship to study procedure.
Any subjects who experience an AE will be followed up by investigators until symptoms 
resolve or until medically significant laboratory abnormalities return to initial levels after 
informed consent, or else (in the case of a permanent or irreversible AE) until the 
observed change can be satisfactorily explained, regardless of the causal relationship to 
study drug. All AEs will be recorded in the eCRF. The following information will be 
documented for each event: event term, start and stop dates, frequency, severity
(intensity), causal relationship to study drug (related, not related), action taken on study 
drug, outcome, causal relationship to study procedures (and procedure considered the 
cause if causally related), and seriousness.
AEs, and PTEs meeting the criteria for seriousness, will be followed up until the 
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10.2.1.3
Reporting of Special Interest Adverse Events
When an AE of special interest that occurs during the period for recording AEs is 
determined to be medically significant based on the following criteria, investigators will 
report the event to the sponsor (see attachment for contact information) within 24 hours 
of the onset of the AE of special interest or within 24 hours after learning of the event 
from the subject. The principal investigator will also prepare a report of LFT 
abnormalities (same report form as for SAEs) within 10 business days, and submit it with 
a signature or printed name and personal seal to the contact identified in the 
attachment.The "Liver Function Test Abnormality Reporting Checklist (Appendix I)" will 
be used as reference to assist in the preparation of the report.
The criteria for LFT abnormalities are given below:
• ALT or AST > 3 ULN
If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN or the PT-
INR is > 1.5, and investigators conclude that the levels cannot be explained by any factor 
other that study drug based on the results of retesting (for procedures, see Section 
10.1.5.1), then they will be handled as serious AEs, and information will be recorded and 
reported by the procedures noted in Section 10.2.2.
AEs of special interest will be recorded as AEs in the eCRF. Related information (such as 
photographs, results of additional diagnostic tests, and records of consultations with 
specialists) will also be submitted to the sponsor.
10.2.2
Collection and Reporting of Serious Adverse Events
SAEs that occur in the period for recording AEs will be reported by the following 
procedures. PTEs meeting the criteria for seriousness noted in Section 10.1.4 will be 
reported by the same procedure as SAEs.
All SAEs that occur from the start of study drug administration in subjects until the safety 
follow-up will be reported by the principal investigator to the sponsor within 24 hours of 
confirming or being notified of the event. The initial report of an SAE and all revised or 
additional information will be recorded in an "SAE Report" to be submitted to the 
sponsor. Copies of related source documentation on medical treatment of subjects will be 
submitted to the sponsor as soon as possible. In cases of death, a copy of the autopsy 
report will be submitted, if possible.
Even after the end of the study, treatment-related SAEs will be reported to the sponsor 
within 24 hours of confirming or being notified of the event.
SAEs leading to withdrawal from the study or discontinuation of study drug will be 
recorded in initial or subsequent "SAE Reports" and in the eCRF.
As a general rule, the initial report of an SAE will be faxed to the Safety Information 
Emergency Response Center using the prescribed "Report of an SAE [Initial Report]" 
form. After faxing the form, the principal investigator will submit the original to the 
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After the initial report of the SAE, the principal investigator will report detailed 
information to the sponsor within 10 calendar days. As a general rule, the detailed 
information will be faxed to the Safety Information Emergency Response Center using 
the prescribed "Report of SAEs (Detailed Information)" form. After faxing the form, the 
principal investigator will submit the original to the monitors. Any modifications of the 
contents of the report will be similarly reported.
Safety Information Emergency Response Center (24 hours a day, 365 days a year)
FAX：
TEL：
When the Safety Information Emergency Response Center cannot be contacted, the 
information will, as a general rule, be reported to the monitors using the prescribed 
"Report of an SAE [Initial Report]" form or "Report of SAEs (Detailed Information)" 
form.
All SAEs occurring onsite will be reported by the principal investigator to the head of the 
investigational site by the established procedures in force at the investigational site and to 
the sponsor in accordance with this protocol.
The expectedness of SAEs will be determined on the basis of the Investigator's Brochure 
(including information on AEs reported to investigational site).
10.2.3
Reporting of Drug-Induced LFT Abnormalities Potentially Leading to 
Severe Liver Disorders
Investigators will report ALT or AST levels > 3 ULN to the sponsor and will promptly 
investigate detailed subject information and potential causes other than study drug 
(presence or absence of acute viral hepatitis type A or B, or other acute liver diseases, 
medical history, and complications). Retesting will also be performed (see Section 
10.1.5). If ALT or AST levels are > 3 ULN and total bilirubin levels are > 2 ULN 
or the PT-INR is > 1.5, and investigators conclude that the levels cannot be explained by 
any factor other that study drug, the information will be reported by the same procedure 
for SAEs (see Section 10.2.1.3).
10.3
Follow-up of Serious Adverse Events
If information not reported in the detailed report becomes available at a later date, 
investigators will record the information on a copy of the SAE report or will prepare a 
separate document, and one or the other will be submitted to the contact identified in the 
attachment. Investigational site-related data (such as ECG findings, laboratory findings, 
summary of report of discharge from hospital, and results of autopsy) will be submitted 
upon request to the sponsor or the IRB.
Investigators will follow-up all SAEs until they resolve or until the final outcome is 
determined.


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10.3.1
Reporting of Serious Adverse Events to Principal Investigators, IRB, and 
Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and other SAEs subject to expedited reporting to the regulatory 
authorities, principal investigators, and the IRBs/head of the investigational site in 
accordance with the local regulations of the counties in which the study is being 
conducted. The sponsor or the sponsor's CRO will submit an expedited report of fatal or 
life-threatening SUSARs within 7 days, and of any other serious events within 15 days, 
of first learning of or obtaining additional information on the event to the regulatory 
authorities. The sponsor will also submit an expedited report of other safety issues
potentially having a significant effect on the benefit-risk assessment of study drug, 
continuation of study drug treatment, or continuation of the study. The investigational 
site also will forward a copy of all expedited reports to his or her IRB.


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11.0
STUDY SPECIFIC COMMITTEES
A SMC will be established in this study. The principal duties of the SMC will be to 
decide when cohorts can progress to the next Part or to make the necessary decisions 
when it is difficult to judge whether or not DLTs have occurred. This is described in 
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent medical conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will 
be coded using the World Health Organization (WHO) Drug Dictionary [generic term] 
and the Japanese Drug Dictionary.
12.1
Electronic Case Report Form
Completed eCRFs are required for each subject who signs informed consent.
The sponsor or its designee will supply the investigational site with access to the eCRF 
system. The sponsor will make arrangements to train the investigators and appropriate 
study support staff in use of the eCRF system. The eCRFs will be used to transmit the 
information collected during the study to the sponsor and regulatory authorities. The 
eCRF must be completed in English. Data will be directly recorded onto eCRF.
The following will be recorded as an audit trail when changes or revisions are made in 
the eCRF: the original and changed/revised information, person making the change or 
revision, and the date and reasons for the change or revision.
The principal investigator must review the eCRFs for completeness and accuracy, and 
must electronically sign the appropriate page of the eCRF. The principal investigator 
bears full responsibility for the accuracy and reliability of all data recorded in the eCRFs.
The following data will not be directly recorded in the eCRF.
1)
Tumor marker, BMP concentration, and pharmacodynamic parameters (except for 
SHBG) measured by an external measurement facilities.
2)
Plasma drug concentration results
Investigators will use the eCRF change and revision record (Data Clarification Form) 
provided by the sponsor when changing or revising recorded entries in the eCRF after the 
clinical trial database has been locked. The principal investigator must review the data 
change for accuracy and completeness, and must provide a signature or printed name and 
personal seal, and the date.
The sponsor or its designee will check the accuracy and completeness of the eCRF when 
visiting the investigational site. The sponsor or its designee will be permitted to review 
subject's medical and hospital records related to the study to ensure the accuracy of the 
eCRFs. Completed eCRFs are the property of the sponsor, and should not be made 
available in any form to third parties other than regulatory authorities without the written 
permission of the sponsor.
12.2
Record Retention
The principal investigator or head of the investigational site will keep the following 
records, including the records and study-specific documents specified in Section 12.1.  
These materials will include the identification log of all participating subjects, medical 
records, source worksheets, all original signed and dated informed consent forms, 


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electronic copies of the eCRFs including audit trail, and drug accountability log. The 
essential relevant documents that are to be archived must also be kept by the principal 
investigator and head of the investigational site until the day specified as 1) or 2) below, 
whichever comes later, unless the sponsor requires records to be kept for longer periods 
of time than this, in which case the head of the investigational site will reach agreement 
on the retention period and record keeping methods with the sponsor.
1)
The day on which marketing approval of the investigational drug is obtained (or the 
day 3 years after the date of notification in the case that the investigation is 
discontinued.)
2)
The day 3 years after the date of early termination or completion of the clinical 
study.
The principal investigator and head of the investigational site will also keep the essential 
relevant documents that are to be archived until notified by the sponsor that the records 
no longer need to be kept.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
Analysts will prepare and finalize the Statistical Analysis Plan before database lock. The 
Statistical Analysis Plan will describe in detail the definitions of the endpoints and 
analytical methods in order to meet all study objectives.
Data review will take place before database lock. The accuracy and completeness of the 
study data, the evaluability of subjects, and the appropriateness of the planned analysis 
will be assessed during data review.
13.1.1
Analysis Sets
Four populations for analysis will be established in this study: the full analysis set, the 
safety analysis set, the DLT analysis set, and the pharmacokinetic analysis set. The safety 
analysis set will be defined as all subjects who receive at least 1 dose of any study drug. 
The DLT analysis set will be defined as all subjects who can be evaluated for DLTs (see 
Section 6.1.2.3). The analysis sets will be defined in detail in the separately prepared 
"Rules for Handling Analytical Data."
Before database lock, the sponsor will consult the medical expert as needed to check on 
the appropriateness of the analysis set definitions and rules for handling the analysis of 
the case data in the sets, and will finalize the "The Rules for Handling Analytical Data" 
after deciding how to handle problematic issues not specified at the planning stage.
13.1.2
Analysis of Demographics and Other Baseline Characteristics
The primary subject characteristics in the safety analysis set will be tabulated. 
Descriptive statistics (number of subjects, mean, median, standard deviation, maximum, 
minimum, and quartiles [same below]) will be calculated for continuous data, and 
frequency tabulations of discrete data will be prepared.
13.1.3
Efficacy Analysis
[Secondary endpoint]
PSA (Part B)
[Analytical method]
The full analysis set will be analyzed as follows.
1)
PSA
Descriptive statistics and the two-sided 95% confidence interval of the mean for PSA in 
Part B will be calculated at each assessment time point specified in the protocol, and the 
changes over time (individual and mean/SD) will be graphed by dose. The changes from 
baseline will also be similarly analyzed. Waterfall plots of the change from baseline at 
Week 13 Day 1 (LOCF) and the change from baseline for the minimum value after the 
start of study drug treatment will be prepared by dose.


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2)
Data conversion and handling of missing data
PSA levels below the lower limit of quantification will be handled as the LLOQ. Test 
data that is not assessed or that is missing, or that is not used per the "Rules for Handling 
Analytical Data," will be excluded from the analysis of assessment.
[Other endpoints]

PSA (Part A)

Disease progression as assessed on the basis of PSA, disease progression as assessed 
on the basis of image assessment (Part B)
13.1.4
Pharmacokinetic Analysis
[Secondary endpoint]
Plasma concentration of unchanged TAK-385
[Analytical method]
The pharmacokinetic profile (such as Cmax and AUC) will be calculated by model-free 
analysis of the plasma concentration profiles of unchanged TAK-385 in the 
pharmacokinetic analysis set. Descriptive statistics of each parameter will be calculated 
by Part and by dose. Descriptive statistics for the plasma concentration of TAK-385 at 
each blood sampling time point specified in the protocol will also be calculated by dose, 
and the changes over time (individual and mean) will be graphed by dose. The plasma 
concentration profiles of TAK-385 will also be analyzed using a compartment model as 
needed.
13.1.5
Pharmacodynamic Analysis
[Secondary endpoint]
Serum testosterone concentration
[Analytical method]
The full analysis set will be analyzed as follows.
1)
Serum testosterone concentration
Descriptive statistics and the two-sided 95% confidence interval of the mean for serum 
testosterone concentration will be calculated by Part and by dose at each assessment time 
point specified in the protocol, and the changes over time (individual and mean/SD) will 
be graphed by Part and by dose.
2)
Data conversion and handling of missing data
Test parameters below the lower limit of quantification will be handled as the LLOQ. 
Test data that is not assessed or that is missing, or that is not used per the "Rules for 
Handling Analytical Data," will be excluded from the analysis of assessment.
[Other endpoints]
Serum concentrations of LH, FSH, DHT, and SHBG


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13.1.6
Other Analysis
[Other endpoints]
QOL assessment based on AMS, EORTC-QLQ-C30, and EPIC (Part B)
13.1.7
Safety Analysis
[Primary endpoints]
DLTs, AEs, clinical laboratory tests, vital signs, and 12-lead ECG
[Analytical methods]
1)
Adverse events
The following analysis will be performed for the safety analysis set.
A treatment-emergent adverse event (TEAE) refers to an event that occurs after the start 
of study drug administration.
The following TEAE will be tabulated by Part and by dose. TEAEs will be coded
according to MedDRA and summarized by System Organ Class (SOC) and Preferred 
Term (PT).

Frequency tabulations of all TEAEs

Frequency tabulations of treatment-related TEAEs

Frequency tabulations of all TEAEs by severity

Frequency tabulations of treatment-related TEAEs by severity

Frequency tabulations of TEAEs for which the study drug action taken was 
"treatment discontinuation"

Frequency tabulations of serious TEAEs

Frequency tabulations of all TEAEs by time of onset
2)
DLT
The following analysis will be performed for the DLT analysis set.
Frequency tabulations of TEAEs determined to be DLTs in Part A will be tabulated by PT 
and by dose.
3)
Clinical laboratory tests, vital signs, and 12-lead ECG
The following analysis will be performed for the safety analysis set.
For continuous data, descriptive statistics for observed values at baseline and at each 
assessment time point as well as for the change from baseline will be calculated by part 
and by dose.
Cross tables for the results of the assessment of each test parameter based on discrete data 
and reference values before and after study drug treatment (such as the determination of 


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whether results are normal or abnormal, or qualitative laboratory values) will be prepared 
by part and by dose.
[Other endpoints]

Bone mineral density
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Planned Sample Size
[Part A]
Each cohort will have 3 or 6 subjects, based on the guidelines on the clinical evaluation 
of antineoplastics.
[Part B]
In order to detect less frequent AEs, 15 subjects per group (total of 30 subjects) were 
established as the number of cases enabling an approximately 80% chance of detecting 
AEs characterized by a true incidence of 10%.


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Monitoring of Investigational Site
Monitoring visits to the investigational site will be made periodically during the study to 
ensure that all aspects of the protocol are followed. Source documents will be reviewed 
for verification of data recorded on the eCRFs. Source documents are defined as original 
documents, data, and records. The investigator and institution guarantee access to source 
documents by the sponsor or its designee and by the IRB.
The sponsor or its designee will access the principal investigator's files, medication, 
medical records of subjects, and records such as the informed consent form to ensure that 
the study is being properly conducted in compliance with the protocol. They will also 
confirm the consistency of the eCRFs with related source documents. Investigators and 
other study support staff members will take the time to accommodate monitors when they 
visit the investigational site for monitoring purposes.
14.2
Protocol Deviations
Investigators may deviate from or modify the protocol without the prior written 
agreement of the sponsor or prior approval of the IRB for medically unavoidable 
circumstances, such as to avoid immediate hazards to subjects. On such occasions, the 
principal investigator will inform the sponsor and head of the investigational site in 
writing of the details of and reasons for the deviation or change, will keep copies of the 
notification, and will reach agreement with the sponsor on protocol revisions as needed.  
If the protocol is to be revised, a draft will be submitted as soon as possible to the head of 
the investigational site, and the approval of the IRB will be required.
Investigators should document all deviations from the protocol.
14.3
Quality Assurance Audits and Regulatory Authority Inspections
The sponsor or designee will audit the investigational site as needed. On such occasions, 
an auditor designated by the sponsor will contact the investigational site beforehand to 
schedule the auditing visit. The auditor may ask to visit the facilities where laboratory 
test samples are kept, the facilities where medication is stored and prepared, and other 
facilities used during the study. During this study, inspections may also be carried out by 
regulatory authorities, including overseas agencies (such as the US Food and Drug 
Administration [FDA] and the UK Medicines and Healthcare Products Regulatory 
Agency [MHRA]).  The sponsor will be notified immediately whenever the 
investigational site receives a request for an inspection by the regulatory authorities.  The 
principal investigator and head of the investigational site will ensure that the auditor has 
access to all study-related documentation set forth in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This trial will be conducted with the highest respect for the individual participants (ie, 
subjects) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and International Conference on Harmonisation (ICH) 
Guidelines for GCP. Investigators will conduct the study in accordance with regional 
regulatory requirements and the "Responsibilities of the Principal Investigator" in
Appendix F.
15.1
IRB Approval
The IRB must be will be constituted according to the applicable local regulations in 
regions participating in the study. The sponsor or designee will obtain documentation of 
the names and affiliations of the IRB members. When IRB members directly participate 
in the study, documentation that they are not involved in the review and decision-making 
process must be obtained.
The sponsor or designee will submit related documents to the IRB for review and 
approval of the protocol. In addition to the study protocol, Investigator's Brochure and 
copies of the informed consent as well as materials and advertising related to the 
recruitment of subjects, if needed, and other documents required by local regulations 
must also be submitted to central or local IRBs for approval. The sponsor or designee 
will obtain documented approval of the protocol and informed consent form by the IRB 
before the start of the study (i.e., before shipment of the sponsor-supplied drug or study 
specific screening activity). The IRB or IEC approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (eg, 
informed consent form) reviewed; and state the approval date. The sponsor will ship drug
after confirming the appropriateness of the documented regulations of the investigational 
site. Until the site receives drug, no protocol activities, including screening may occur.
The investigational site will follow all requirements specified by the IRB. This includes 
notifications to the IRB regarding protocol amendments, updates to the informed consent 
form, revisions of materials related to subject recruitment, reports on safety required by 
local regulatory requirements, periodic reports on the conduct of the study as stipulated 
by the IRB, and the study completion report. The sponsor or designee will obtain all 
documented IRB approval of the above and related materials.
Financial compensation paid to subjects should be kept to a level that will not provide 
undue incentive to participate in the study. Financial relief must be approved by the IRB 
and sponsor.
PGx analysis of collected and stored samples will perform at the time when the details 
have been decided. At that time, the sponsor will prepare a PGx protocol, and the
protocol will require prior approval of the sponsor.
15.2
Patient Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form will describe the 


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planned and permitted use (either in Japan or abroad: submission to third parties) and 
disclosure of the personal information and personal medical information of subjects in 
this study. The informed consent form will further explain the nature of the study, 
objectives, and of the potential risks and benefits. The informed consent form will also 
detail the requirements of the participant and the fact that he or she is free to withdraw at 
any time without giving a reason and without prejudice to his or her further medical care.
The principal investigator is responsible for the preparation and contents of the informed 
consent form, and for obtaining the approval of the IRB. The informed consent form 
must be approved by the IRB before being used.
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. Investigators will be responsible for providing subjects with a 
detailed explanation of the contents of the informed consent form. Information should be 
provided verbally and in writing by a method deemed suitable by the IRB whenever 
possible.
Investigators will give subjects (1) a chance to ask questions about the study and 
(2) enough time to decide whether to participate in the study. Subjects who decide to 
participate in the study will personally sign and date the informed consent form before 
participating in the study. Investigators will ask subjects to use a black or blue ball point 
pen to sign the form using their full legal names. Investigators will also sign and date the 
informed consent form before the subject can participate in the study.
Investigators will keep the signed original informed consent form. The date on which 
subjects sign the informed consent form will be recorded by investigators in the medical 
records of the subjects. Subjects will be given a copy of the signed informed consent 
form.
If the informed consent form is revised, investigators will again obtain the informed 
consent of the subjects using the same procedures that were used to obtain initial consent. 
The date on which informed consent is again obtained will be recorded in the medical 
records of the subjects, and subjects will be given a copy of the revised informed consent 
form.
Subjects who have received an explanation of the study based on the informed consent 
form will be given an explanation of PGx analysis based on the "Informed Consent Form 
for PGx Analysis in the TAK-385 Study." Specimens for PGx analysis will be obtained 
from subjects who sign both the informed consent for the study and the informed consent 
for PGx analysis.
The procedure in Section 9.4 will be followed whenever subjects would prefer their 
stored samples to be disposed of.
15.3
Subject Confidentiality
The sponsor or designee affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data will 
only be linked to the sponsor’s clinical study database or documentation via a unique 
subject identification number. As permitted by all applicable laws and regulations, limited 


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subject attributes, such as sex, age, or date of birth, and subject initials may be used to 
verify the subject and accuracy of the subject identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (such as the FDA, MHRA, and PMDA), the 
sponsor’s designated auditors, and the appropriate IRBs and IECs to review the subject’s 
original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a subject’s study participation, and autopsy reports. 
Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (ie, the subject's name, address, and 
other identifier fields not collected on the subject's eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The principal investigator is obliged to provide the sponsor with complete test results and 
all data derived by the investigator from the study. During the study, except when 
required by laws or regulations, only the sponsor may disclose study information to other 
investigators or regulatory authorities. Except where otherwise permitted by the Clinical 
Study Agreement, any public disclosure of the protocol and study results (including 
public websites) is the responsibility of the sponsor.
The sponsor may publish any data or information obtained from the study (including data 
and information provided by the principal investigator) without the consent of the 
principal investigator.
Investigators need to obtain the prior written permission of the sponsor to publish any 
information obtained from the study, such as to a professional associations.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner 
and to comply with applicable laws, regulations and guidance, Takeda will, at a minimum 
register interventional clinical trials it sponsors anywhere in the world on a public 
website (JAPIC-CTI) before the start of the clinical trial. The sponsor's contact 
information will be registered for general access along with the city, state (in the USA), 
and country where the trial is being conducted as well as subject recruitment status.
For some registries, Takeda will assist callers in locating trial sites closest to their homes 
by providing the investigator name, address, and phone number to the callers requesting 
trial information. Once subjects receive investigator contact information, they may call 
the site requesting enrollment into the trial. The investigative sites are encouraged to 
handle the trial inquiries according to their established subject screening process. If the 


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caller asks additional questions beyond the topic of trial enrollment, they should be 
referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must 
provide Takeda with a written notice requesting that their information not be listed on the 
registry site.
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on a public website (JAPIC-CTI), as required 
by applicable laws and/or regulations, regardless of the results.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to 
the site where the subject is participating. If a local underwriter is required, then the 
sponsor or its designee will obtain clinical study insurance against the risk of injury to 
clinical study subjects.
Refer to the Clinical Study Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or its designee.


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16.0
REFERENCES
1. Jemal A, Bray F, Melissa M, et al. Global Cancer Statistics. CA Cancer J Clin. 2011; 
61(2): 69-90.
2. Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health 
Syst Pharm 1996;53(4):381-96; quiz 446-8.
3. Cancer Statistics in Japan-2013. Foundation for Promotion of Cancer Research. 
November 2013.
4. Prostate Cancer Treatment Guidelines (2012 Edition). Japanese Urological 
Association.
5. Most recent version of the TAK-385 Investigator’s Brochure.
6. Nagata S. Showa Ikaishi Vol. 48, No. 2. 2007. 134-140.
7. Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM. The Aging 
Males' Symptoms scale (AMS) as outcome measure for treatment of androgen 
deficiency. Eur Urol 2004;46(1):80-7.
8. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a qualityof 
life instrument for use in international clinical trials in oncology. Journal of the 
National Cancer Institute 1993;85(5):365-76
9. Fayers P, Bottomley A, EORTC Quality of Life Group, Quality of Life Unit. Quality 
of life research within the EORTC-the EORTC QLQ-C30. European Organisation for 
Research and Treatment of Cancer. European Journal of Cancer 2002;38 Suppl 
4:S125-33.
10. Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. 
EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: EORTC; 2001
11. Takegami M. Journal of the Japanese Urological Association. 2005; 96:657-69.
12. Kakehi Y, Takegami M, Suzukamo Y, Namiki S, Arai Y, Kamoto T, Ogawa O and 
Fukuhara S. Health related quality of life in Japanese men with localized prostate 
cancer treated with current multiple modalities assessed by a newly developed 
Japanese version of the Expanded Prostate Cancer Index Composite. The Journal of 
Urology, 2007; 177: 1856-61.
13. U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010
14. Tengstrand E, Miwa G, and Hsieh F. Bis(monoacylglycerol)phosphate as a non-
invasive biomarker to monitor the onset and time-course of phospholipidosis with 
drug-induced toxicities. Expert Opin. Drug Metab. Toxicol. 2010 6(5):555-570
15. Tengstrand-Baronas E, Lee JW, Alden C, Hsieh F. Biomarkers to monitor drug-
induced phospholipidosis. Toxicology and Applied Pharmacology 2007;218:72-78


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16. Prostate Cancer Handling Guidelines (December 2010, Fourth Edition). Edited by the 
Japanese Urological Association/Japanese Society of Pathology/Japan Radiological 
Society.
17. Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982 (5) :649-655
18. Circulatory Disease Diagnosis and Treatment Guidelines (2010 Joint Research Team 
Report) – Acute Cardiac Failure Treatment Guidelines (2011 Revised Edition).


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Appendix A
Schedule of Study Procedures (Part A)
Procedurea
Subject consentb
Screening
Treatment Periodc
Post-treatment 
Observation Periodd
Withdrawale
SFU
Inpatientf
Outpatient
30 to 40 
days after 
the last dose
Before 
treatment 
initiation
D -28 to D -1g
D1h
D2
D3
D7
D12
D13
D14
D15
D21
D28
D29
D30
D31
D35i
Allowable visit window
0
± 1
0
0
+ 3
+ 3
0
+ 7
Confirmation of eligibility
X
Subject backgroundj
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
X
Weight/heightl
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
12-lead ECGm
X
Xo
X
X
X
X
Chest X-ray examination
X
Imaging assessmentn
X
Measure as appropriate
Hematology tests
X
Xo
X
X
X
X
X
X
Blood biochemistry tests
X
Xo
X
X
X
X
X
X
Blood lipid, sugar, etc. tests
X
Xo
X
X
X
Urinalysis
X
Xo
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
X
X
X
X
X
X
X
X
X
Tumor marker
X
X
X
Pharmacokinetic 
assessmentsp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xq
PGx sample collection
X (during the treatment period)
Concomitant medications/ 
therapies
Collected from the time of informed consent until 30 to 40 days after the last dose
Adverse events, etc.
PTEsr
Information collected from study treatment initiation until 30 to 40 days after the last dose
Study treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: D = Day; ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; SFU = safety follow-up


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a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Except for procedures that are normally part of a physical examination, subjects must sign the informed consent form before any study-related procedures are performed.
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
d Days 27 to 35 are performed either on an outpatient or an inpatient basis.
e Unnecessary if the subject withdraws between Day 29 and Day 35.
f Day 1: Day of treatment initiation. As a rule, subjects will not be allowed to leave the investigational site or return home during the inpatient period. However, the 
investigator or sub-investigator may allow the subject to return home temporarily.
g Day -1: Day before treatment initiation
h Day 1: Day of treatment initiation
i If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
j Including past and current medical history and previous therapeutic medications
k Measurements will be taken after the subject has been sitting down for 5 minutes.
l Height will be measured only at screening.
m 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
n Performed at screening only if imaging assessments were not performed within 28 days prior to treatment initiation, or if no usable images are available for the subject.
o Results of tests performed up to 3 days before treatment initiation may be used at the D1 test results.
p See Appendix D for detailed collection times.
q As a rule, blood samples will be collected at subject withdrawal as well, but the blood samples corresponding to the post-treatment observation period will not be necessary.
r Collected from consent acquisition until study treatment initiation.


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Appendix B
Schedule of Study Procedures (Part B – Screening to Week 48, SFU)
Procedurea
Informed consentb
Screening
Treatment Periodcd
Withdra
wal
SFU
Visit Day
Before 
treatment 
initiatione
D -28 to D -
1f
WK
1
WK
1
WK
1
WK
2
WK
3
WK
5
WK
9
WK
13
WK
17
WK
21
WK
25
WK
29
WK
33
WK
37
WK
41
WK
45
WK
49g
30 to 40 
days after 
the last dose
D1h
D2
D4
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Allowable visit 
window
0
0
0
±1
±1
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±7
+7
Confirmation of 
eligibility
X
Subject backgroundi
X
Physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
X
X
X
X
X
Weight/heightk
X
X
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
12-lead ECGl
X
Xn
X
X
X
X
X
X
Chest X-ray 
examination
X
Ophthalmology tests
X
X
X
X
Imaging assessmentm
X
X
X
Bone density (DXA 
method)
X
X
X
X
Hematology tests
X
Xn
X
X
X
X
X
X
X
X
Blood biochemistry 
tests
X
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood lipid, sugar, 
etc. tests
X
Xn
X
X
X
X
X
X
X
Urinalysis
X
Xn
X
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
Xo
X
X
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
Xo
X
Tumor marker
X
X
X
X
X
X
X
X
X
X
BMP concentrationp
X
X
X
X
X
X
Pharmacokinetic 
assessmentsq
X
X
X
X
X
X
X
X
X
X
X
X
X
Xr


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PGx sample 
collection
X (randomization through the treatment period)
QOL assessments
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/ 
therapies
Collected from the time of informed consent until 30 to 40 days after the last dose
Adverse events, etc.
PTEss
Information collected from study treatment initiation until 30 to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: WK = Week; D = Day;  ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; QOL = quality of life; SFU = safety follow-up
                                               
a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Except for procedures that are normally part of a physical examination, subjects must sign the informed consent form before any study-related procedures are performed.
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
d Except for pharmacokinetic assessments, if the assessment and test results can be obtained, then the assessments will be performed before study treatment initiation.
e Randomization will be performed by Day -1 (1 day before treatment initiation)
f Day -1: Day before treatment initiation
g If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
h Day 1: Day of treatment initiation
i Including past and current medical history and previous therapeutic medications
j Measurements will be taken after the subject has been sitting down for 5 minutes.
k Height will be measured only at screening.
l 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
m Performed at screening only if imaging assessments were not performed within 28 days prior to treatment initiation, or if no usable images are available for the subject.
n Results of tests performed up to 3 days before treatment initiaion may be used as the D1 test results.
o Blood samples will also be collected for the serum testosterone high sensitivity measurements.  However, at WK1D1, only the high-sensitivity measurements will be 
performed.
p Blood and urine sample collection
q See Appendix E for detailed sample collection times
r As a rule, blood samples will also be collected at withdrawal from the study.
s Information will be collected from consent acquisition until treatment initiation.


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Appendix C
Schedule of Study Procedures (Part B – Weeks 49 to 96)
Procedurea
Continuation Treatment Periodb
Withdrawal
SFU
Scheduled Day
WK49 (WK48)
D1 (D8)
WK61
D1
WK73
D1
WK85
D1
WK97c
D1
30 to 40 days 
after the last dose
Visit Day Allowable Window
±7
±7
±7
±7
±7
+7
Physical examination
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
12-lead ECGe
X
X
X
X
X
Imaging assessment
X
X
X
Bone density (DXA method)
X
X
X
X
Hematology tests
X
X
X
X
X
X
X
Blood biochemistry tests
X
X
X
X
X
X
X
Blood lipid, sugar, etc. tests
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Pharmacodynamic assessments
X
X
X
X
X
X
Tumor marker
X
X
X
X
X
X
QOL assessments
X
X
X
X
X
X
X
Concomitant medications/ 
therapies
Information collected until 30 to 40 days after the last dose
Adverse events, etc.
Information collected until 30 to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfastf
Abbreviations: WK = Week; D = Day; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; SFU = safety follow-up
                                               
a Unless otherwise specified, the assessments will be completed before study drug dosing.
b Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
c If a subject is going to be switched to a GnRH agonist or a GnRH antagonist, this will be done after PK analysis sample collection and assessments have been completed.
d Measurements will be taken after the subject has been sitting down for 5 minutes.
e Measurements will be taken after the subject has been lying down for 5 minutes.
f Study drug will not be taken at WK97D1.


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Appendix D
Schedule of Blood Samples Collection for Pharmacokinetic Analysis (Part A)
Time Pointa
Dosing Time Pointb
D1
D2
D3
D7
D12
D13
D14
D15
D21
D28
D29
D30
D31
D35
Before dosingc
X
X
X
X
X
X
X
X
X
X
Xd
Xe
Xf
Xg
0.5 hour (± 10 min) postdose
X
X
1 hour (± 15 min) postdose
X
X
X
1.5 hours (± 15 min) postdose
X
X
2 hours (± 20 min) postdose
X
X
X
X
X
4 hours (± 20 min) postdose
X
X
X
6 hours (± 30 min) postdose
X
X
8 hours (± 30 min) postdose
X
X
X
12 hours (± 1 hour) postdose
X
X
X
Abbreviations: D = day
                                               
a If a blood sample is going to be collected on an outpatient basis, then the subject will come in for the visit without taking the study drug.
b As a rule, a blood sample will be collected at discontinuation as well, but the blood sample for the post-treatment observation period will not have to be collected.
c Blood samples for PK analysis will be collected within 1 hour before dosing.
d 24 hours (± 1 hour) after dosing on D28
e 48 hours (± 4 hours) after dosing on D28
f 72 hours (± 4 hours) after dosing on D28
g Collected before starting the next treatment


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Appendix E
Schedule of Blood Samples Collection for Pharmacokinetic Analysis (Part B)
Time Pointa
Dosing Time Pointb
WK1
WK2
WK3
WK5
WK9
WK13
WK17
WK21
WK25
WK37
WK49
D1c
D2
D4
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Before dosingd
X
X
X
X
X
X
X
X
X
X
X
X
X
2 hours postdose
(± 20 min)
X
X
Abbreviations: WK = week; D = day
                                               
a If a blood sample is going to be collected on an outpatient basis, then the subject will come in for the visit without taking the study drug.
b As a rule, blood samples will be collected at discontinuation as well.
c Blood samples will be collected after the subjects have taken the first dose of study drug at the hospital, and then eaten after an interval of at least 30 minutes, and then after 
another 2 hours have passed.
d Blood samples for PK analysis will be collected within 1 hour before dosing.


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Appendix F
Responsibilities of Principal Investigator
1.
Conduct the appropriate study in accordance with the protocol and GCP considering 
the rights, safety and wellbeing of human subjects.
2.
When a part of the important activities related to the study are delegated to the sub-
investigator or the study support staff, prepare the lists of activities to be delegated 
and responsible personnel, submit the lists to the head of the site in advance to get 
them accepted.
3.
Prepare a written informed consent form and other written information, and update as 
appropriate.
4.
Confirm the contents of the Clinical Study Agreement.
5.
Provide necessary information on the protocol, drugs and responsibilities of 
individual personnel to the sub-investigator and study support staff, and provide 
guidance and supervision.
6.
Screen subjects who meet the requirements of the protocol, provide the explanation 
of the study in writing and obtain the written consent.
7.
Assume responsibility for all the medical judgement related to the study.
8.
Ensure in collaboration with the head of the site that sufficient information on all 
clinicaly significant advesrse events related to the study are provided to subjects 
throughout and beyond the period when subjects participate in the study.
9.
If a subject consult other medical institution or other department, notify the physician 
of the medical institution or department of the subject's participation in the study, as 
well as the end and termination of the study in writing, and document such records.
10. In case of urgent report of a SAE, immediately notify the head of the site and the 
sponsor in writing.
11. Prepare correct and complete eCRFs, and submit them to the sponsor with electronic 
signature.
12. Check and confirm the contents of eCRFs prepared by the sub-investigator or 
transcribed from the souce data by the study support staff, and submit them to the 
sponsor with electronic signature.
13. Discuss any proposal from the sponsor including update of the protocol.
14. Notify the head of the site of the end of the study in writing.


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Appendix G
ECOG Performance Status
Score
Activity Level
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours.
3
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Dead.


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Appendix H
New York Heart Association (NYHA) Functional Classification
Class
Patient Symptoms
I
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased.


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Appendix I
Liver Function Test Abnormality Reporting Checklist
AS MUCH INFORMATION AS POSSIBLE WILL BE OBTAINED ABOUT THE 
FOLLOWING PARAMETERS
RELATED MEDICAL HISTORY/SYMPTOMS
Viral hepatitis
Auto-immune disorders
Alcohol use
Biliary disorders
Heart disorders, particularly right heart failure or hypotension
Recent viral diseases
Recent travel
Blood transfusions
Allergies
Recent anesthesia/surgical procedures
Drug abuse
Exposure to toxins
Recent tattoos
Family history of liver disease
EVENT INFORMATION
Signs and symptoms
NOTEWORTHY CLINICAL TEST DATA AND TEST RESULTS
Hepatic enzymes (ALT, AST, total bilirubin, ALP, GGT)
Coagulation system parameters
Albumin
Virus serum tests
Auto-immune markers
Liver imaging tests (ultrasound, CT, MRI)
Endoscopic retrograde cholangiopancreatography (ERCP)
Liver biopsy
Eosinophil count


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Appendix J
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment 
No.1.
Page 1, Cover page Sponsor
Existing Text
Takeda Bio Development Center
Marunouchi Eiraku Building
1-4-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005
Revised Text
Takeda Pharmaceutical Company Limited
1-1 Doshomachi 4-chome, Chuo-ku, Osaka
Rationale for Amendment
Change in company name and address due to business consolidation.
Page 1, Cover page CONFIDENTIAL PROPERTY
Existing Text
This document is a confidential communication of Takeda Bio Development Center.  
Acceptance of this document constitutes the agreement by the recipient that no 
information contained herein will be published or disclosed without written authorization 
from Takeda Bio Development Center except to the extent necessary to obtain informed
consent from those persons to whom the drug may be administered.
Revised Text
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be 
published or disclosed without written authorization from Takeda except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be 
administered.
Rationale for Amendment
Change in company name due to business consolidation.


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Page 8, Section 2.0 STUDY SUMMARY
Existing Text
Name of Sponsor:
Takeda Bio Development Center
Revised Text
Name of Sponsor:
Takeda Pharmaceutical Company Limited
Rationale for Amendment
Change in company name due to business consolidation.
Page 31, Section 6.1 Study Design
Existing Text
Cohort/Part Advancement Criteria
•••
In each cohort, if no DLT occurs in even 1 of the 3 subjects during the DLT evaluation 
period (see Section 6.1.1.2), then the dose will be judged tolerable, and the study will 
proceed to the next cohort.•••
Revised Text
6.1.1
Cohort/Part Advancement Criteria
•••
In each cohort, if no DLT occurs in even 1 of the 3 subjects during the DLT evaluation 
period (see Section 6.1.2.2), then the dose will be judged tolerable, and the study will 
proceed to the next cohort.•••
Rationale for Amendment
Editorial change.


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Page 104 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 32 to 33, Section 6.1 Study Design
Existing Text
6.1.1
DLT
6.1.1.1 Definition of DLT
•••
6.1.1.2 DLT Evaluation Period
•••
6.1.1.3 DLT Evaluable Subjects
•••
Revised Text
6.1.2
DLT
6.1.2.1 Definition of DLT
•••
6.1.2.2 DLT Evaluation Period
•••
6.1.2.3 DLT Evaluable Subjects
•••
Rationale for Amendment
Editorial change.
Page 46, Section 8.1.3 Dose and Regimen
Existing Text
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B)
Treatment 
Group
Dosage/Number of Tablets
80 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Day 2 to Week 48*3): Two 40 mg tablets per day
120 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Day 2 to Week 48*3): One 80 mg tablet and one 40 mg tablet per day
40 mg*2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Day 2 to Week 48*3): One 40 mg tablet per day
At uptitration
One TAK-385 40 mg tablet per day will be added


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Page 105 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Revised Text
Table 8.b
Treatment Groups, Dosages, and Numbers of Tablets (Part B)
Treatment 
Group
Dosage/Number of Tablets
80 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 80 mg (Day 2 to Week 48*3): Two 40 mg tablets per day
120 mg
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 120 mg (Day 2 to Week 48*3): One 80 mg tablet and one 40 mg tablet per day
40 mg*2
TAK-385 320 mg (Day 1): Four 80 mg tablets per day
TAK-385 40 mg (Day 2 to Week 48*3): One 40 mg tablet per day
At uptitration
One TAK-385 40 mg tablet per day will be added
Rationale for Amendment
Correction of typographical error.
Page 46 to 47, Section 8.1.3.1 Criteria for Upward Dose Adjustments
Existing Text
Part A: The dose of TAK-385 will not be increased even if inadequate testosterone 
suppression occurs (< 50 ng/dL). If after treatment initiation the serum testosterone level 
does not drop below 50 ng/dL at 2 or more time points separated by at least 7 days and 
the investigator determines that the patient needs to be switched to some other treatment, 
then TAK-385 treatment will be stopped and the patient withdrawn from the study.
Part B: If the following conditions are met, the dose may be adjusted, taking efficacy and 
safety into consideration. Dose adjustment will be performed when the subject is 
examined by the investigator.
•••
Revised Text
Part A: The dose of TAK-385 will not be increased even if inadequate testosterone 
suppression occurs (< 50 ng/dL). If after treatment initiation the serum testosterone level 
does not drop below 50 ng/dL at 2 or more time points separated by at least 7 days and 
the investigator or sub-investigator determines that the patient needs to be switched to 
some other treatment, then TAK-385 treatment will be stopped and the patient withdrawn 
from the study.
Part B: If the following conditions are met, the dose may be adjusted, taking efficacy and 
safety into consideration. Dose adjustment will be performed when the subject is 
examined by the investigator or sub-investigator.
•••


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Page 106 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Rationale for Amendment
Revised to better fit the actual situation at investigational sites.
Page 47, Section 8.1.3.2 Criteria for Dose Holds and Dose Reduction
Existing Text
•••
Part B: If a treatment-related AE occurs or if it would be difficult to continue with 
TAK-385 treatment, then study treatment will be interrupted.•••
Revised Text
•••
Part B: If a treatment-related AE occurs or if it would be difficult to continue with 
TAK-385 treatment, then study treatment will be interrupted if necessary.•••
Rationale for Amendment
Revised for consistency with text regarding Part A.


TAK-385 
TB-AK160108
Page 107 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 48, Section 8.1.3.2 Criteria for Dose Holds and Dose Reduction
Existing Text
Table 8.c
Guidelines for Handling Liver Function Test Abnormalities
Category ALT, AST, and Total 
Bilirubin
Study Drug
ALT and AST Tests Treatment 
Interruption
Dose 
Adjustment
A
ALT or AST ≥ 1.5 ULN to 
< 3 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week for 2 weeks, 
and then every 2 
weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
B
ALT or AST ≥ 3 ULN to 
< 5 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week for 2 weeks, and 
then every 2 weeks
for 4 weeks until 
stable*1
Not 
necessary
Not necessary
C
ALT or AST ≥ 5 ULN to 
< 8 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests in the 
first week, then every 
week for 2 weeks, 
and then every 2 
weeks until stable*1
Interrupt
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg
D
ALT or AST > 8 ULN to 
< 20 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests a 
week for the first 2 
weeks, and then every 
2 weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg*2
E
ALT or AST ≥ 3ULN
AND
Total bilirubin > 2 ULN
(Hy’s law)
Permanently 
discontinue 
treatment
Perform 2 tests a 
week until the test 
values drop, and then 
every week until 
stable*1
N/A
N/A


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23 January, 2015
CONFIDENTIAL
Revised Text
Table 8.c
Guidelines for Handling Liver Function Test Abnormalities
Category ALT, AST, and Total 
Bilirubin
Study Drug
ALT and AST Tests Treatment 
Interruption
Dose 
Adjustment
A
ALT or AST ≥ 1.5 ULN to 
< 3 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week for 2 weeks, 
and then every 2 
weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
B
ALT or AST ≥ 3 ULN to 
< 5 ULN
AND
Total bilirubin < 1.5 ULN
Continue 
without 
changing the 
dose
Perform tests every 
week, and then every 
2 weeks for 4 weeks 
until stable*1
Not 
necessary
Not necessary
C
ALT or AST ≥ 5 ULN to 
< 8 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests in the 
first week, then every 
week for 2 weeks, 
and then every 2 
weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg
D
ALT or AST ≥ 8 ULN to 
< 20 ULN
AND
Total bilirubin < 1.5 ULN
Interrupt 
treatment
Perform 2 tests a 
week for the first 2 
weeks, and then every 
2 weeks until stable*1
Interrupt 
treatment 
until stable*1
Reduce the 
TAK-385 dose 
to 40 mg*2
E
ALT or AST ≥ 3ULN
AND
Total bilirubin > 2 ULN
(Hy’s law)
Permanently 
discontinue 
treatment
Perform 2 tests a 
week until the test 
values drop, and then 
every week until 
stable*1
N/A
N/A
Rationale for Amendment
Correction of typographical error.


TAK-385 
TB-AK160108
Page 109 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 52, Section 9.1.8 Clinical Laboratory Tests
Existing Text
Table 9.a
Clinical Laboratory Tests
Hematology
Chemistry
Metabolic Panel
Urinalysis
RBC
WBC
Hemoglobin
Hematocrit
Platelet count
Differential WBC 
(neutrophils [including 
absolute count], 
basophils, eosinophils, 
lymphocytes, 
monocytes)
Total protein
Albumin
Glucose
Creatinine
BUN
Uric acid
Total bilirubin
ALT
AST
LDH
-GTP
ALP
CK (CPK)
Na
K
Cl
Ca
P
PT-INR
Triglycerides
Total cholesterol
HDL cholesterol
LDL cholesterol
TSH
HbA1c
pH
Specific gravity
Protein (qualitative)
Glucose (qualitative) 
Occult blood 
(qualitative)
Ketones (qualitative)
Urobilinogen 
(qualitative)
Bilirubin (qualitative)
Tests to be conducted when determining eligibility
(to be performed only when deemed necessary)
HIV test, hepatititis tests including HBsAg and anti-HCV


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Page 110 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Revised Text
Table 9.a
Clinical Laboratory Tests
Hematology
Chemistry
Metabolic Panel
Urinalysis
RBC
WBC
Hemoglobin
Hematocrit
Platelet count
Differential WBC 
(neutrophils [including 
absolute count], 
basophils, eosinophils, 
lymphocytes, 
monocytes)
Total protein
Albumin
Glucose
Creatinine
BUN
Uric acid
Total bilirubin
ALT
AST
LDH
-GTP
ALP
CK (CPK)
Na
K
Cl
Ca
P
PT-INR
Triglycerides
Total cholesterol
HDL cholesterol
LDL cholesterol
TSH
HbA1c
pH
Specific gravity
Protein (qualitative)
Glucose (qualitative) 
Occult blood 
(qualitative)
Ketones (qualitative)
Urobilinogen 
(qualitative)
Bilirubin (qualitative)
Tests to be conducted when determining eligibility
(to be performed only when deemed necessary)
HIV test; hepatititis tests including HBsAg and anti-HCV; serologic test for syphilis
Rationale for Amendment
Editorial change.
Page 57, Section 9.3.1 Screening
Existing Text
•••

12-lead ECG

Imaging assessments
•••
Revised Text
•••

12-lead ECG


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CONFIDENTIAL

Chest X-ray examination

Imaging assessments
•••
Rationale for Amendment
Editorial change.
Page 58, Section 9.3.3 Day of Study Treatment Initiation
Existing Text
The following tests, observations, and assessments will be performed before study drug is 
administered on the day of study treatment initiation. If clinical laboratory tests were 
performed at screening up to 3 days prior to treatment initiation, then they may be used as 
the tests performed prior to treatment initiation.
•••
Revised Text
The following tests, observations, and assessments will be performed before study drug is 
administered on the day of study treatment initiation. If 12-lead ECG or clinical
laboratory tests were performed at screening up to 3 days prior to treatment initiation, 
then they may be used as the tests performed prior to treatment initiation.
•••
Rationale for Amendment
Revised to better fit the actual situation at investigational sites.
Page 66, Section 10.1.3 Additional Points to Consider for Pretreatment Events and 
Adverse Events
Existing Text
•••
Changes in severity of AEs/serious PTEs:
If the subject experiences changes in severity of an AE/serious PTE, the event sould be 
captured once withmaximum severity recorded.
Underlying disease:
•••
Revised Text
•••
Underlying disease:


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23 January, 2015
CONFIDENTIAL
•••
Rationale for Amendment
Deleted due to inconsistency with the conditions stipulated in Section 10.1.6.
Page 73, Section 10.2.1.3 Reporting of Special Interest Adverse Events
Existing Text
•••The principal investigator will also prepare a report of LFT abnormalities (same report 
form as for SAEs) within 10 business days, and submit it with a signature or printed 
name and personal seal to the contact identified in the attachment.  The " Liver Function 
Test Abnormality Reporting Checklist (Appendix I)" will be used as reference to assist in 
the preparation of the report.
•••
Revised Text
•••The principal investigator will also prepare a report of LFT abnormalities (same report 
form as for SAEs) within 10 business days, and submit it with a signature or printed 
name and personal seal to the contact identified in the attachment. The "Liver Function 
Test Abnormality Reporting Checklist (Appendix I)" will be used as reference to assist in 
the preparation of the report.
•••
Rationale for Amendment
Correction of typographical error. (Note: Does not apply to English protocol.)
Page 74, Section 10.2.2 Collection and Reporting of Serious Adverse Events
Existing Text
•••
After the initial report of the SAE, the principal investigator will immediately report 
detailed information to the sponsor.•••
Revised Text
•••
After the initial report of the SAE, the principal investigator will report detailed 
information to the sponsor within 10 calendar days.•••
Rationale for Amendment
Clarification of the due date for reporting.


TAK-385 
TB-AK160108
Page 113 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 79, Section 13.1.1 Analysis Sets
Existing Text
•••The DLT analysis set will be defined as all subjects who can be evaluated for DLTs 
(see Section 6.1.1.3).  The analysis sets will be defined in detail in the separately prepared 
"Rules for Handling Analytical Data."
Revised Text
•••The DLT analysis set will be defined as all subjects who can be evaluated for DLTs 
(see Section 6.1.2.3).  The analysis sets will be defined in detail in the separately prepared 
"Rules for Handling Analytical Data."
Rationale for Amendment
Editorial change.
Page 79, Section 13.1.3 Efficacy Analysis
Existing Text
1)
PSA
•••Waterfall plots of the change from baseline at the Week 12 dose (LOCF) and the 
change from baseline for the minimum value after the start of study drug treatment will 
be prepared by dose.
Revised Text
1)
PSA
•••Waterfall plots of the change from baseline at Week 13 Day 1 (LOCF) and the change 
from baseline for the minimum value after the start of study drug treatment will be 
prepared by dose.
Rationale for Amendment
Editorial change.


TAK-385 
TB-AK160108
Page 114 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 90 to 91, Appendix A Schedule of Study Procedures (Part A)
Existing Text
Procedurea
Subject consentb
Screening
Treatment Periodc
SFU
Inpatientf
Outpatient
30 to 40 
days after 
the last 
dose
Before 
treatment 
initiation
D -28 to 
D -1g
D1h
D2
D3
D7
D12
D13
D14
D15
D21
D28
Allowable visit 
window
0
±1
0
Confirmation of 
eligibility
X
Subject backgroundj
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
Weight/heightl
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
12-lead ECGm
X
X
X
X
X
Imaging assessmentn
X
Measure as appropriate
Hematology tests
X
Xo
X
X
X
X
X
Blood biochemistry 
tests
X
Xo
X
X
X
X
X
Blood lipid, sugar, 
etc. tests
X
Xo
X
X
Urinalysis
X
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
X
X
X
X
X
X
Tumor marker
X
X
Pharmacokinetic 
assessmentsp
X
X
X
X
X
X
X
X
X
X
PGx sample 
collection
X (during the treatment period)
Concomitant 
medications/ therapies
Collected from the time of informed consent until 30 to 40 days after the last 
dose
Adverse events, etc.
PTEsr
Information collected from study treatment initiation until 30 to 
40 days after the last dose
Study treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: D = Day; ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; PSA = prostate-
specific antigen; SFU = safety follow-up
•••
c Additional examinations/assessments may be performed at the discretion of the investigator.
•••
f Day 1: Day of treatment initiation. As a rule, subjects will not be allowed to leave the investigational site or return 
home during the inpatient period. However, if this is unavoidable, then it may be allowed, at the discretion of the 
investigator.
•••


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Amendment 1
23 January, 2015
CONFIDENTIAL
Revised Text
Appendix A
Schedule of Study Procedures (Part A)
Procedurea
Subject consentb
Screening
Treatment Periodc
SFU
Inpatientf
Outpatient
30 to 40 
days after 
the last 
dose
Before 
treatment 
initiation
D -28 to 
D -1g
D1h
D2
D3
D7
D12
D13
D14
D15
D21
D28
Allowable visit 
window
0
±1
0
Confirmation of 
eligibility
X
Subject backgroundj
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signsk
X
X
X
X
X
X
X
Weight/heightl
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
12-lead ECGm
X
Xo
X
X
X
Chest X-ray 
examination
X
Imaging assessmentn
X
Measure as appropriate
Hematology tests
X
Xo
X
X
X
X
X
Blood biochemistry 
tests
X
Xo
X
X
X
X
X
Blood lipid, sugar, 
etc. tests
X
Xo
X
X
Urinalysis
X
Xo
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
X
X
X
X
X
X
Tumor marker
X
X
Pharmacokinetic 
assessmentsp
X
X
X
X
X
X
X
X
X
X
PGx sample 
collection
X (during the treatment period)
Concomitant 
medications/ therapies
Collected from the time of informed consent until 30 to 40 days after the last 
dose
Adverse events, etc.
PTEsr
Information collected from study treatment initiation until 30 to 
40 days after the last dose
Study treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: D = Day; ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; SFU = safety 
follow-up
•••
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
•••
f Day 1: Day of treatment initiation. As a rule, subjects will not be allowed to leave the investigational site or return 
home during the inpatient period. However, the investigator or sub-investigator may allow the subject to return 
home temporarily.
•••
Rationale for Amendment
Editorial change, and revision for consistency with description in Section 7.4.


TAK-385 
TB-AK160108
Page 116 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 92 to 93, Appendix B Schedule of Study Procedures (Part B – Screening to 
Week 48, SFU)
Existing Text
Procedurea
Informed consentb
Screening
Treatment Periodcd
SFU
Visit Day
Before 
treatment 
initiatione
D -28 to D -1f
WK
1
WK
1
WK
1
WK
2
WK
3
WK
5
WK
9
WK
13
30 to 40 
days after 
the last 
dose
D1h
D2
D4
D1
D1
D1
D1
D1
Allowable visit 
window
0
0
0
±1
±1
±2
±2
±2
Confirmation of 
eligibility
X
Subject backgroundi
X
Physical examination
X
X
X
X
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
X
X
Weight/heightk
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
12-lead ECGl
X
X
X
X
X
Ophthalmology tests
X
Imaging assessment
X
Bone density (DXA 
method)
X
Hematology tests
Xm
Xm
X
X
X
X
Blood biochemistry 
tests
Xm
Xm
X
X
X
X
Blood lipid, sugar, etc. 
tests
Xm
Xm
X
X
X
X
Urinalysis
X
X
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
Xn
X
X
Xn
Xn
Xn
Xn
Xn
Tumor marker
X
X
X
X
BMP concentrationo
X
X
Pharmacokinetic 
assessmentsp
X
X
X
X
X
X
X
X
PGx sample collection
X (randomization through the treatment period)
QOL assessments
X
X
X
X
X
X
Concomitant 
medications/ therapies
Collected from the time of informed consent until 30 to 40 days after the last 
dose
Adverse events, etc.
PTEsr
Information collected from study treatment initiation until 30 
to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: WK = Week; D = Day;  ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; 
QOL = quality of life; SFU = safety follow-up
•••
c Additional examinations/assessments may be performed at the discretion of the investigator.
•••
l 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
m Results of tests performed up to 3 days before treatment initiation may be used at the D1 test results.
n Blood samples will also be collected for the serum testosterone high-sensitivity measurements. However, at W1D1, 
only the high-sensitivity measurements will be performed.
o Blood and urine sample collection
p See Appendix E for detailed sample collection times
q As a rule, blood samples will also be collected at withdrawal from the study.
r Information will be collected from consent acquisition until treatment initiation.


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23 January, 2015
CONFIDENTIAL
Revised Text (Note: Footnote number carried down in the same manner in the area 
of the table not displayed below)
Procedurea
Informed consentb
Screening
Treatment Periodcd
SFU
Visit Day
Before 
treatment 
initiatione
D -28 to D -1f
WK
1
WK
1
WK
1
WK
2
WK
3
WK
5
WK
9
WK
13
30 to 40 
days after 
the last 
dose
D1h
D2
D4
D1
D1
D1
D1
D1
Allowable visit 
window
0
0
0
±1
±1
±2
±2
±2
Confirmation of 
eligibility
X
Subject backgroundi
X
Physical examination
X
X
X
X
X
X
X
X
X
X
Vital signsj
X
X
X
X
X
X
X
X
Weight/heightk
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
12-lead ECGl
X
Xn
X
X
X
Chest X-ray 
examination
X
Ophthalmology tests
X
Imaging assessmentm
X
Bone density (DXA 
method)
X
Hematology tests
X
Xn
X
X
X
X
Blood biochemistry 
tests
X
Xn
X
X
X
X
Blood lipid, sugar, 
etc. tests
X
Xn
X
X
X
X
Urinalysis
X
Xn
X
X
X
X
Heart-related tests
X
Measure as appropriate
Pharmacodynamic 
assessments
X
Xo
X
X
Xo
Xo
Xo
Xo
Xo
Tumor marker
X
X
X
X
BMP concentrationp
X
X
Pharmacokinetic 
assessmentsq
X
X
X
X
X
X
X
X
PGx sample 
collection
X (randomization through the treatment period)
QOL assessments
X
X
X
X
X
X
Concomitant 
medications/ 
therapies
Collected from the time of informed consent until 30 to 40 days after the last 
dose
Adverse events, etc.
PTEss
Information collected from study treatment initiation until 
30 to 40 days after the last dose
treatment
Oral doses once a day at least 30 minutes before breakfast
Abbreviations: WK = Week; D = Day;  ECOG = Eastern Cooperative Oncology Group; PGx = pharmacogenomics; 
QOL = quality of life; SFU = safety follow-up
•••
c Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
•••
l 12-lead ECG measurements will be taken after the subject has been lying down for at least 5 minutes.
m Performed at screening only if imaging assessments were not performed within 28 days prior to treatment 
initiation, or if no usable images are available for the subject.
n Results of tests performed up to 3 days before treatment initiation may be used as the D1 test results.
o Blood samples will also be collected for the serum testosterone high sensitivity measurements.  However, at WK1D1, 
only the high-sensitivity measurements will be performed.


TAK-385 
TB-AK160108
Page 118 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
p Blood and urine sample collection
q See Appendix E for detailed sample collection times
r As a rule, blood samples will also be collected at withdrawal from the study.
s Information will be collected from consent acquisition until treatment initiation.
Rationale for Amendment
Editorial change, and revision to better fit the actual situation at investigational sites.
Page 94, Appendix C Schedule of Study Procedures (Part B – Weeks 49 to 96)
Existing Text
Abbreviations: WK = Week; D = Day; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; SFU = 
safety follow-up
•••
b
Additional examinations/assessments may be performed at the discretion of the investigator.
•••
Revised Text
Abbreviations: WK = Week; D = Day; ECOG = Eastern Cooperative Oncology Group; QOL = quality of life; SFU = 
safety follow-up
•••
b
Additional examinations/assessments may be performed at the discretion of the investigator or sub-investigator.
•••
Rationale for Amendment
Correction of typographical error (Note: Does not apply to English protocol.), and 
revision to better fit the actual situation at investigational sites.
Page 95, Appendix D Schedule of Blood Samples Collection for Pharmacokinetic 
Analysis (Part A)
Existing Text
Abbreviations: WK = week; D = day
•••
c
Blood samples for PK analysis will be collected within 1 hour before dosing.
•••
Revised Text
Abbreviations: D = day
•••
c
Blood samples for PK analysis will be collected within 1 hour before dosing.
•••
Rationale for Amendment
Editorial change.


TAK-385 
TB-AK160108
Page 119 of 119
Amendment 1
23 January, 2015
CONFIDENTIAL
Page 96, Appendix E Schedule of Blood Samples Collection for Pharmacokinetic 
Analysis (Part B)
Existing Text
Time Pointa
Dosing Time Pointb
WK1
WK2
WK 3
WK 5
WK 25
WK 37
WK 49
D1c
D2
D4
D1
D1
D1
D1
D1
D1
Before dosingd
X
X
X
X
X
X
X
X
X
2 hours postdose
X
X
Abbreviations: WK = week; D = day
•••
Revised Text
Time Pointa
Dosing Time Pointb
WK1
WK2
WK3
WK5
WK25
WK37
WK49
D1c
D2
D4
D1
D1
D1
D1
D1
D1
Before dosingd
X
X
X
X
X
X
X
X
X
2 hours postdose 
(± 20 min)
X
X
Abbreviations: WK = week; D = day
•••
Rationale for Amendment
Editorial change.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d6806c6dd6
A Phase 1, Open-label, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and
Pharmacodynamics of TAK-385 Alone in Hormone Treatment-naive Japanese Patients With Non-metastatic
Prostate Cancer
Clinical Approval
26-Sep-2017 01:43 UTC

SAP_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or company 
confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 


Protocol No. TAK-385/TB-AK160108 
 
 
Statistical Analysis Plan 
 
 
 
Study Title: A Phase 1, Open-label, Multicenter Study to Evaluate the Tolerability, 
Safety, Pharmacokinetics, and Pharmacodynamics of TAK-385 Alone in 
Hormone Treatment-naive Japanese Patients With Non-metastatic Prostate 
Cancer 
Study Number: TAK-385/TB-AK160108 
Sponsor: Takeda Pharmaceutical Company Limited 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 2.0: July 20, 2017 
 


Protocol No. TAK-385/TB-AK160108 
 
1 
Table of Contents  
 
Glossary ................................................................................................................................................ 4 
Definition of Visit Window .................................................................................................................. 5 
Others .................................................................................................................................................. 19 
1 Study Subjects, Demographics, and Other Baseline Characteristics (Part A) ................................. 20 
1.1 Disposition of Subjects ................................................................................................................. 20 
1.1.1 Study Information (Part A and Part B) .................................................................................. 20 
1.1.2 Screen Failures ....................................................................................................................... 20 
1.1.3 Subject Eligibility .................................................................................................................. 21 
1.1.4 Number of Subjects Who Entered the Treatment Period by Site and Treatment Group........ 21 
1.1.5 Disposition of Subjects .......................................................................................................... 22 
1.1.6 Protocol Deviations and Analysis Sets .................................................................................. 23 
1.2 Demographics and Other Baseline Characteristics ....................................................................... 24 
1.2.1 Summary of Demographics and Other Baseline Characteristics ........................................... 24 
1.2.2 Medical History and Concurrent Medical Conditions ........................................................... 25 
1.2.3 Medication History and Concomitant Medications ............................................................... 25 
1.3 Treatment Compliance .................................................................................................................. 26 
1.3.1 Study Drug Exposure and Compliance .................................................................................. 26 
2 Study Subjects, Demographics, and Other Baseline Characteristics (Part B) .................................. 27 
2.1 Disposition of Subjects ................................................................................................................. 27 
2.1.1 Screen Failures ....................................................................................................................... 27 
2.1.2 Subject Eligibility .................................................................................................................. 27 
2.1.3 Number of Subjects Randomized by Site and Treatment Group ........................................... 27 
2.1.4 Disposition of Subjects .......................................................................................................... 28 
2.1.5 Study Drug Completion Status .............................................................................................. 29 
2.1.6 Protocol Deviations and Analysis Sets .................................................................................. 30 
2.2 Demographics and Other Baseline Characteristics ....................................................................... 31 
2.2.1 Summary of Demographics and Other Baseline Characteristics ........................................... 31 
2.2.2 Medical History and Concurrent Medical Conditions ........................................................... 32 
2.2.3 Medication History and Concomitant Medications ............................................................... 32 
2.3 Treatment Compliance .................................................................................................................. 33 
2.3.1 Study Drug Exposure and Compliance .................................................................................. 33 
2.3.2 Dosing Pattern Details ........................................................................................................... 34 
3 Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis (Part A) ............................................ 35 
3.1 Efficacy Analysis .......................................................................................................................... 35 
3.1.1 Antitumor Effects................................................................................................................... 35 


Protocol No. TAK-385/TB-AK160108 
 
2 
3.2 Pharmacokinetic Analysis ............................................................................................................. 35 
3.2.1 Plasma Concentrations ........................................................................................................... 35 
3.2.2 Pharmacokinetic Parameters .................................................................................................. 35 
3.3 Pharmacodynamic Analysis .......................................................................................................... 37 
3.3.1 Serum Testosterone Concentrations ....................................................................................... 37 
3.3.2 Serum Concentrations of LH, FSH, DHT, and SHBG .......................................................... 37 
3.4 Statistical/Analytical Issues .......................................................................................................... 37 
3.4.1 Adjustments for Covariates .................................................................................................... 37 
3.4.2 Handling of Dropouts or Missing Data .................................................................................. 38 
3.4.3 Interim Analyses and Data Monitoring .................................................................................. 38 
3.4.4 Multicenter Studies ................................................................................................................ 38 
3.4.5 Multiple Comparison/Multiplicity ......................................................................................... 38 
3.4.6 Use of an "Efficacy Subset" of Subjects ................................................................................ 38 
3.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority ........................... 38 
3.4.8 Examination of Subgroups ..................................................................................................... 38 
4 Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis (Part B) ............................................ 39 
4.1 Efficacy Analysis .......................................................................................................................... 39 
4.1.1 Antitumor Effects................................................................................................................... 39 
4.1.2 QOL Assessment ................................................................................................................... 40 
4.2 Pharmacokinetic Analysis ............................................................................................................. 40 
4.2.1 Plasma Concentrations ........................................................................................................... 40 
4.3 Pharmacodynamic Analysis .......................................................................................................... 41 
4.3.1 Serum Testosterone Concentrations ....................................................................................... 41 
4.3.2 Serum Concentrations of LH, FSH, DHT, and SHBG .......................................................... 41 
4.4 Statistical/Analytical Issues .......................................................................................................... 43 
4.4.1 Adjustments for Covariates .................................................................................................... 43 
4.4.2 Handling of Dropouts or Missing Data .................................................................................. 43 
4.4.3 Interim Analyses and Data Monitoring .................................................................................. 43 
4.4.4 Multicenter Studies ................................................................................................................ 43 
4.4.5 Multiple Comparison/Multiplicity ......................................................................................... 43 
4.4.6 Use of an "Efficacy Subset" of Subjects ................................................................................ 43 
4.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority ........................... 43 
4.4.8 Examination of Subgroups ..................................................................................................... 43 
5 Safety Analysis (Part A) .................................................................................................................. 44 
5.1 Treatment-Emergent Adverse Events ........................................................................................... 44 
5.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 44 
5.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 45 


Protocol No. TAK-385/TB-AK160108 
 
3 
5.1.3 Displays of Dose-Limiting Toxicities .................................................................................... 47 
5.2 Pretreatment Events ...................................................................................................................... 47 
5.2.1 Displays of Pretreatment Events ............................................................................................ 47 
5.3 Laboratory and Other Safety Data ................................................................................................ 48 
5.3.1 Laboratory Test Results ......................................................................................................... 48 
5.3.2 Vital Signs, Physical Findings, and Other Observations Related to Safety ........................... 50 
5.4 Displays of Treatment-Emergent Adverse Events (Japanese) ...................................................... 52 
6 Safety Analysis (Part B)................................................................................................................... 53 
6.1 Treatment-Emergent Adverse Events ........................................................................................... 53 
6.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 53 
6.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 54 
6.2 Pretreatment Events ...................................................................................................................... 56 
6.2.1 Displays of Pretreatment Events ............................................................................................ 56 
6.3 Laboratory and Other Safety Data ................................................................................................ 57 
6.3.1 Laboratory Test Results ......................................................................................................... 57 
6.3.2 Vital Signs, Physical Findings, and Other Observations Related to Safety ........................... 60 
6.4 Displays of Treatment-Emergent Adverse Events (Japanese) ...................................................... 62 
7 Significance Level and Confidence Coefficient (Part A and Part B) ............................................... 62 
Amendment History ............................................................................................................................ 63 
Appendix 1. Amendments from the Previous Version ......................................................................... 1 
Appendix 2. Criteria for Markedly Abnormal Values and Elevated Liver Enzyme ............................. 1 
Appendix 3. QOL Scoring Procedures ................................................................................................. 1 
 


Protocol No. TAK-385/TB-AK160108 
 
4 
Glossary 
• 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs on or 
after the start of study drug 
• 
Descriptive statistics: number of subjects, mean, standard deviation (SD), maximum (max), 
minimum (min), and quartiles 
• 
CV: coefficient of variation 
• 
Randomized set: All subjects who were randomized. The first maintenance dose prescribed will 
be used as the treatment group when conducting analyses. 
• 
Treatment group: For part A, the assigned cohort will be the treatment group. For part B, the 
first maintenance dose prescribed will be the treatment group. 
• 
PK: pharmacokinetic 
• 
MAV: markedly abnormal value 
• 
ATC: anatomical therapeutic chemical 
• 
LDH: lactic dehydrogenase 
• 
GGT: gamma-glutamyl transpeptidase 
• 
CK (CPK): creatine phosphokinase/kinase 
• 
Study Day: The day before the first dose of the study drug will be defined as Study Day -1 and 
the day of the first dose will be defined as Study Day 1. If the date of the observation is on the 
same date or after the day of the first dose, Study Day will be calculated relative to Study Day 1. 
Otherwise, Study Day will be calculated relative to Study Day -1. 
• 
Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up Day 
1. Follow-up Day will be calculated relative to Day 1. 


Protocol No. TAK-385/TB-AK160108 
 
5 
Definition of Visit Window 
When calculating Study Day relative to a reference date (i.e., date of first dose of study drug [Day 
1]), if the date of the observation is on the same date or after the reference date, it will be calculated 
as: date of observation - reference date + 1; otherwise, it will be calculated as: date of observation - 
reference date. Hence, reference day is always Day 1 and there is no Day 0. When calculating Study 
Time relative to a reference time (i.e., time of each dose of study drug), it will be calculated as: time 
of observation - reference time. 
When calculating Follow-up Day relative to a reference date (i.e., date of last dose of study drug 
[Follow-up Day 0]), it will be calculated as: date of observation - reference date. Hence, reference 
day is always Follow-up Day 0.  
 
All evaluable data (i.e., non-missing and acceptable according to the Handling Rules for Analysis 
Data) will be handled according to the following rules. 
 
For each visit, observation obtained in the corresponding time interval will be used. If more than one 
observation lies within the same visit window, the observation with the closest Study Day/Study 
Time to the scheduled Study Day/Study Time will be used. If there are two observations equidistant 
to the scheduled Study Day/Study Time, the later observation will be used. This does not apply to 
the end of study visit. For the end of study visit, the last observation obtained in the corresponding 
time interval will be used. 
 


Protocol No. TAK-385/TB-AK160108 
 
6 
<Part A> 
PSA 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
D28 
Study Day: 28 
2 - 35 
 
Pharmacokinetic Assessments 
Visit 
Scheduled 
Study Time (hours) 
Time Interval 
Study Day 
(days) 
Study Time 
(hours) 
D1 
-1 
1 
-3.00 - 0.00 
D1 
0.5 
1 
0.33 - 0.67 
D1 
1 
1 
0.75 - 1.24 
D1 
1.5 
1 
1.25 - 1.74 
D1 
2 
1 
1.75 - 2.33 
D1 
4 
1 
3.67 - 4.33 
D1 
6 
1 
5.50 - 6.50 
D1 
8 
1 
7.50 - 8.50 
D1 
12 
1 
11.00 - 13.00 
D2 
-1 
2 
-2.00 - 0.00 
D3 
-1 
3 
-2.00 - 0.00 
D3 
2 
3 
1.67 - 2.33 
D7 
-1 
7 
-2.00 - 0.00 
D7 
2 
7 
1.67 - 2.33 
D12 
-1 
12 
-2.00 - 0.00 
D13 
-1 
13 
-2.00 - 0.00 
D14 
-1 
14 
-2.00 - 0.00 
D14 
0.5 
14 
0.33 - 0.67 


Protocol No. TAK-385/TB-AK160108 
 
7 
Visit 
Scheduled 
Study Time (hours) 
Time Interval 
Study Day 
(days) 
Study Time 
(hours) 
D14 
1 
14 
0.75 - 1.24 
D14 
1.5 
14 
1.25 - 1.74 
D14 
2 
14 
1.75 - 2.33 
D14 
4 
14 
3.67 - 4.33 
D14 
6 
14 
5.50 - 6.50 
D14 
8 
14 
7.50 - 8.50 
D14 
12 
14 
11.00 - 13.00 
D15 
Study Day: 15 
15 
16.00 - 34.00 
(from last dose) 
D21 
Study Day: 21 
18 - 24 
16.00 - 34.00 
(from last dose) 
D28 
-1 
28 
-2.00 - 0.00 
D28 
1 
28 
0.75 - 1.24 
D28 
2 
28 
1.67 - 2.33 
D28 
4 
28 
3.67 - 4.33 
D28 
8 
28 
7.50 - 8.50 
D28 
12 
28 
11.00 - 13.00 
D29 
24 (from D28) 
29 
23.00 - 25.00 
(from D28) 
D30 
48 (from D28) 
30 
44.00 - 52.00 
(from D28) 
D31 
72 (from D28) 
31 
68.00 - 76.00 
(from D28) 
D35 
168 (from D28) 
35 
164.00 - 172.00 
(from D28) 
 


Protocol No. TAK-385/TB-AK160108 
 
8 
Pharmacodynamic Assessments 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
D2 
Study Day: 2 
2 
D3 
Study Day: 3 
3 - 4 
D7 
Study Day: 7 
5 - 10 
D14 
Study Day: 14 
11 - 17 
D21 
Study Day: 21 
18 - 24 
D28 
Study Day: 28 
25 - 29 
D31 
Study Day: 31 
30 - 34 
D35 
Study Day: 35 
35  
 
Laboratory Tests (Hematology, Biochemistry, Urinalysis) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
- 1 
 
D7 
Study Day: 7 
2 - 10 
< 15 
D14 
Study Day: 14 
11 - 17 
< 15 
D21 
Study Day: 21 
18 - 24 
< 15 
D28 
Study Day: 28 
25 – 42 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Laboratory Tests (Lipid and Glycated Hemoglobin in Blood) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
- 1 
 
D28 
Study Day: 28 
2 - 42 
< 15 


Protocol No. TAK-385/TB-AK160108 
 
9 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Vital Signs, Weight 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 
D7 
Study Day: 7 
2 - 10 
< 15 
D14 
Study Day: 14 
11 - 17 
< 15 
D21 
Study Day: 21 
18 - 24 
< 15 
D28 
Study Day: 28 
25 – 42 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
12-Lead Electrocardiogram 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 
D14 
Study Day: 14 
2 - 20 
< 15 
D28 
Study Day: 28 
21 - 42 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
ECOG Performance Status 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 


Protocol No. TAK-385/TB-AK160108 
 
10 
<Part B> 
PSA 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
WK5D1 
Study Day: 29 
2 - 42 
WK9D1 
Study Day: 57 
43 - 70 
WK13D1 
Study Day: 85 
71 - 98 
WK17D1 
Study Day: 113 
99 - 126 
WK21D1 
Study Day: 141 
127 - 154 
WK25D1 
Study Day: 169 
155 - 210 
WK37D1 
Study Day: 253 
211 - 294 
WK49D1 
Study Day: 337 
295 - 378 
WK61D1 
Study Day: 421 
379 - 462 
WK73D1 
Study Day: 505 
463 - 546 
WK85D1 
Study Day: 589 
547 - 630 
WK97D1 
Study Day: 673 
631 - 680 
WK13D1 (LOCF) 
Study Day: 85 
2 - 98 
End of Study 
  
2 -   
 
Pharmacokinetic Assessments 
Visit 
Scheduled 
Study Time (hours) 
Time Interval 
Study Day 
(days) 
Study Time 
(hours) 
WK1D1 
-1 
1 
-3.00 - 0.00 
WK1D1 
2 
1 
1.75 - 2.33 
WK1D2 
-1 
2 
-2.00 - 0.00 
WK1D4 
Study Day: 4 
3 - 6 
16.00 - 34.00 
(from last dose) 


Protocol No. TAK-385/TB-AK160108 
 
11 
Visit 
Scheduled 
Study Time (hours) 
Time Interval 
Study Day 
(days) 
Study Time 
(hours) 
WK2D1 
Study Day: 8 
7 - 12 
16.00 - 34.00 
(from last dose) 
WK3D1 
Study Day: 15 
13 - 22 
16.00 - 34.00 
(from last dose) 
WK5D1 
Study Day: 29 
23 - 43 
-2.00 - 0.00 
WK5D1 
2 
23 - 43 
1.67 - 2.33 
WK9D1 
Study Day: 57 
44 - 71 
16.00 - 34.00 
(from last dose) 
WK13D1 
Study Day: 85 
72 - 99 
16.00 - 34.00 
(from last dose) 
WK17D1 
Study Day: 113 
100 – 127 
16.00 - 34.00 
(from last dose) 
WK21D1 
Study Day: 141 
128 - 155 
16.00 - 34.00 
(from last dose) 
WK25D1 
Study Day: 169 
156 - 183 
16.00 - 34.00 
(from last dose) 
WK37D1 
Study Day: 253 
233 - 274 
16.00 - 34.00 
(from last dose) 
WK49D1 
Study Day: 337 
317 - 358 
16.00 - 34.00 
(from last dose) 
 
Imaging Assessments 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
WK49D1 
Study Day: 337 
2 – 344 
WK97D1 
Study Day: 673 
345 - 680 
 
 


Protocol No. TAK-385/TB-AK160108 
 
12 
QOL Assessment 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0) 
Study Day: 1 
-28 - 1 
 
WK5D1 
Study Day: 29 
2 - 42 
< 15 
WK9D1 
Study Day: 57 
43 - 70 
< 15 
WK13D1 
Study Day: 85 
71 - 112 
< 15 
WK21D1 
Study Day: 141 
113 - 154 
< 15 
WK25D1 
Study Day: 169 
155 - 238 
< 15 
WK45D1 
Study Day: 309 
239 - 322 
< 15 
WK49D1 
Study Day: 337 
323 - 378 
< 15 
WK61D1 
Study Day: 421 
379 - 462 
< 15 
WK73D1 
Study Day: 505 
463 - 546 
< 15 
WK85D1 
Study Day: 589 
547 - 630 
< 15 
WK97D1 
Study Day: 673 
631 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Pharmacodynamic Assessments (Excluding High-Sensitivity Serum Testosterone) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
WK1D2 
Study Day: 2 
2 - 3 
WK1D4 
Study Day: 4 
4 - 5 
WK2D1 
Study Day: 8 
6 - 11 
WK3D1 
Study Day: 15 
12 - 21 
WK5D1 
Study Day: 29 
22 - 42 
WK9D1 
Study Day: 57 
43 - 70 
WK13D1 
Study Day: 85 
71 - 98 


Protocol No. TAK-385/TB-AK160108 
 
13 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
WK17D1 
Study Day: 113 
99 - 126 
WK21D1 
Study Day: 141 
127 - 154 
WK25D1 
Study Day: 169 
155 - 210 
WK37D1 
Study Day: 253 
211 - 294 
WK49D1 
Study Day: 337 
295 - 378 
WK61D1 
Study Day: 421 
379 - 462 
WK73D1 
Study Day: 505 
463 - 546 
WK85D1 
Study Day: 589 
547 - 630 
WK97D1 
Study Day: 673 
631 - 680 
 
ECOG Performance Status 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 
 
Pharmacodynamic Assessments (High-Sensitivity Serum Testosterone) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
WK2D1 
Study Day: 8 
2 - 11 
WK3D1 
Study Day: 15 
12 - 21 
WK5D1 
Study Day: 29 
22 - 42 
WK9D1 
Study Day: 57 
43 - 70 
WK13D1 
Study Day: 85 
71 - 98 
WK17D1 
Study Day: 113 
99 - 126 
WK21D1 
Study Day: 141 
127 - 154 


Protocol No. TAK-385/TB-AK160108 
 
14 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
WK25D1 
Study Day: 169 
155 - 210 
WK37D1 
Study Day: 253 
211 - 294 
WK49D1 
Study Day: 337 
295 - 344 
  


Protocol No. TAK-385/TB-AK160108 
 
15 
Laboratory Tests (Hematology) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
 - 1 
 
WK5D1 
Study Day: 29 
2 - 42 
< 15 
WK9D1 
Study Day: 57 
43 - 70 
< 15 
WK13D1 
Study Day: 85 
71 - 126 
< 15 
WK25D1 
Study Day: 169 
127 - 210 
< 15 
WK37D1 
Study Day: 253 
211 - 294 
< 15 
WK49D1 
Study Day: 337 
295 - 378 
< 15 
WK61D1 
Study Day: 421 
379 - 462 
< 15 
WK73D1 
Study Day: 505 
463 - 546 
< 15 
WK85D1 
Study Day: 589 
547 - 630 
< 15 
WK97D1 
Study Day: 673 
631 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Laboratory Tests (Biochemistry) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
 – 1 
 
WK5D1 
Study Day: 29 
2 - 42 
< 15 
WK9D1 
Study Day: 57 
43 - 70 
< 15 
WK13D1 
Study Day: 85 
71 - 98 
< 15 
WK17D1 
Study Day: 113 
99 - 126 
< 15 
WK21D1 
Study Day: 141 
127 - 154 
< 15 
WK25D1 
Study Day: 169 
155 - 182 
< 15 
WK29D1 
Study Day: 197 
183 - 210 
< 15 
WK33D1 
Study Day: 225 
211 - 238 
< 15 


Protocol No. TAK-385/TB-AK160108 
 
16 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
WK37D1 
Study Day: 253 
239 - 266 
< 15 
WK41D1 
Study Day: 281 
267 - 294 
< 15 
WK45D1 
Study Day: 309 
295 - 322 
< 15 
WK49D1 
Study Day: 337 
323 - 378 
< 15 
WK61D1 
Study Day: 421 
379 - 462 
< 15 
WK73D1 
Study Day: 505 
463 - 546 
< 15 
WK85D1 
Study Day: 589 
547 - 630 
< 15 
WK97D1 
Study Day: 673 
631 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Laboratory Tests (Lipid and Glycated Hemoglobin in Blood, Urinalysis) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
 - 1 
 
WK5D1 
Study Day: 29 
2 - 42 
< 15 
WK9D1 
Study Day: 57 
43 - 70 
< 15 
WK13D1 
Study Day: 85 
71 - 126 
< 15 
WK25D1 
Study Day: 169 
127 - 252 
< 15 
WK49D1 
Study Day: 337 
253 - 378 
< 15 
WK61D1 
Study Day: 421 
379 - 462 
< 15 
WK73D1 
Study Day: 505 
463 - 546 
< 15 
WK85D1 
Study Day: 589 
547 - 630 
< 15 
WK97D1 
Study Day: 673 
631 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 


Protocol No. TAK-385/TB-AK160108 
 
17 
12-Lead Electrocardiogram 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 
WK3D1 
Study Day: 15 
2 – 21 
< 15 
WK5D1 
Study Day: 29 
22 - 98 
< 15 
WK25D1 
Study Day: 169 
99 – 252 
< 15 
WK49D1 
Study Day: 337 
253 – 420 
< 15 
WK73D1 
Study Day: 505 
421 – 588 
< 15 
WK97D1 
Study Day: 673 
589 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 
 
Vital Signs, Weight 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
 
WK2D1 
Study Day: 8 
2 – 11 
< 15 
WK3D1 
Study Day: 15 
12 - 21 
< 15 
WK5D1 
Study Day: 29 
22 - 42 
< 15 
WK9D1 
Study Day: 57 
43 - 70 
< 15 
WK13D1 
Study Day: 85 
71 - 126 
< 15 
WK25D1 
Study Day: 169 
127 - 252 
< 15 
WK49D1 
Study Day: 337 
253 - 378 
< 15 
WK61D1 
Study Day: 421 
379 - 462 
< 15 
WK73D1 
Study Day: 505 
463 - 546 
< 15 
WK85D1 
Study Day: 589 
547 - 630 
< 15 
WK97D1 
Study Day: 673 
631 - 687 
< 15 
SFU 
Follow-up Day: 40 
 
15 - 40 


Protocol No. TAK-385/TB-AK160108 
 
18 
Bone Mineral Density (DXA) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Baseline (Week 0)  
Study Day: 1 
-28 - 1 
WK25D1 
Study Day: 169 
2 - 252 
WK49D1 
Study Day: 337 
253 - 420 
WK73D1 
Study Day: 505 
421 - 588 
WK97D1 
Study Day: 673 
589 - 713 
 


Protocol No. TAK-385/TB-AK160108 
 
19 
Others 
• 
Duration of exposure to study drug (days) : date of last dose of study drug - date of first dose of 
study drug + 1 
• 
Dose intensity (mg/day): total amount of doses taken / duration of exposure to study drug 
(rounded to 1 decimal place) 
• 
Relative dose intensity (%): (total amount of doses taken / total dose expected per initial dose) * 
100 (rounded to 1 decimal place) 
• 
Dosing compliance: (total amount of doses taken / total dose expected) * 100 (rounded to 1 
decimal place) 
• 
Disease duration (days): date subject signed Informed Consent Form - date of diagnosis + 1 
 
For the date subject signed Informed Consent Form, the year, the month, and the day will 
be used for the calculation. 
 
If the year is unknown, then the date of diagnosis will be treated as missing. If the month is 
unknown, then the month will be treated as January and the day will be treated as the 1st 
day of the month. If only the day is unknown, then the day will be treated as the 1st day of 
the month for the calculation. 
• 
PK parameters: 
 
AUClast --Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration. 
 
AUClast, ss --Area under the concentration-time curve from time 0 to time of the last 
quantifiable concentration, at steady state. 
 
AUCτ --Area under the concentration-time curve during a dosing interval (= 24 hours). 
 
AUCτ, ss --Area under the concentration-time curve during a dosing interval (= 24 hours), 
at steady state. 
 
AUCτ, ss/D --Dose-normalized AUCτ, at steady state. 
 
CL/Fss --Apparent clearance after extravascular administration, at steady state, calculated 
using AUCτ. 
 
Cmax --Maximum observed concentration. 
 
Cmax, ss --Maximum observed concentration, at steady state. 
 
Cmax, ss/D --Dose-normalized Cmax, at steady state. 
 
Cmin, ss --Minimum observed concentration during a dosing interval, at steady state. 
 
λz --Terminal disposition phase rate constant. 
 
tmax --Time of first occurrence of Cmax. 
 
tmax, ss --Time of first occurrence of Cmax, at steady state. 
 
t1/2z --Terminal disposition phase half-life. 
 
Vz/Fss --Apparent volume of distribution during the terminal disposition phase after 
extravascular administration, calculated using AUCτ. 


Protocol No. TAK-385/TB-AK160108 
 
20 
1 Study Subjects, Demographics, and Other Baseline Characteristics (Part A) 
1.1 Disposition of Subjects 
1.1.1 Study Information (Part A and Part B) 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Date First Subject Signed Informed Consent Form 
 
Date of Last Subject’s Last Visit/Contact 
 
MedDRA Version 
 
WHO Drug Version 
 
SAS Version Used for Creating the Datasets 
Analytical 
Method(s) : 
 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
 
1.1.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis 
Variable(s) : 
 
Age (years)  
 
[Min<= - <=64, 65<= - <=74, 
75<= - <=Max] 
 
Gender 
[Male, Female] 
Analytical 
Method(s) : 
 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 
 


Protocol No. TAK-385/TB-AK160108 
 
21 
1.1.3 Subject Eligibility 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
Eligibility Status 
 
 
Primary Reason for Subject Not 
Being Eligible 
[Eligible for Entrance into the 
Treatment Period, Not Eligible for 
Entrance into the Treatment Period] 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Did Not Meet 
Entrance Criteria, Other] 
Analytical 
Method(s) : 
 
(1) Eligibility for Entrance into the Treatment Period 
Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being eligible, the total number of 
ineligible subjects will be used as the denominator. 
 
1.1.4 Number of Subjects Who Entered the Treatment Period by Site and Treatment Group 
Analysis Set: All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s) : 
 
Status 
of 
Entrance 
into 
the 
Treatment Period 
 
[Entered] 
Stratum: 
Site 
[Site numbers will be used as categories] 
Analytical 
Method(s) : 
 
(1) Number of Subjects Who Entered the Treatment Period by Site and 
Treatment Group 
Frequency distribution will be provided for each stratum by treatment group 
and overall. 
 


Protocol No. TAK-385/TB-AK160108 
 
22 
1.1.5 Disposition of Subjects 
Analysis Set: All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s) : 
 
Study Drug Administration Status 
 
[Eligible but Not Treated] 
 
Reason for Not Being Treated 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
 
Study Drug Completion Status 
[Completed Study Drug, Prematurely 
Discontinued Study Drug] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
 
Completion Status of the Safety 
Follow-up 
[Completed Safety Follow-up, 
Prematurely Discontinued Safety 
Follow-up] 
 
Reason for Discontinuation of the 
Safety Follow-up 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
Analytical 
Method(s) : 
 
(1) Disposition of Subjects 
Frequency distributions will be provided for each treatment group and 
overall. When calculating percentages for the reasons for not being treated, 
the total number of subjects not treated by the study drug will be used as the 
denominator. 
When 
calculating 
percentages 
for 
the 
reasons 
for 
discontinuation of study drug, the total number of subjects who prematurely 
discontinued the study drug will be used as the denominator. When 
calculating percentages for the reasons for discontinuation of the safety 
follow-up, the total number of subjects who prematurely discontinued the 
safety follow-up will be used as the denominator. 
 


Protocol No. TAK-385/TB-AK160108 
 
23 
1.1.6 Protocol Deviations and Analysis Sets 
1.1.6.1 
Protocol Deviations 
Analysis Set: All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s) : 
 
Protocol Deviation 
 
[Major GCP Violations, Deviations of Protocol 
Entry Criteria, Deviations of Discontinuation 
Criteria, Deviations Related to Treatment 
Procedure or Dose, Deviations Concerning 
Excluded Medication or Therapy, Deviations to 
Avoid Emergency Risk] 
Analytical 
Method(s) : 
 
(1) Protocol Deviations 
Frequency distribution will be provided by treatment group and overall for 
each deviation category. A subject who has several deviations will be counted 
once in each appropriate category. A subject who has several deviations that 
can be classified into the same category will be counted only once. 
 
1.1.6.2 
Analysis Sets 
Analysis Set: All Subjects Who Entered the Treatment Period 
Analysis 
Variable(s) : 
 
Handling of Subjects and Subject Data 
 
 
Analysis Sets 
Full Analysis Set 
Safety Analysis Set 
DLT Analysis Set 
Pharmacokinetic Analysis Set 
 
[Categories are based on the 
specifications 
in 
Handling 
Rules for Analysis Data] 
 
[Included] 
[Included]  
[Included] 
[Included] 
Analytical 
Method(s) : 
 
(1) Subjects Excluded from Analysis Sets 
(2) Subject Data Excluded from Analysis Sets 
(3) Analysis Sets 
Frequency distributions will be provided by treatment group for (1) and (2) 
and by treatment group and overall for (3). For (1) and (2), a subject who has 
several reasons for exclusion will be counted once in each appropriate 
category. A subject who has several reasons for exclusion that can be 
classified into the same category will be counted only once. 


Protocol No. TAK-385/TB-AK160108 
 
24 
1.2 Demographics and Other Baseline Characteristics 
1.2.1 Summary of Demographics and Other Baseline Characteristics 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
[Min<= - <=64, 65<= - <=74, 
75<= - <=Max]  
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) (Week 0) 
 
 
BMI (kg/m2) (Week 0) 
 
 
Smoking Classification 
 
 
[The subject has never smoked,  
The subject is a current smoker,  
The subject is an ex-smoker] 
 
ECOG Performance Status (Week 
0) 
[0, 1, 2, 3, 4] 
 
Diagnostic Method 
[Histological Diagnosis, Cytological 
Diagnosis, Other] 
 
Disease Duration (days) 
 
 
Gleason Grading System (Gleason 
Score) 
[2, 3, 4, 5, 6, 7, 8, 9, 10] 
 
Histologic Type 
[Adenocarcinoma, Other] 
 
Degree of Differentiation 
[Well Differentiated 
Adenocarcinoma, Moderately 
Differentiated Adenocarcinoma, 
Poorly Differentiated 
Adenocarcinoma,  
Unclassified Adenocarcinoma] 
 
TNM Classification T 
[T0, T1, T2, T3, T4, TX] 
 
TNM Classification N 
[N0, N1, NX] 
 
TNM Classification M 
[M0, M1, MX] 
 
Prostatectomy 
[Yes, No] 
 
Radical Prostatectomy 
[Yes, No] 
 
High-Intensity Focused Ultrasound 
[Yes, No] 
 
Radiation Therapy 
[Yes, No] 
 
Other Treatment 
[Yes, No] 
 
PSA (ng/mL) (Week 0) 
 
 
Testosterone (ng/mL) (Week 0) 
 


Protocol No. TAK-385/TB-AK160108 
 
25 
Analytical 
Method(s) : 
 
(1) Summary of Demographics and Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics 
for continuous variables will be provided by treatment group and overall. 
 
1.2.2 Medical History and Concurrent Medical Conditions 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medical History 
 
Concurrent Medical Conditions 
Analytical 
Method(s) : 
 
(1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and Preferred 
Term 
Frequency distributions will be provided for each treatment group and 
overall. MedDRA dictionary will be used for coding. Summaries will be 
provided using SOC and PT, where SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency.  
A subject with multiple occurrences of medical history or concurrent medical 
condition within a SOC will be counted only once in that SOC. A subject 
with multiple occurrences of medical history or concurrent medical condition 
within a PT will be counted only once in that PT. 
 
1.2.3 Medication History and Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medication History 
 
Concomitant Medications 
Analytical 
Method(s) : 
 
(1) Medication History by Preferred Medication Name 
(2) Concomitant Medications That Started Prior to and Were Ongoing at 
Baseline as well as Those That Started After Baseline by ATC    
Pharmacological Subgroup and Preferred Medication Name 
Frequency distributions will be provided for each treatment group and 
overall. WHO Drug dictionary will be used for coding. Summaries will be 
provided using preferred medication names for (1) and using both ATC 
pharmacological subgroup and preferred medication names for (2). ATC 


Protocol No. TAK-385/TB-AK160108 
 
26 
pharmacological subgroup will be sorted alphabetically and preferred 
medication names will be sorted in decreasing frequency based on the 
number of reports. A subject who has been administered several medications 
with the same preferred medication name will be counted only once for that 
preferred medication name. 
 
1.3 Treatment Compliance 
1.3.1 Study Drug Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Duration of Exposure to Study Drug 
(days) 
 
[1<= - <=7, 8<= - <=14, 15<= - <=21, 
22<= - <=Max] 
 
Total Amount of Doses Taken (mg) 
 
 
Dose Intensity (mg/day) 
 
 
Relative Dose Intensity (%) 
 
 
Subjects with Any Dose Held 
[Yes, No] 
 
Reason for Dose Being Held  
 
Adverse Event [Yes] 
 
Other [Yes] 
 
Dosing Compliance (%) 
[Min<= - <=79.9, 80.0<= - <=89.9, 
90.0<= - <=Max] 
Analytical 
Method(s) : 
 
 
(1) Study Drug Exposure and Compliance 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by treatment group and overall. 


Protocol No. TAK-385/TB-AK160108 
 
27 
2 Study Subjects, Demographics, and Other Baseline Characteristics (Part B) 
2.1 Disposition of Subjects 
2.1.1 Screen Failures 
Analysis Set: 
All Subjects Who Were Not Randomized 
 
Analysis 
Variable(s) : 
 
Age (years)  
 
[Min<= - <=64, 65<= - <=74, 
75<= - <=Max] 
 
Gender 
[Male, Female] 
Analytical 
Method(s) : 
 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 
 
2.1.2 Subject Eligibility 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
Eligibility Status 
 
Primary Reason for 
Subject Not Being Eligible 
[Eligible for Randomization, Not Eligible for 
Randomization] 
[Pretreatment Event/Adverse Event, Major 
Protocol Deviation, Lost to Follow-Up, 
Voluntary Withdrawal, Study Termination, 
Did Not Meet Entrance Criteria, Other] 
Analytical 
Method(s) : 
 
(1) Eligibility for Randomization 
Frequency distributions will be provided. When calculating percentages for 
the primary reasons for subject not being eligible, the total number of 
ineligible subjects will be used as the denominator. 
 
2.1.3 Number of Subjects Randomized by Site and Treatment Group 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
 
Randomization Status 
 
[Randomized] 
Stratum: 
Site 
[Site numbers will be used as categories] 
Analytical 
Method(s) : 
 
(1) Number of Subjects Randomized by Site and Treatment Group 
Frequency distribution will be provided for each stratum by treatment group 
and overall. 


Protocol No. TAK-385/TB-AK160108 
 
28 
 
2.1.4 Disposition of Subjects 
Analysis Set: Randomized Set 
Subjects from the Randomized Set Who Completed Study Drug (48 Weeks) 
Analysis 
Variable(s) : 
 
Study Drug Administration Status 
 
[Randomized but Not Treated] 
 
Reason for Not Being Treated 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
 
Study Drug Completion Status (48 
Weeks) 
[Completed Study Drug (48 Weeks), 
Prematurely Discontinued Study 
Drug (48 Weeks)] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
 
Entrance into the Extension 
Treatment Period 
[Entered the Extension Treatment 
Period, Did Not Enter the Extension 
Treatment Period] 
 
Reason for Not Entering the 
Extension Treatment Period 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Start of Other Treatment, Other] 
 
Study Drug Completion Status (96 
Weeks) 
[Completed Study Drug (96 Weeks), 
Prematurely Discontinued Study 
Drug (96 Weeks)] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Completed 48 Weeks of Treatment 
but Did Not Enter Extension, Other] 


Protocol No. TAK-385/TB-AK160108 
 
29 
 
Completion Status of the Safety 
Follow-up 
[Completed Safety Follow-up, 
Prematurely Discontinued Safety 
Follow-up] 
 
Reason for Discontinuation of the 
Safety Follow-up 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Other] 
Analytical 
Method(s) : 
 
(1) Disposition of Subjects 
Randomized set will be used to perform the following analysis, with the 
exception of the summary for entrance into the extension treatment period 
and the reasons for not entering which will use subjects from the randomized 
set who completed study drug (48 weeks). Frequency distributions will be 
provided for each treatment group and overall. When calculating percentages 
for the reasons for not being treated, the total number of subjects not treated 
by the study drug will be used as the denominator. When calculating 
percentages for the reasons for discontinuation at 48 weeks and 96 weeks, the 
total number of subjects who prematurely discontinued the study drug before 
48 weeks and 96 weeks (including subjects who completed 48 weeks of study 
drug treatment but did not enter the extension treatment period), respectively, 
will be used as the denominator. When calculating percentages for the reasons 
for not entering the extension treatment period, the total number of subjects 
who completed 48 weeks of study drug treatment but did not enter the 
extension treatment period will be used as the denominator. 
 
2.1.5 Study Drug Completion Status 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
Study Drug Completion Status (96 
Weeks) 
[Completed Study Drug (96 Weeks), 
Prematurely Discontinued Study 
Drug (96 Weeks)] 
 
Reason for Discontinuation of 
Study Drug 
[Pretreatment Event/Adverse Event, 
Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Lack of Efficacy, 
Completed 48 Weeks of Treatment 
but Did Not Enter Extension, Other] 


Protocol No. TAK-385/TB-AK160108 
 
30 
Categories: 
Duration of Exposure to Study Drug 
(days) 
[0<= - <=90, 91<= - <=180,  
181<= - <=270, 271<= - <=360, 
361<= - <=450, 451<= - <=540, 
541<= - <=630, 631<= - <=Max] 
Analytical 
Method(s) : 
 
(1) Study Drug Completion Status 
Frequency distribution will be provided for each category of duration of 
exposure to study drug by treatment group and overall. 
 
2.1.6 Protocol Deviations and Analysis Sets 
2.1.6.1 
Protocol Deviations 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
 
Protocol Deviation 
 
[Major GCP Violations, Deviations of Protocol 
Entry Criteria, Deviations of Discontinuation 
Criteria, Deviations Related to Treatment 
Procedure or Dose, Deviations Concerning 
Excluded Medication or Therapy, Deviations to 
Avoid Emergency Risk] 
Analytical 
Method(s) : 
 
(1) Protocol Deviations 
Frequency distribution will be provided by treatment group and overall for 
each deviation category. A subject who has several deviations will be counted 
once in each appropriate category. A subject who has several deviations that 
can be classified into the same category will be counted only once. 
 
2.1.6.2 
Analysis Sets 
Analysis 
Set: 
Randomized Set 
Analysis 
Variable(s) : 
 
Handling of Subjects and Subject Data 
 
 
Analysis Sets 
Full Analysis Set 
Safety Analysis Set 
Pharmacokinetic Analysis Set 
 
[Categories 
are 
based 
on 
the 
specifications in Handling Rules for 
Analysis Data] 
 
[Included] 
[Included] 
[Included] 


Protocol No. TAK-385/TB-AK160108 
 
31 
Analytical 
Method(s) : 
 
(1) Subjects Excluded from Analysis Sets 
(2) Subject Data Excluded from Analysis Sets 
(3) Analysis Sets 
Frequency distributions will be provided by treatment group for (1) and (2) 
and by treatment group and overall for (3). For (1) and (2), a subject who 
has several reasons for exclusion will be counted once in each appropriate 
category. A subject who has several reasons for exclusion that can be 
classified into the same category will be counted only once. 
 
2.2 Demographics and Other Baseline Characteristics 
2.2.1 Summary of Demographics and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
[Min<= - <=64, 65<= - <=74, 
75<= - <=Max]  
 
Gender 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) (Week 0) 
 
 
BMI (kg/m2) (Week 0) 
 
 
Smoking Classification 
 
 
[The subject has never smoked,  
The subject is a current smoker,  
The subject is an ex-smoker] 
 
ECOG Performance Status (Week 0) 
[0, 1, 2, 3, 4] 
 
Diagnostic Method 
[Histological Diagnosis, Cytological 
Diagnosis, Other] 
 
Disease Duration (days) 
 
 
Gleason Grading System (Gleason 
Score) 
[2, 3, 4, 5, 6, 7, 8, 9, 10] 
 
Histologic Type 
[Adenocarcinoma, Other] 
 
Degree of Differentiation 
[Well Differentiated 
Adenocarcinoma, Moderately 
Differentiated Adenocarcinoma, 
Poorly Differentiated 
Adenocarcinoma, Unclassified 
Adenocarcinoma] 
 
TNM Classification T 
[T0, T1, T2, T3, T4, TX] 


Protocol No. TAK-385/TB-AK160108 
 
32 
 
TNM Classification N 
[N0, N1, NX] 
 
TNM Classification M 
[M0, M1, MX] 
 
Prostatectomy 
[Yes, No] 
 
Radical Prostatectomy 
[Yes, No] 
 
High-Intensity Focused Ultrasound 
[Yes, No] 
 
Radiation Therapy 
[Yes, No] 
 
Other Treatment 
[Yes, No] 
 
PSA (ng/mL) (Week 0) 
 
 
Testosterone (ng/mL) (Week 0) 
 
Analytical 
Method(s) : 
 
(1) Summary of Demographics and Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by treatment group and overall. 
 
2.2.2 Medical History and Concurrent Medical Conditions 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medical History 
 
Concurrent Medical Conditions 
Analytical 
Method(s) : 
 
(1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and Preferred 
Term 
Frequency distributions will be provided for each treatment group and 
overall. MedDRA dictionary will be used for coding. Summaries will be 
provided using SOC and PT, where SOC will be sorted alphabetically and PT 
will be sorted in decreasing frequency.  
A subject with multiple occurrences of medical history or concurrent medical 
condition within a SOC will be counted only once in that SOC. A subject 
with multiple occurrences of medical history or concurrent medical condition 
within a PT will be counted only once in that PT. 
 
2.2.3 Medication History and Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Medication History 
 
Concomitant Medications 


Protocol No. TAK-385/TB-AK160108 
 
33 
Analytical 
Method(s) : 
 
(1) Medication History by Preferred Medication Name 
(2) Concomitant Medications That Started Prior to and Were Ongoing at 
Baseline as well as Those That Started After Baseline by ATC    
Pharmacological Subgroup and Preferred Medication Name 
Frequency distributions will be provided for each treatment group and 
overall. WHO Drug dictionary will be used for coding. Summaries will be 
provided using preferred medication names for (1) and using both ATC 
pharmacological subgroup and preferred medication names for (2). ATC 
pharmacological subgroup will be sorted alphabetically and preferred 
medication names will be sorted in decreasing frequency based on the 
number of reports. A subject who has been administered several medications 
with the same preferred medication name will be counted only once for that 
preferred medication name. 
 
2.3 Treatment Compliance 
2.3.1 Study Drug Exposure and Compliance 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Duration of Exposure to Study Drug 
(days) 
 
[1<= - <=90, 91<= - <=180, 
181<= - <=270, 271<= - <=360, 
361<= - <=450, 451<= - <=540, 
541<= - <=630, 631<= - <=Max] 
 
Total Amount of Doses Taken (mg) 
 
 
Dose Intensity (mg/day) 
 
 
Relative Dose Intensity (%) 
 
 
Subjects with Any Dose Held 
[Yes, No] 
 
Reason for Dose Being Held  
 
Adverse Event [Yes] 
 
Other [Yes] 
 
Subjects with Any Dose Reduction 
[Yes, No] 
 
Reason for Dose Being Reduced  
 
Adverse Event [Yes] 
 
Other [Yes] 
 
Dosing Compliance (%) 
[Min<= - <=79.9, 80.0<= - <=89.9, 
90.0<= - <=Max] 
Analytical 
 


Protocol No. TAK-385/TB-AK160108 
 
34 
Method(s) : 
 
(1) Study Drug Exposure and Compliance 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by treatment group and overall. 
 
2.3.2 Dosing Pattern Details 
Analysis Set: 
Safety Analysis Set 
Analysis 
Variable(s) : 
 
Dosing Pattern 
 
[80 mg, 
120 mg, 
80 / 120 mg, 
80 / 120 / 80 mg, 
80 / 40 mg, 
120 / 160 mg, 
120 / 160 / 120 mg,  
120 / 80 mg, etc.] 
*These categories are merely an 
example and may change in 
accordance with the actual data. 
 
Last Dose 
[40 mg, 80 mg, 120 mg, 160 mg] 
Analytical 
Method(s) : 
 
 
(1) Dosing Pattern Details 
Frequency distributions will be provided by treatment group and overall. 


Protocol No. TAK-385/TB-AK160108 
 
35 
3 Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis (Part A) 
3.1 Efficacy Analysis 
3.1.1 Antitumor Effects 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
PSA (ng/mL) 
 
 
Visit : 
Baseline, D28 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
For the observed values, descriptive statistics and two-sided 95% confidence 
intervals of the mean will be provided for each visit by treatment group. The 
same analysis will be performed for the percent change from baseline.  
 
3.2 Pharmacokinetic Analysis 
3.2.1 Plasma Concentrations 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
 
Plasma concentrations of TAK-385 (ng/mL) 
 
 
Visit : 
D1 and D14: Before dosing, 0.5, 1, 1.5, 2, 4, 6, 8 and 12 hours after dosing 
D28: Before dosing, 1, 2, 4, 8, 12, 24, 48 and 72 hours after dosing 
D3 and D7: Before dosing and 2 hours after dosing 
D2, D12, D13, D15, D21 and D35: Before dosing 
Analytical 
Method(s) : 
 
Number of subjects, mean, SD, min, median, max, geometric mean, and CV 
will be used to summarize plasma concentrations at each visit for each 
treatment group.  
Linear plots of plasma concentration-time profiles will be provided for each 
treatment group using individual and mean (SD) concentrations in separate 
plots. Mean (SD) plots will include the plasma concentration plot for all 
visits, separate plots for each of Day 1, Day 14, Day 28, and a plot for the 
plasma trough concentrations. 
 
3.2.2 Pharmacokinetic Parameters 
Listing 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
D1:  AUCτ, Cmax and tmax 
D14:  AUClast, ss, AUCτ, ss, AUCτ, ss/D, Cmax, ss, Cmax, ss/D, Cmin, ss, tmax, ss 


Protocol No. TAK-385/TB-AK160108 
 
36 
D28:  AUClast, ss, AUCτ, ss, AUCτ, ss/D, CL/Fss, Cmax, ss, Cmax, ss/D, tmax, ss , t1/2z, 
Vz/Fss, λz, number of data points with first and last data points used in 
the terminal disposition phase regression analysis and adjusted R2 
(coefficient of determination) for the terminal disposition phase 
regression analysis 
Analytical 
Method(s) : 
 
 
PK parameters will be calculated by using individual plasma concentrations 
with actual sampling times. Plasma concentrations from D1 to D2, D14 to 
D15 and D28 to D35 will be used for the calculation of PK parameters on D1, 
D14 and D28 respectively. Plasma concentrations deviated from the visit 
window will be also used for the calculation. A standard non-compartmental 
analysis will be performed using the linear trapezoidal rule. If subject 
received prohibited concomitant medications, therapies or foods, then the 
plasma concentrations measured on and after this day will be used to estimate 
the PK parameters for the listing but the results will be treated as reference 
values. 
Individual PK parameters will be listed. The listings will include the 
treatment group, subject ID and evaluation day (D1, D14, and D28) in 
addition to the PK parameters.  
 
Descriptive Statistics 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
D1:  AUCτ, Cmax and tmax 
D14:  AUClast, ss, AUCτ, ss, AUCτ, ss/D, Cmax, ss, Cmax, ss/D, Cmin, ss, tmax, ss 
D28:  AUClast, ss, AUCτ, ss, AUCτ, ss/D, CL/Fss, Cmax, ss, Cmax, ss/D, tmax, ss , t1/2z, 
Vz/Fss, λz  
Analytical 
Method(s) : 
 
 
For the pharmacokinetic parameters, the number of subjects, mean, SD, min, 
median, max, geometric mean, and CV will be provided for each treatment 
group. PK parameters which are treated as reference values will be excluded 
from the summary statistics. 
Graphical assessment of dose-proportionality on Cmax, ss and AUCτ, ss will be 
conducted on D14 and D28 by plotting individual dose-normalized exposure 
parameters, i.e., Cmax, ss/D or AUCτ, ss/D versus dose. 
 
 


Protocol No. TAK-385/TB-AK160108 
 
37 
3.3 Pharmacodynamic Analysis 
3.3.1 Serum Testosterone Concentrations 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
Serum Testosterone Concentrations (ng/mL) 
Visit : 
Baseline, D2, D3, D7, D14, D21, D28, D31, D35 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
For observed values and percent change from baseline, descriptive statistics 
and two-sided 95% confidence intervals of the mean will be provided for 
each visit by treatment group. Case plots as well as the mean and standard 
deviation plots of changes over time will be provided for observed values for 
each treatment group. A reference line will be drawn where the serum 
testosterone concentration is 0.5 ng/mL. 
 
3.3.2 Serum Concentrations of LH, FSH, DHT, and SHBG 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
(1) Serum Concentrations of LH (mIU/mL) 
(2) Serum Concentrations of FSH (mIU/mL) 
(3) Serum Concentrations of DHT (ng/mL) 
(4) Serum Concentrations of SHBG (nmol/L) 
Visit : 
Baseline, D2, D3, D7, D14, D21, D28, D31, D35 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
For the analysis variables (1) to (4), descriptive statistics of the observed 
values and the two-sided 95% confidence intervals of the mean will be 
provided for each visit by treatment group. The same analysis will be 
performed for the percent change from baseline. Case plots as well as the 
mean and standard deviation plots of changes over time will be provided for 
observed values for each treatment group. 
 
3.4 Statistical/Analytical Issues 
3.4.1 Adjustments for Covariates 
Not applicable in this study. 
 


Protocol No. TAK-385/TB-AK160108 
 
38 
3.4.2 Handling of Dropouts or Missing Data 
Missing test results and data determined to be non-evaluable according to the Handling Rules 
for Analysis Data will not be used for hypothesis testing and estimations.  
Values less than or equal to the lower limit of quantification will be treated as the value of the 
lower limit of quantification for PSA, serum testosterone, LH, FSH, DHT, and SHBG, and all 
others will be treated as zero when calculating the descriptive statistics. 
Values less than the lower limit of quantification will be treated as zero except for the 
calculation of geometric mean for plasma concentration of TAK-385. For the geometric 
mean, values less than the lower limit of quantification will be treated as missing. 
 
3.4.3 Interim Analyses and Data Monitoring 
No interim analysis is planned in this study. 
 
3.4.4 Multicenter Studies 
Although this study is a multicenter study, treatment-by-center interaction will not be 
explored since the number of subjects for each center is not sufficient for such exploration. 
 
3.4.5 Multiple Comparison/Multiplicity 
Not applicable in this study. 
 
3.4.6 Use of an "Efficacy Subset" of Subjects 
Not applicable in this study. 
 
3.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable in this study. 
 
3.4.8 Examination of Subgroups 
Not applicable in this study. 
 


Protocol No. TAK-385/TB-AK160108 
 
39 
4 Efficacy, Pharmacokinetic, and Pharmacodynamic Analysis (Part B) 
4.1 Efficacy Analysis 
4.1.1 Antitumor Effects 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
(1) PSA (ng/mL) 
 
(2) Rate of Progression Based on PSA (%) 
 
(3) Rate of Progression Based on Imaging Assessments (%) 
Visit : 
(1) Baseline, WK5D1, WK9D1, WK13D1, WK17D1, WK21D1, WK25D1, 
WK37D1, WK49D1, WK61D1, WK73D1, WK85D1, WK97D1, 
WK13D1 (LOCF), End of Study 
(3) WK49D1, WK97D1 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
(1) For the observed values, descriptive statistics and two-sided 95% 
confidence intervals of the mean will be provided for each visit by treatment 
group. Case plots as well as the mean and standard deviation plots of changes 
over time will be provided for each treatment group. The same analysis will 
be performed for the percent change from baseline. 
The percent change from baseline at WK13D1 (LOCF) as well as the percent 
change from baseline when the PSA value is at its minimum since the start of 
the study drug administration will be shown using waterfall plots for each 
treatment group. 
(2) Rate of progression based on PSA will be defined as the proportion of 
subjects who have a 25% or greater increase as well as an absolute increase 
of 2 ng/mL or more in the value of PSA at least 4 weeks from the nadir. If the 
value of PSA never decreased from baseline, the above conditions will be fit 
to the value obtained after WK13D1. A missing value will be assigned if 
neither of the following conditions is met: "there are at least two observations 
after study drug administration" or "there is at least one observation on or 
after WK13D1 and the baseline is not missing". If the same minimum PSA 
value occurs at several visits, then the PSA value with the earliest date will be 
used as the nadir. Frequency distributions will be provided for each treatment 
group. 
(3) Rate of progression based on imaging assessments will be defined as the 
proportion of subjects who have developed new lesions. Frequency 
distributions will be provided for each visit by treatment group. 


Protocol No. TAK-385/TB-AK160108 
 
40 
4.1.2 QOL Assessment 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
(1) AMS 
 
(2) EORTC-QLQ-C30 
 
(3) EPIC 
Visit : 
Baseline, WK5D1, WK9D1, WK13D1, WK21D1, WK25D1, WK45D1, 
WK49D1, WK61D1, WK73D1, WK85D1, WK97D1, SFU 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. The 
scoring procedures are described in detail in the Appendix. 
(1) Descriptive statistics for the actual values and the percent change from 
baseline of AMS subscale scores and total scores will be provided for each 
visit by treatment group. 
(2) Descriptive statistics for the actual values and the change from baseline of 
Global health status/QoL score and each Functional scales score (physical, 
role, emotional, cognitive, social) will be provided for each visit by treatment 
group. 
(3) Descriptive statistics for the actual values and the change from baseline of 
each HRQOL Domain Summary Score (urinary, bowel, sexual, hormonal) 
will be provided for each visit by treatment group. 
 
4.2 Pharmacokinetic Analysis 
4.2.1 Plasma Concentrations 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis 
Variable(s) : 
Plasma concentrations of TAK-385 (ng/mL) 
Visit : 
WK1D1 and WK5D1: Before dosing and 2 hours after dosing. 
WK1D2, WK1D4, WK2D1, WK3D1, WK9D1, WK13D1, WK17D1, 
WK21D1, WK25D1, WK37D1 and WK49D1: Before dosing 
Analytical 
Method(s) : 
 
 
Descriptive statistics, geometric mean, and CV will be used to summarize 
plasma concentrations at each visit for each treatment group.  
Case plots as well as the mean and standard deviation plots of changes over 
time will be provided for plasma concentrations for each treatment group. 
 


Protocol No. TAK-385/TB-AK160108 
 
41 
4.3 Pharmacodynamic Analysis 
4.3.1 Serum Testosterone Concentrations 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
(1) Serum Testosterone Concentrations (ng/mL) 
 
(2) High-sensitivity Serum Testosterone Concentrations (ng/dL) 
 
(3) Castration Rate (%) 
Visit : 
(1) Baseline, WK1D2, WK1D4, WK2D1, WK3D1, WK5D1, WK9D1, 
WK13D1, WK17D1, WK21D1, WK25D1, WK37D1, WK49D1, 
WK61D1, WK73D1, WK85D1, WK97D1 
(2) Baseline, WK2D1, WK3D1, WK5D1, WK9D1, WK13D1, WK17D1, 
WK21D1, WK25D1, WK37D1, WK49D1 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
For the analysis variables (1) and (2), descriptive statistics and two-sided 
95% confidence intervals of the mean will be provided for the observed 
values and the percent change from baseline for each visit by treatment 
group. Case plots as well as the mean and standard deviation plots of changes 
over time will be provided for observed values for each treatment group. For 
(1), a reference line will be drawn where the serum testosterone concentration 
is 0.5 ng/mL. 
(3) Castration rate will be defined as the proportion of subjects who have 
serum testosterone concentrations of less than 0.5 ng/mL at all visits through 
WK5D1 to WK25D1. Subjects who have no testosterone measurements 
between WK5D1 and WK25D1 will be excluded from this analysis. 
Frequency distributions will be provided for each treatment group. The 
two-sided 95% confidence interval will also be provided. 
 
4.3.2 Serum Concentrations of LH, FSH, DHT, and SHBG 
Analysis Set: 
Full Analysis Set 
Analysis 
Variable(s) : 
 
(1) Serum Concentrations of LH (mIU/mL) 
(2) Serum Concentrations of FSH (mIU/mL) 
(3) Serum Concentrations of DHT (ng/mL) 
(4) Serum Concentrations of SHBG (nmol/L) 
Visit : 
Baseline, WK1D2, WK1D4, WK2D1, WK3D1, WK5D1, WK9D1, 
WK13D1, WK17D1, WK21D1, WK25D1, WK37D1, WK49D1, WK61D1, 


Protocol No. TAK-385/TB-AK160108 
 
42 
WK73D1, WK85D1, WK97D1 
Analytical 
Method(s) : 
 
 
The following analysis will be performed using the full analysis set. 
For the analysis variables (1) to (4), descriptive statistics of the observed 
values and the two-sided 95% confidence intervals of the mean will be 
provided for each visit by treatment group. The same analysis will be 
performed for the percent change from baseline. Case plots as well as the 
mean and standard deviation plots of changes over time will be provided for 
observed values for each treatment group. 
 


Protocol No. TAK-385/TB-AK160108 
 
43 
4.4 Statistical/Analytical Issues 
4.4.1 Adjustments for Covariates 
Not applicable in this study. 
 
4.4.2 Handling of Dropouts or Missing Data 
Missing test results and data determined to be non-evaluable according to the Handling Rules 
for Analysis Data will not be used for hypothesis testing and estimations.  
Values less than or equal to the lower limit of quantification will be treated as the value of the 
lower limit of quantification for PSA, serum testosterone, high-sensitivity serum testosterone, 
LH, FSH, DHT, and SHBG, and all others will be treated as zero when calculating the 
descriptive statistics. 
Values less than the lower limit of quantification will be treated as zero for the calculation of 
descriptive statistics except for geometric mean for plasma concentration of TAK-385. For 
the geometric mean, values less than the lower limit of quantification will be treated as 
missing. 
 
4.4.3 Interim Analyses and Data Monitoring 
No interim analysis is planned in this study. 
 
4.4.4 Multicenter Studies 
Although this study is a multicenter study, treatment-by-center interaction will not be 
explored since the number of subjects for each center is not sufficient for such exploration. 
 
4.4.5 Multiple Comparison/Multiplicity 
Not applicable in this study. 
 
4.4.6 Use of an "Efficacy Subset" of Subjects 
Not applicable in this study. 
 
4.4.7 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable in this study. 
 
4.4.8 Examination of Subgroups 
Not applicable in this study. 
 


Protocol No. TAK-385/TB-AK160108 
 
44 
5 Safety Analysis (Part A) 
In this study, safety will be evaluated as the primary endpoint. 
5.1 Treatment-Emergent Adverse Events 
Analysis will be performed on TEAEs that occurred in Part A. 
5.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical 
Method(s) : 
 
The following summaries will be provided for each treatment group. 
TEAEs will be graded using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
 
(1)  Overview of Treatment-Emergent Adverse Events 
 
 
1)  All Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
 
2)  Relationship of Treatment-Emergent Adverse Events to study 
drug (number of events, number and percentage of subjects)  
 
 
3)  Intensity of Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects)  
 
 
4)  Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of 
subjects)  
 
 
5)  Serious Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
 
6)  Relationship of serious Treatment-Emergent Adverse Events to 
study drug (number of events, number and percentage of subjects)  
 
 
7)  Serious Treatment-Emergent Adverse Events leading to study 
drug discontinuation (number of events, number and percentage of 
subjects)  
 
 
8)  Treatment-Emergent Adverse Events resulting in death (number 
of events, number and percentage of subjects)  
 
TEAEs will be counted according to the rules below. 
Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and 


Protocol No. TAK-385/TB-AK160108 
 
45 
Not Related) will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for the 
TEAE with the maximum intensity. 
• Summaries other than 2), 3), and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
 
5.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
 
Time of Onset (day)  
[1<= - <=7, 8<= - <=14, 15<= - <=21,  
22<= - <=Max] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution for 
each treatment group. 
TEAEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency for tables provided by SOC and PT. SOC and PT will be sorted in 
decreasing frequency for tables provided by System Organ Class only or PT 
only. 
TEAEs will be graded using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
 
(1)  Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(2)  Treatment-Emergent Adverse Events by System Organ Class 
 
(3)  Treatment-Emergent Adverse Events by Preferred Term 
 
(4)  Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(5)  Drug-Related Treatment-Emergent Adverse Events by Preferred Term 
 
(6)  Intensity of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(7)  Intensity of Drug-Related Treatment-Emergent Adverse Events by 


Protocol No. TAK-385/TB-AK160108 
 
46 
System Organ Class and Preferred Term 
 
(8)  Treatment-Emergent Adverse Events with Intensity of Grade 3 or 
Higher by System Organ Class and Preferred Term 
 
(9)  Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
 
(10)  Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(11)  Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term Over Time 
 
(12)  Special Interest Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
• Summary tables other than (6), (7), (8), and (11) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. Percentages 
will be based on the number of subjects in the safety analysis set. 
• Summary tables for (6), (7), and (8)  
A subject with multiple occurrences of TEAE within a SOC or a PT 
will be counted only once for the TEAE with the maximum intensity. 
Percentages will be based on the number of subjects in the safety 
analysis set. 
• Summary table for (11)  
A subject with a TEAE that occurs in more than one interval is counted 
in all the intervals that the TEAE occurs. For each time interval, a 
subject with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once in that SOC or PT. 
When calculating percentages for each time interval, the number of 
subjects at risk (i.e., subjects who either have an exposure or have an 
occurrence of TEAE, during or after the corresponding time interval) 
will be used as the denominator. The number of subjects whose onset 
of any one of the TEAEs is within the time interval will be used as the 
numerator. 
 


Protocol No. TAK-385/TB-AK160108 
 
47 
5.1.3 Displays of Dose-Limiting Toxicities 
Analysis Set: DLT Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution for 
each treatment group. 
TEAEs considered as dose-limiting toxicities will be coded using the 
MedDRA and will be summarized using SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency. 
 
(1)  Treatment-Emergent Adverse Events Considered as Dose-Limiting 
Toxicities by System Organ Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. Percentages 
will be based on the number of subjects in the DLT analysis set. 
 
5.2 Pretreatment Events 
5.2.1 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
PTE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency. 
 
(1)  Pretreatment Events by System Organ Class and Preferred Term 
(2)  Serious Pretreatment Events by System Organ Class and Preferred Term 
 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
PTE within a PT will be counted only once in that PT. 
 


Protocol No. TAK-385/TB-AK160108 
 
48 
5.3 Laboratory and Other Safety Data 
5.3.1 Laboratory Test Results 
5.3.1.1 Hematology, Biochemistry, and Lipid and Glycated Hemoglobin in Blood 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Hematology 
 
Red Blood Cell 
White Blood Cell 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
Differential WBC (Neutrophils, Neutrophil Count, Basophils, Eosinophils, 
Lymphocytes, Monocytes)  
 
Biochemistry 
 
Protein Total 
Albumin 
Glucose 
 
Creatinine 
Blood Urea 
Nitrogen 
Uric Acid 
 
Bilirubin Total 
ALT (GPT) 
AST (GOT) 
 
LDH 
GGT 
Alkaline Phosphatase 
 
CK (CPK) 
Sodium 
Potassium 
 
Chloride 
Calcium 
Corrected Calcium 
 
Phosphorus 
PT-INR 
 
 
Lipid and Glycated Hemoglobin in Blood 
 
Triglycerides 
Total Cholesterol 
HDL Cholesterol 
 
LDL Cholesterol 
TSH 
HbA1c 
Categories: 
Intensity 
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4] 
Visit: 
(1) and (2): 
Hematology, Biochemistry: Baseline, D7, D14, D21, D28, SFU 
Lipid and Glycated Hemoglobin in Blood: Baseline, D28, SFU  
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment group. 
For applicable variables, summaries (3), (4), and (5) will be provided by 
treatment group. Takeda Preferred SI Units will be used for all summaries. 
 
(1)  Summary of Laboratory Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Elevated Liver Enzyme 


Protocol No. TAK-385/TB-AK160108 
 
49 
Laboratory Parameters 
Overall frequency distributions of elevated hepatic parameters will be 
provided. Further details are given in the Appendix. 
 
(4)  Number and Percentage of Subjects with Laboratory Test Abnormalities 
by Grade 
Frequency distributions for each laboratory test abnormality will be 
provided by grade. Evaluable data (i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data) obtained after 
baseline will be used. A subject with multiple occurrences of laboratory 
test abnormality will be counted once for the abnormality with the 
maximum intensity. 
 
(5)  Maximum Grade Shift From Baseline of Laboratory Parameters 
The maximum post-baseline grade will be determined for each subject. 
Shift tables showing the number of subjects in each grade category at 
baseline and post-baseline visit will be provided using evaluable data 
(i.e., non-missing and acceptable according to the Handling Rules for 
Analysis Data). 
 
5.3.1.2 
Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
pH 
 
 
Specific Gravity 
 
 
Protein 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Glucose 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Occult blood 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Ketones 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Urobilinogen 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Bilirubin 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
Categories: 
Intensity 
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4] 
Visit: 
(1), (2), and (3): Baseline, D7, D14, D21, D28, SFU 
Analytical 
Method(s) : 
 
For pH and specific gravity, summaries (1) and (2) will be provided by 
treatment group. 
For each variable other than pH and specific gravity, summary (3) will be 
provided by treatment group. 
For protein, summaries (4) and (5) will also be provided by treatment group. 


Protocol No. TAK-385/TB-AK160108 
 
50 
 
(1)  Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided. 
 
(4)  Number and Percentage of Subjects with Urine Laboratory Test 
Abnormalities by Grade 
Frequency distributions for each urine laboratory test abnormality will 
be provided by grade. Evaluable data (i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data) obtained after 
baseline will be used. A subject with multiple occurrences of laboratory 
test abnormality will be counted once for the abnormality with the 
maximum intensity. 
 
(5)  Maximum Grade Shift From Baseline of Urine Laboratory Parameters 
The maximum post-baseline grade will be determined for each subject. 
Shift tables showing the number of subjects in each grade category at 
baseline and post-baseline visit will be provided using evaluable data 
(i.e., non-missing and acceptable according to the Handling Rules for 
Analysis Data). 
 
5.3.2 Vital Signs, Physical Findings, and Other Observations Related to Safety 
5.3.2.1 
Vital Signs and Weight 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Body Temperature (C) 
 
 
Systolic Blood Pressure (mmHg) 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
Pulse (bpm) 
 
 
Weight (kg) 
 
Visit: 
(1) and (2): Baseline, D7, D14, D21, D28, SFU 
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment group. 
For applicable variables, summary (3) will be provided by treatment group. 
 
(1)  Summary of Vital Signs and Weight Parameters and Change from 


Protocol No. TAK-385/TB-AK160108 
 
51 
Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Markedly Abnormal Values of 
Vital Signs Parameters 
Overall frequency distributions of MAV will be provided. If a vital sign 
parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in Appendix. 
 
5.3.2.2 
12-lead ECG 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Heart Rate (bpm) 
 
 
RR Interval (msec) 
 
 
PR Interval (msec) 
 
 
QRS Interval (msec) 
 
 
QT Interval (msec) 
 
 
QTcF Interval (msec) 
observed value: [Min<= - <=449, 450<= - <=479, 
480<= - <=499, 500<= - <=Max] 
 
 
change from baseline :  
[Min<= - <=29, 30<= - <=59, 60<= - <=Max] 
 
QTcB Interval (msec) 
observed value: [Min<= - <=449, 450<= - <=479, 
480<= - <=499, 500<= - <=Max] 
 
 
change from baseline : 
[Min<= - <=29, 30<= - <=59, 60<= - <=Max] 
 
12-Lead ECG 
Interpretation 
 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and Clinically 
Significant] 
Visit: 
(1), (2), and (4): Baseline, D14, D28, SFU 
Analytical 
Method(s) : 
 
For each variable other than 12-lead ECG interpretations, summaries (1) and 
(2) will be provided by treatment group. 
For applicable variables, summary (3) will be provided by treatment group. 
For 12-lead ECG interpretation, summary (4) will be provided by treatment 


Protocol No. TAK-385/TB-AK160108 
 
52 
group. 
 
(1)  Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. Frequency distributions for the 
categorical variables will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Markedly Abnormal Values of 
ECG Parameters 
Overall frequency distributions of MAV will be provided. If an ECG 
parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in Appendix. 
 
(4)  Summary of Shifts of ECG Parameters 
Shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided. 
 
5.4 Displays of Treatment-Emergent Adverse Events (Japanese) 
Analysis Set: Safety Analysis Set 
DLT Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Analytical 
Method(s) : 
 
The following TEAEs will be summarized in the same way as in section 5.1.2 
and section 5.1.3. All SOC and PT will be presented in Japanese. 
(1)  Treatment-Emergent Adverse Events by Preferred Term 
(2)  Drug-Related Treatment-Emergent Adverse Events by Preferred Term 
(3)  Treatment-Emergent Adverse Events with Intensity of Grade 3 or 
Higher by System Organ Class and Preferred Term 
(4)  Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
(5)  Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
(6)  Treatment-Emergent Adverse Events Considered as Dose-Limiting 
Toxicities by System Organ Class and Preferred Term 
 


Protocol No. TAK-385/TB-AK160108 
 
53 
6 Safety Analysis (Part B) 
In this study, safety will be evaluated as the primary endpoint. 
6.1 Treatment-Emergent Adverse Events 
Analysis will be performed on TEAEs that occurred in Part B. 
6.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical 
Method(s) : 
 
The following summaries will be provided for each treatment group. 
TEAEs will be graded using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
 
(1)  Overview of Treatment-Emergent Adverse Events 
 
 
1)  All Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
 
2)  Relationship of Treatment-Emergent Adverse Events to study 
drug (number of events, number and percentage of subjects)  
 
 
3)  Intensity of Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects)  
 
 
4)  Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of 
subjects)  
 
 
5)  Serious Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects)  
 
 
6)  Relationship of serious Treatment-Emergent Adverse Events to 
study drug (number of events, number and percentage of subjects)  
 
 
7)  Serious Treatment-Emergent Adverse Events leading to study 
drug discontinuation (number of events, number and percentage of 
subjects)  
 
 
8)  Treatment-Emergent Adverse Events resulting in death (number 
of events, number and percentage of subjects)  
 
TEAEs will be counted according to the rules below. 
Number of subjects 
• Summaries for 2) and 6)  
A subject with occurrences of TEAE in both categories (i.e., Related and 


Protocol No. TAK-385/TB-AK160108 
 
54 
Not Related) will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once for the 
TEAE with the maximum intensity. 
• Summaries other than 2), 3), and 6)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
 
6.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
 
Time of Onset (day)  
[1<= - <=90, 91<= - <=180, 181<= - <=270, 
271<= - <=360, 361<= - <=450, 451<= - <=540, 
541<= - <=630, 631<= - <=Max] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution for 
each treatment group. 
TEAEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency for tables provided by SOC and PT. SOC and PT will be sorted in 
decreasing frequency for tables provided by System Organ Class only or PT 
only. 
TEAEs will be graded using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 
 
(1)  Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
 
(2)  Treatment-Emergent Adverse Events by System Organ Class 
 
(3)  Treatment-Emergent Adverse Events by Preferred Term 
 
(4)  Drug-Related Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(5)  Drug-Related Treatment-Emergent Adverse Events by Preferred Term 
 
(6)  Intensity of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 


Protocol No. TAK-385/TB-AK160108 
 
55 
 
(7)  Intensity of Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
 
(8)  Treatment-Emergent Adverse Events with Intensity of Grade 3 or 
Higher by System Organ Class and Preferred Term 
 
(9)  Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
 
(10)  Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
(11)  Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term Over Time 
 
(12) Special Interest Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
• Summary tables other than (6), (7), (8), and (11) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
TEAE within a PT will be counted only once in that PT. Percentages 
will be based on the number of subjects in the safety analysis set. 
• Summary tables for (6), (7), and (8)  
A subject with multiple occurrences of TEAE within a SOC or a PT 
will be counted only once for the TEAE with the maximum intensity. 
Percentages will be based on the number of subjects in the safety 
analysis set. 
• Summary table for (11)  
A subject with a TEAE that occurs in more than one interval is counted 
in all the intervals that the TEAE occurs. For each time interval, a 
subject with multiple occurrences of TEAE within a SOC or a PT will 
be counted only once in that SOC or PT. 
When calculating percentages for each time interval, the number of 
subjects at risk (i.e., subjects who either have an exposure or have an 
occurrence of TEAE, during or after the corresponding time interval) 
will be used as the denominator. The number of subjects whose onset 
of any one of the TEAEs is within the time interval will be used as the 
numerator. 


Protocol No. TAK-385/TB-AK160108 
 
56 
6.2 Pretreatment Events 
6.2.1 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
PTE 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in decreasing 
frequency. 
 
(1)  Pretreatment Events by System Organ Class and Preferred Term 
(2)  Serious Pretreatment Events by System Organ Class and Preferred Term 
 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
PTE within a PT will be counted only once in that PT. 
 


Protocol No. TAK-385/TB-AK160108 
 
57 
6.3 Laboratory and Other Safety Data 
6.3.1 Laboratory Test Results 
6.3.1.1 Hematology, Biochemistry, and Lipid and Glycated Hemoglobin in Blood 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Hematology 
 
Red Blood Cell 
White Blood Cell 
Hemoglobin 
 
Hematocrit 
Platelets 
 
 
Differential WBC (Neutrophils, Neutrophil Count, Basophils, Eosinophils, 
Lymphocytes, Monocytes)  
 
Biochemistry 
 
Protein Total 
Albumin 
Glucose 
 
Creatinine 
Blood Urea 
Nitrogen 
Uric Acid 
 
Bilirubin Total 
ALT (GPT) 
AST (GOT) 
 
LDH 
GGT 
Alkaline Phosphatase 
 
CK (CPK) 
Sodium 
Potassium 
 
Chloride 
Calcium 
Corrected Calcium 
 
Phosphorus 
PT-INR 
 
 
Lipid and Glycated Hemoglobin in Blood 
 
Triglycerides 
Total Cholesterol 
HDL Cholesterol 
 
LDL Cholesterol 
TSH 
HbA1c 
Categories: 
Intensity 
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4] 
Visit: 
(1) and (2): 
Hematology: Baseline, WK5D1, WK9D1, WK13D1, WK25D1, WK37D1, 
WK49D1, WK61D1, WK73D1, WK85D1, WK97D1, SFU 
Biochemistry: Baseline, WK5D1, WK9D1, WK13D1, WK17D1, WK21D1, 
WK25D1, WK29D1, WK33D1, WK37D1, WK41D1, 
WK45D1, WK49D1, WK61D1, WK73D1, WK85D1, 
WK97D1, SFU 
Lipid and Glycated Hemoglobin in Blood:  
Baseline, WK5D1, WK9D1, WK13D1, WK25D1, WK49D1, 
WK61D1, WK73D1, WK85D1, WK97D1, SFU  
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment group. 
For applicable variables, summaries (3), (4), and (5) will be provided by 
treatment group. Takeda Preferred SI Units will be used for all summaries. 


Protocol No. TAK-385/TB-AK160108 
 
58 
 
(1)  Summary of Laboratory Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Elevated Liver Enzyme 
Laboratory Parameters 
Overall frequency distributions of elevated hepatic parameters will be 
provided. Further details are given in Appendix. 
 
(4)  Number and Percentage of Subjects with Laboratory Test Abnormalities 
by Grade 
Frequency distributions for each laboratory test abnormality will be 
provided by grade. Evaluable data (i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data) obtained after 
baseline will be used. A subject with multiple occurrences of laboratory 
test abnormality will be counted once for the abnormality with the 
maximum intensity. 
 
(5)  Maximum Grade Shift From Baseline of Laboratory Parameters 
The maximum post-baseline grade will be determined for each subject. 
Shift tables showing the number of subjects in each grade category at 
baseline and post-baseline visit will be provided using evaluable data 
(i.e., non-missing and acceptable according to the Handling Rules for 
Analysis Data). 
 
6.3.1.2 
Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
pH 
 
 
Specific Gravity 
 
 
Protein 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Glucose 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Occult blood 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Ketones 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Urobilinogen 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
 
Bilirubin 
[-, +-, 1+, 2+, 3+, 4+, 5+] 
Categories: 
Intensity 
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4] 


Protocol No. TAK-385/TB-AK160108 
 
59 
Visit: 
(1), (2), and (3):  
Baseline, WK5D1, WK9D1, WK13D1, WK25D1, WK49D1, WK61D1, 
WK73D1, WK85D1, WK97D1, SFU 
Analytical 
Method(s) : 
 
For pH and specific gravity, summaries (1) and (2) will be provided by 
treatment group. 
For each variable other than pH and specific gravity, summary (3) will be 
provided by treatment group. 
For protein, summaries (4) and (5) will also be provided by treatment group. 
 
(1)  Summary of Urine Laboratory Test Results and Change from Baseline 
by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number of Subjects in Categories of Urine Laboratory Test Results 
Shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided. 
 
(4)  Number and Percentage of Subjects with Urine Laboratory Test 
Abnormalities by Grade 
Frequency distributions for each urine laboratory test abnormality will 
be provided by grade. Evaluable data (i.e., non-missing and acceptable 
according to the Handling Rules for Analysis Data) obtained after 
baseline will be used. A subject with multiple occurrences of laboratory 
test abnormality will be counted once for the abnormality with the 
maximum intensity. 
 
(5)  Maximum Grade Shift From Baseline of Urine Laboratory Parameters 
The maximum post-baseline grade will be determined for each subject. 
Shift tables showing the number of subjects in each grade category at 
baseline and post-baseline visit will be provided using evaluable data 
(i.e., non-missing and acceptable according to the Handling Rules for 
Analysis Data). 
 


Protocol No. TAK-385/TB-AK160108 
 
60 
6.3.2 Vital Signs, Physical Findings, and Other Observations Related to Safety 
6.3.2.1 
Vital Signs and Weight 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Body Temperature (C) 
 
 
Systolic Blood Pressure (mmHg) 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
Pulse (bpm) 
 
 
Weight (kg) 
 
Visit: 
(1) and (2): 
Baseline, WK2D1, WK3D1, WK5D1, WK9D1, WK13D1, WK25D1, 
WK49D1, WK61D1, WK73D1, WK85D1, WK97D1, SFU 
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment group. 
For applicable variables, summary (3) will be provided by treatment group. 
 
(1)  Summary of Vital Signs and Weight Parameters and Change from 
Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Markedly Abnormal Values of 
Vital Signs Parameters 
Overall frequency distributions of MAV will be provided. If a vital sign 
parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in Appendix. 
 
6.3.2.2 
12-lead ECG 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Heart Rate (bpm) 
 
 
RR Interval (msec) 
 
 
PR Interval (msec) 
 
 
QRS Interval (msec) 
 
 
QT Interval (msec) 
 
 
QTcF Interval (msec) 
observed value: [Min<= - <=449, 450<= - <=479, 
480<= - <=499, 500<= - <=Max] 


Protocol No. TAK-385/TB-AK160108 
 
61 
 
 
change from baseline :  
[Min<= - <=29, 30<= - <=59, 60<= - <=Max] 
 
QTcB Interval (msec) 
observed value: [Min<= - <=449, 450<= - <=479, 
480<= - <=499, 500<= - <=Max] 
 
 
change from baseline : 
[Min<= - <=29, 30<= - <=59, 60<= - <=Max] 
 
12-Lead ECG 
Interpretation 
 
[Within Normal Limits, Abnormal but not Clinically 
Significant, Abnormal and Clinically Significant] 
Visit: 
(1), (2), and (4): 
Baseline, WK3D1, WK5D1, WK25D1, WK49D1, WK73D1, WK97D1, SFU 
Analytical 
Method(s) : 
 
For each variable other than 12-lead ECG interpretations, summaries (1) and 
(2) will be provided by treatment group. 
For applicable variables, summary (3) will be provided by treatment group. 
For 12-lead ECG interpretation, summary (4) will be provided by treatment 
group. 
 
(1)  Summary of ECG Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline 
will be provided for each visit. Frequency distributions for the 
categorical variables will be provided for each visit. 
 
(2)  Case Plots 
Plots over time for each subject will be presented. 
 
(3)  Number and Percentage of Subjects with Markedly Abnormal Values of 
ECG Parameters 
Overall frequency distributions of MAV will be provided. If an ECG 
parameter has both lower and upper MAV criteria, analysis will be 
performed for each. Further details are given in Appendix. 
 
(4)  Summary of Shifts of ECG Parameters 
Shift tables showing the number of subjects in each category at baseline 
and each post-baseline visit will be provided. 
 


Protocol No. TAK-385/TB-AK160108 
 
62 
6.3.2.3 
Bone Mineral Density 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
(1) Bone Mineral Density (L2-4) 
(2) Bone Mineral Density (Femoral Neck) 
(3) Bone Mineral Density (Total Hip) 
Visit: 
Baseline, WK25D1, WK49D1, WK73D1, WK97D1 
Analytical 
Method(s) : 
 
The following analysis will be performed using the safety analysis set. 
For (1) to (3), the descriptive statistics of the observed values and the 
two-sided 95% confidence intervals of the mean will be provided for each 
visit by treatment group. The same analysis will be performed for the percent 
change from baseline. 
 
6.4 Displays of Treatment-Emergent Adverse Events (Japanese) 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Analytical 
Method(s) : 
 
The following TEAEs will be summarized in the same way as in section 
6.1.2. All SOC and PT will be presented in Japanese. 
(1)  Treatment-Emergent Adverse Events by Preferred Term 
(2)  Drug-Related Treatment-Emergent Adverse Events by Preferred Term 
(3)  Treatment-Emergent Adverse Events with Intensity of Grade 3 or 
Higher by System Organ Class and Preferred Term 
(4)  Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
(5)  Serious Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term 
 
7 Significance Level and Confidence Coefficient (Part A and Part B) 
・ Confidence coefficient: 95% (two-sided) 
 
 


Protocol No. TAK-385/TB-AK160108 
 
63 
Amendment History 
 
Version 
Date 
Author 
Detailed Description 
of Amendments to Text 
1 
April 16, 2015 
 
 
 
Not applicable 
2 
July 20, 2017 
 
 
 
Refer to Appendix 1. 
 


Protocol No. TAK-385/TB-AK160108 
 
1 
Appendix 1. Amendments from the Previous Version 
 
Page 
Existing Text 
Revised Text 
Rationale for Amendment 
Cover 
 
 
 
 
 
 
 
 
 
 
Updated in accordance with the 
current organization. 
Cover 
 
 
 
 
 
 
 
Updated in accordance with the 
current organization. 
4 
Glossary 
Descriptive statistics: number of subjects, mean, 
standard deviation, maximum, minimum, and quartiles 
Glossary 
Descriptive statistics: number of subjects, mean, 
standard deviation (SD), maximum (max), minimum 
(min), and quartiles 
Added to clearly define the 
abbreviation. 
4 
Glossary 
(New) 
Glossary 
CV: coefficient of variation 
Added to clearly define the 
abbreviation. 
4 
Glossary 
(New) 
Glossary 
PK: pharmacokinetic 
Added to clearly define the 
abbreviation. 
6 
Definition of Visit Window 
<Part A> Pharmacokinetic Assessments 
Headers of the table: Visit, Scheduled Study Day 
Definition of Visit Window 
<Part A> Pharmacokinetic Assessments 
Headers of the table: Visit, Scheduled Study Time 
Corrected to a more appropriate 
expression. 


Protocol No. TAK-385/TB-AK160108 
 
2 
Page 
Existing Text 
Revised Text 
Rationale for Amendment 
(days), Scheduled Study Time (hours), and Time 
Interval (Study Day (days), Study Time (hours)) 
(hours), and Time Interval (Study Day (days), Study 
Time (hours)) 
6 
Definition of Visit Window 
<Part A> Pharmacokinetic Assessments 
Definition of Visit Window 
<Part A> Pharmacokinetic Assessments 
The visit windows in the whole table were revised. 
Corrected to a more appropriate 
expression. 
11 
Definition of Visit Window 
<Part B> Pharmacokinetic Assessments 
Headers of the table: Visit, Scheduled Study Day 
(days), Scheduled Study Time (hours), and Time 
Interval (Study Day (days), Study Time (hours)) 
Definition of Visit Window 
<Part B> Pharmacokinetic Assessments 
Headers of the table: Visit, Scheduled Study Time 
(hours), and Time Interval (Study Day (days), Study 
Time (hours)) 
Corrected to a more appropriate 
expression. 
11 
Definition of Visit Window 
<Part B> Pharmacokinetic Assessments 
Definition of Visit Window 
<Part B> Pharmacokinetic Assessments 
The visit windows in the whole table were revised. 
Corrected to a more appropriate 
expression. 
20 
Others 
PK parameters 
Others 
The symbols and the definitions of PK parameter were 
revised.  
Corrected according to the latest 
standard PK terminology 
20 
Others 
AUC(0-inf) --Area under the plasma/blood/serum 
concentration-time curve from time 0 to infinity, 
calculated as AUC(0-inf)=AUC(0-tlqc)+lqc/λz, where 
tlqc is the time of last quantifiable concentration and 
lqc is the last quantifiable concentration.  
Others 
(deleted) 
Deleted unnecessary PK parameters 


Protocol No. TAK-385/TB-AK160108 
 
3 
Page 
Existing Text 
Revised Text 
Rationale for Amendment 
AUMC(0-inf) -- Area under the first moment 
plasma/blood/serum concentration-time curve from 
time 0 to infinity, calculated as 
AUMC(0-inf)=AUMC(0-tlqc)+lqc×tlqc/λz+lqc/λz2, 
where tlqc is the time of last quantifiable concentration 
and lqc is the last quantifiable concentration. 
20 
Others 
Cmax/D --Dose-adjusted Cmax. 
Others 
Cmax, ss/D --Dose-normalized Cmax, ss. 
Corrected to a more appropriate 
expression. 
20 
Others 
MRT -- Mean residence time, calculated as 
MRT=AUMC(0-inf)/AUC(0-inf). 
Others 
(deleted) 
Deleted unnecessary PK parameters 
20 
Others 
Vss/F --Apparent volume of distribution at steady state 
after extravascular administration, calculated as Vss/F= 
CL/F×MRT. 
Others 
Vz/Fss --Apparent volume of distribution during the 
terminal disposition phase after extravascular 
administration, calculated using AUCτ 
Corrected to a more appropriate 
expression. 
36 
3.2.1 Plasma Concentrations 
Descriptive statistics, geometric mean, and coefficient 
of variation will be used to summarize plasma 
concentrations at each visit. Plasma concentration-time 
profiles will be provided for each treatment group 
using individual or mean concentrations. 
3.2.1 Plasma Concentrations 
Number of subjects, mean, SD, min, median, max, 
geometric mean, and CV will be used to summarize 
plasma concentrations at each visit for each treatment 
group. 
Linear plots of plasma concentration-time profiles will 
be provided for each treatment group using individual 
Corrected to clarify which descriptive 
statistics and linear plots will be 
provided. 


Protocol No. TAK-385/TB-AK160108 
 
4 
Page 
Existing Text 
Revised Text 
Rationale for Amendment 
and mean (SD) concentrations in separate plots. Mean 
(SD) plots will include the plasma concentration plot 
for all visits, separate plots for each of Day 1, Day 14, 
Day 28, and a plot for the plasma trough 
concentrations. 
36 
(New) 
Listing 
Analysis Set: Full Analysis Set 
Analysis Variable(s) : 
D1: AUCτ, Cmax and tmax 
D14: AUClast, ss, AUCτ, ss, AUCτ, ss/D, Cmax, ss, Cmax, ss/D, 
Cmin, ss, tmax, ss 
D28: AUClast, ss, AUCτ, ss, AUCτ, ss/D, CL/Fss, Cmax, ss, 
Cmax, ss/D, tmax, ss , t1/2z, Vz/Fss, λz, number of data points 
with first and last data points used in the terminal 
disposition phase regression analysis and adjusted R2 
(coefficient of determination) for the terminal 
disposition phase regression analysis 
Analytical Method(s) : 
PK parameters will be calculated by using individual 
plasma concentrations with actual sampling times. 
Plasma concentrations from D1 to D2, D14 to D15 and 
D28 to D35 will be used for the calculation of PK 
Added to separate the listing for PK 
parameters from the table of 
descriptive statistics. PK parameter 
calculation methods were also moved 
to this new section. 


Protocol No. TAK-385/TB-AK160108 
 
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Existing Text 
Revised Text 
Rationale for Amendment 
parameters on D1, D14 and D28 respectively. Plasma 
concentrations deviated from the visit window will be 
also used for the calculation. A standard 
non-compartmental analysis will be performed using 
the linear trapezoidal rule. If subject received 
prohibited concomitant medications, therapies or foods, 
then the plasma concentrations measured on and after 
this day will be used to estimate the PK parameters for 
the listing but the results will be treated as reference 
values. 
Individual PK parameters will be listed. The listings 
will include the treatment group, subject ID and 
evaluation day (D1, D14, and D28) in addition to the 
PK parameters. 
37 
Descriptive Statistics 
D1: AUC(0-24), Cmax and Tmax 
D14: AUC(0-tlqc), AUC(0-tau), AUC(0-tau)/D, Cmax, 
Cmax/D, Cmin, Tmax 
D28: AUC(0-tlqc), AUC(0-tau), CL/F, Cmax, Tmax , 
T1/2, Vss/F 
Descriptive Statistics 
D1: AUCτ, Cmax and tmax 
D14: AUClast, ss, AUCτ, ss, AUCτ, ss/D, Cmax, ss, Cmax, 
ss/D, Cmin, ss, tmax, ss 
D28: AUClast, ss, AUCτ, ss, AUCτ, ss/D, CL/Fss, Cmax, ss, 
Cmax, ss/D, tmax, ss , t1/2z, Vz/Fss, λz 
Added the dose-normalized PK 
parameters (Cmax, ss/D and AUCτ, ss/D) 
and corrected PK parameter symbols 
according to the latest standard PK 
terminology. 
37 
Descriptive Statistics 
Pharmacokinetic (PK) parameters will be calculated by 
Descriptive Statistics 
For the pharmacokinetic parameters, the number of 
Corrected to specify which 
descriptive statistics will be provided. 


Protocol No. TAK-385/TB-AK160108 
 
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using individual plasma concentrations with actual 
sampling times. Plasma concentrations from D1 to D2, 
D14 to D15 and D28 to D35 will be used for the 
calculation of PK parameters on D1, D14 and D28 
respectively. Plasma concentrations deviated from the 
visit window will be also used for the calculation. A 
standard non-compartmental analysis will be 
performed. The listing of calculated PK parameters 
will be prepared for each subject. Descriptive statistics, 
geometric mean, and coefficient of variation will be 
used to summarize each pharmacokinetic parameter for 
each treatment group. Graphical assessment of 
dose-linearity on Cmax or AUC(0-tau) will be 
conducted on D14 and D28. 
subjects, mean, SD, min, median, max, geometric 
mean, and CV will be provided for each treatment 
group. PK parameters which are treated as reference 
values will be excluded from the summary statistics. 
Graphical assessment of dose-proportionality on Cmax, 
ss and AUCτ, ss will be conducted on D14 and D28 by 
plotting individual dose-normalized exposure 
parameters, i.e., Cmax, ss/D or AUCτ, ss/D versus dose. 
The rules for data handling and the 
method for dose-proportionality 
assessment were changed to what 
was considered more appropriate. 
39 
3.4.2 Handling of Dropouts or Missing Data 
(New) 
3.4.2 Handling of Dropouts or Missing Data 
Values less than the lower limit of quantification will 
be treated as zero except for the calculation of 
geometric mean for plasma concentration of TAK-385. 
For the geometric mean, values less than the lower 
limit of quantification will be treated as missing. 
Added to define the rules for 
handling values less than the lower 
limit of quantification. 
41 
4.1.2 QOL Assessment 
The following analysis will be performed using the full 
4.1.2 QOL Assessment 
The following analysis will be performed using the full 
Appendix containing details on the 
scoring procedures was added. 


Protocol No. TAK-385/TB-AK160108 
 
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analysis set. 
analysis set. The scoring procedures are described in 
detail in the Appendix. 
41 
4.2.1 Plasma Concentrations 
Descriptive statistics, geometric mean, and coefficient 
of variation will be used to summarize plasma 
concentrations at each visit. Plots of plasma 
concentrations at each visit will be provided for each 
treatment group using individual or mean 
concentrations. 
4.2.1 Plasma Concentrations 
Descriptive statistics, geometric mean, and CV will be 
used to summarize plasma concentrations at each visit 
for each treatment group. Case plots as well as the 
mean and standard deviation plots of changes over time 
will be provided for plasma concentrations for each 
treatment group. 
Corrected to a more appropriate 
expression. 
42 
4.3.1 Serum Testosterone Concentrations 
(2) High-sensitivity Serum Testosterone (ng/dL) 
4.3.1 Serum Testosterone Concentrations 
(2) High-sensitivity Serum Testosterone 
Concentrations (ng/dL) 
Added to align with other similar 
expressions. 
42 
4.3.1 Serum Testosterone Concentrations 
Case plots as well as the mean and standard deviation 
plots of changes over time will be provided for 
observed values for each treatment group. A reference 
line will be drawn where the serum testosterone 
concentration is 0.5 ng/mL. 
4.3.1 Serum Testosterone Concentrations 
Case plots as well as the mean and standard deviation 
plots of changes over time will be provided for 
observed values for each treatment group. For (1), a 
reference line will be drawn where the serum 
testosterone concentration is 0.5 ng/mL. 
Added to clarify which analysis will 
include the reference line. 
44 
4.4.2 Handling of Dropouts or Missing Data 
(New) 
4.4.2 Handling of Dropouts or Missing Data 
Values less than the lower limit of quantification will 
be treated as zero for the calculation of descriptive 
statistics except for geometric mean for plasma 
Added to define the rules for 
handling values less than the lower 
limit of quantification. 


Protocol No. TAK-385/TB-AK160108 
 
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concentration of TAK-385. For the geometric mean, 
values less than the lower limit of quantification will be 
treated as missing. 
65 
Appendix. Criteria for Markedly Abnormal Values and 
Elevated Liver Enzyme 
Appendix 2. Criteria for Markedly Abnormal Values 
and Elevated Liver Enzyme 
Appendix number was updated since 
Appendix 1 and 3 were added to the 
SAP. 
70 
(New) 
Appendix 3. QOL Scoring Procedures 
Added Appendix 3 to make clear of 
each of the QOL scoring procedures. 


Protocol No. TAK-385/TB-AK160108 
 
1 
Appendix 2. Criteria for Markedly Abnormal Values and Elevated Liver Enzyme 
(1) 
Criteria for Markedly Abnormal Values 
1) 
Vital Signs, and 12-lead ECG (except Upper MAV Criteria of QTcF Interval) 
For each parameter, all evaluable data (i.e., non-missing and acceptable according to the Handling 
Rules for Analysis Data) obtained after baseline will be classified as a MAV or not. The criteria in 
the table below will be used. The lower limit of the normal range and the upper limit of the normal 
range are abbreviated as LLN and ULN.  
 
Vital Signs 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Systolic Blood Pressure (mmHg) 
- 
- 
<85 
>180 
Diastolic Blood Pressure (mmHg) 
- 
- 
<50 
>110 
Pulse (bpm) 
- 
- 
<50 
>120 
Body Temperature (°C) 
- 
- 
<35.6 
>37.7 
 
12-lead ECG 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
Heart Rate (bpm) 
- 
- 
<50 
>120 
QT Interval (msec) 
- 
- 
<=50 
>=460 
QTcF Interval (msec) 
- 
- 
<=50 
- 
 
Classifying Subjects for the Overall Treatment Period 
For each parameter and subject, classifications will be made according to the conditions i) to iii) 
provided below. The lower and the upper criteria will be considered separately. 
i) 
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV. 
ii) 
A subject who does not meet condition i) and has at least one evaluable data after baseline that 
doesn't meet the MAV criteria will be considered as a subject without MAV. 
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV for 
that parameter. 
 


Protocol No. TAK-385/TB-AK160108 
 
2 
2) 
12-lead ECG (Upper MAV Criteria of QTcF Interval) 
All evaluable data (i.e., non-missing and acceptable according to the Handling Rules for Analysis 
Data) obtained after baseline will be classified as a MAV or not. The criteria in the table below will 
be used.  Note that the observed value and the change from baseline used for classification should 
be measurements taken on the same day. 
 
Parameter 
Gender 
Age 
MAV Criteria 
Lower Criteria 
Upper Criteria 
QTcF Interval 
(msec) 
- 
- 
- 
If either of the following conditions 
is met: 
- observed value >=500 
- change from baseline >= 30 and  
 observed value >=450 
 
Classifying Subjects for the Overall Treatment Period 
For each subject, classifications will be made according to the conditions i) to iii) provided below. 
i) 
A subject with at least one evaluable data after baseline that meets the MAV criteria will be 
classified as a subject with MAV. 
ii) 
A subject who does not meet condition i) and has at least one evaluable data after baseline that 
meets any of the following will be considered as a subject without MAV. 
・ Observed value is less than 450 msec and not missing. 
・ Change from baseline is less than 30 msec and not missing, and observed value is less than 
500 msec and not missing. 
iii) A subject who does not meet conditions i) or ii) will be excluded from the analysis of MAV. 
 


Protocol No. TAK-385/TB-AK160108 
 
3 
(2) 
Criteria for Elevated Liver Enzyme 
All evaluable data (i.e., non-missing and acceptable according to the Handling Rules for Analysis 
Data) obtained after baseline will be used to determine whether each criteria for elevated liver 
enzyme in the table below is met or not. If there is more than one parameter that need to be 
considered for a criteria, parameter measurements taken on the same day will be used. The 
following abbreviations are used: LLN for lower limit of the normal range, ULN for upper limit of 
the normal range, ALT for alanine aminotransferase, AST for aspartate aminotransferase, Tbili for 
total bilirubin, and ALP for alkaline phosphatase. 
 
Label 
Criteria for Elevated Liver Enzyme 
(a) Elevated 
(b) Not Elevated 
ALT > 3xULN 
ALT is greater than 3 times the ULN 
ALT is non-missing and less than or equal 
to 3 times the ULN 
ALT > 5xULN 
ALT is greater than 5 times the ULN 
ALT is non-missing and less than or equal 
to 5 times the ULN 
ALT > 8xULN  
ALT is greater than 8 times the ULN 
ALT is non-missing and less than or equal 
to 8 times the ULN 
ALT > 3xULN  
with Tbili > 2xULN 
ALT is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
AST > 3xULN  
AST is greater than 3 times the ULN 
AST is non-missing and less than or equal 
to 3 times the ULN 
AST > 5xULN  
AST is greater than 5 times the ULN 
AST is non-missing and less than or equal 
to 5 times the ULN 
AST > 8xULN  
AST is greater than 8 times the ULN 
AST is non-missing and less than or equal 
to 8 times the ULN 
AST > 3xULN  
with Tbili > 2xULN 
AST is greater than 3 times the ULN and 
the total bilirubin is greater than twice the 
ULN 
Either AST is non-missing and less than or 
equal to 3 times the ULN, or the total 
bilirubin is non-missing and less than or 
equal to twice the ULN 
ALT or AST > 3xULN 
Either ALT or AST is greater than 3 times 
the ULN 
Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN 
ALT or AST > 5xULN  
Either ALT or AST is greater than 5 times 
the ULN 
Both ALT and AST are non-missing and 
less than or equal to 5 times the ULN 
ALT or AST > 8xULN  
Either ALT or AST is greater than 8 times 
Both ALT and AST are non-missing and 


Protocol No. TAK-385/TB-AK160108 
 
4 
Label 
Criteria for Elevated Liver Enzyme 
(a) Elevated 
(b) Not Elevated 
the ULN 
less than or equal to 8 times the ULN 
ALT or AST > 3xULN  
with Tbili > 2xULN 
Either ALT or AST is greater than 3 times 
the ULN and the total bilirubin is greater 
than twice the ULN 
If any of the following conditions is met: 
- Both ALT and AST are non-missing and 
less than or equal to 3 times the ULN. 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN. 
ALT and AST > 3xULN  
Both ALT and AST are greater than 3 
times the ULN 
Either ALT is non-missing and less than 
or equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 
ALT and AST > 5xULN  
Both ALT and AST are greater than 5 
times the ULN 
Either ALT is non-missing and less than 
or equal to 5 times the ULN, or AST is 
non-missing and less than or equal to 5 
times the ULN 
ALT and AST > 8xULN 
Both ALT and AST are greater than 8 
times the ULN 
Either ALT is non-missing and less than 
or equal to 8 times the ULN, or AST is 
non-missing and less than or equal to 8 
times the ULN 
ALT and AST > 3xULN  
with Tbili > 2xULN 
Both ALT and AST are greater than 3 
times the ULN and the total bilirubin is 
greater than twice the ULN 
If any of the following conditions is met: 
- ALT is non-missing and less than or 
equal to 3 times the ULN 
- AST is non-missing and less than or 
equal to 3 times the ULN 
- Total bilirubin is non-missing and less 
than or equal to twice the ULN 
ALP > 3xULN  
ALP is greater than 3 times the ULN 
ALP is non-missing and less than or equal 
to 3 times the ULN 
ALP > 3xULN  
with ALT > 3xULN  
Both ALP and ALT are greater than 3 
time the ULN 
Either ALP is non-missing and less than or 
equal to 3 times the ULN, or ALT is 
non-missing and less than or equal to 3 
times the ULN 
 
 
ALP > 3xULN  
Both ALP and AST are greater than 3 
Either ALP is non-missing and less than or 


Protocol No. TAK-385/TB-AK160108 
 
5 
Label 
Criteria for Elevated Liver Enzyme 
(a) Elevated 
(b) Not Elevated 
with AST > 3xULN 
times the ULN 
equal to 3 times the ULN, or AST is 
non-missing and less than or equal to 3 
times the ULN 


Protocol No. TAK-385/TB-AK160108 
 
1 
Appendix 3. QOL Scoring Procedures 
(1) 
AMS 
AMS subscale scores and total scores will be calculated as follows. If one or more of the scores 
required for the calculation of a subscale are missing, then that particular subscale and the total score 
will be treated as missing. 
・ Psychological subscale: sum of severity points from questions 6, 7, 8, 11, 13 
・ Somatic subscale: sum of severity points from questions 1, 2, 3, 4, 5, 9, 10 
・ Sexual subscale: sum of severity points from questions 12, 14, 15, 16, 17 
・ Total score: sum of severity points from all questions from 1 to 17 
 
Reference: Moore C, Huebler D, Zimmermann T, Heinemann LA, Saad F, Thai DM. The Aging 
Males' Symptoms scale (AMS) as outcome measure for treatment of androgen deficiency. Eur Urol 
2004;46(1):80-7 
 
(2) 
EORTC QLQ-C30 
The Global health status/QoL score and each Functional scales score (physical, role, emotional, 
cognitive, social) will be calculated as follows. The "range" used in the calculations is the difference 
between the maximum possible values of the score and the minimum possible value. If more than 
half of the scores are missing, then the Global health status/QoL score or the Functional scales score 
will be treated as missing. If at least half of the scores are available, then the scores that are available 
will be used for the calculation. 
・ Global health status/QoL score: {[(average of item 29 & 30)-1]/range}*100 
・ Physical functioning: {1-[(average of item 1 to 5)-1]/range}*100 
・ Role functioning: {1-[(average of item 6 & 7)-1]/range}*100 
・ Emotional functioning: {1-[(average of item 21 to 24)-1]/range}*100 
・ Cognitive functioning: {1-[(average of item 20 & 25)-1]/range}*100 
・ Social functioning: {1-[(average of item 26 & 27)-1]/range}*100 
 
Reference: Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, on behalf 
of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd 
edition). Published by: European Organisation for Research and Treatment of Cancer, 
Brussels 2001. 
 


Protocol No. TAK-385/TB-AK160108 
 
2 
(3) 
EPIC 
Each of the HRQOL Domain Summary Scores (urinary, bowel, sexual, hormonal) will be calculated 
according to the following steps. 
1) Convert score using the conversion table below. 
Conversion Table 
Question No. 
Answer 
Converted 
Score 
1, 2, 3, 8, 9, 14, 20, 21, 22, 23, 26, 27, 28, 29, 32 
1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
4 
1 
0 
2 
33 
3 
67 
4 
100 
5 
0 
100 
1 
67 
2 
33 
3 
0 
6A, 6B, 6C, 6D, 6E, 6F, 15A, 15B, 15C, 15D, 
15E, 15F, 24A, 24B, 24C, 31A, 31B, 31C, 31D, 
31E, 31F 
0 
100 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
7, 10, 11, 12, 16, 25 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
13 
1 
100 
2 
50 
3 
0 
17A, 17B, 17C, 19 
0 
0 
1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
18 
0 
0 
1 
0 
2 
33 
3 
67 
4 
100 
30 
1 
0 
2 
50 
3 
100 
4 
50 
5 
0 
 


Protocol No. TAK-385/TB-AK160108 
 
3 
2) Each of the HRQOL Domain Summary Scores (urinary, bowel, sexual, hormonal) will be 
calculated as follows. If 20% or more of the answers are missing then the summary score will not be 
calculated. 
・ Urinary summary score: average of converted scores of question no. 1 to 7 
・ Bowel summary score: average of converted scores of question no. 8 to 16 
・ Sexual summary score: average of converted scores of question no. 17 to 25 
・ Hormonal summary score: average of converted scores of question no. 26 to 31 
 
Reference: Takegami M, Suzukamo Y, iHope International. EPIC. 2002.