Clinical trial NCT02655237
Conditions: Uterine Fibroids
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2016-03-05; Completion date: 2017-09-25
Enrollment: 281 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of Relugolix (TAK-385) 40 mg administered orally once daily for 12 weeks, compared with leuprorelin injection (once every 4 weeks, 1.88 mg or 3.75 mg subcutaneously \[SC\]/time) in patients with uterine fibroids.

Detailed description:
The drug tested in this study was called Relugolix (TAK-385). Relugolix was tested to treat people who had uterine fibroids.

The study enrolled 281 patients. Participants received relugolix placebo and leuprorelin acetate placebo in run in period for 3 to 6 weeks. After run-in period, participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in 1:1 ratio:

* Relugolix 40 mg
* Leuprorelin 1.88 or 3.75 mg

Participants received relugolix tablets once daily along with leuprorelin 1.88 mg or 3.75 mg subcutaneous injection once in 4 weeks for 24 weeks in treatment period.

This multi-center trial was conducted in Japan. The overall time to participate in this study was approximately 32 to 40 weeks including run-in period of 3 to 6 weeks and a treatment period of 24 weeks. Participants will make multiple visits to the clinic, and a final visit 4 weeks after last dose of study drug for a follow-up assessment.

Arms: arm 1: Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 3 to 6 weeks in run-in period followed by relugolix 40 mg, tablets, orally, once daily and leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 24 weeks in treatment period. arm 2: Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 3 to 6 weeks in run-in period followed by leuprorelin acetate 1.88 mg or 3.75 mg, injection, SC, once in 4 weeks and relugolix placebo matching tablets, orally, once daily for 24 weeks in treatment period.
Interventions: intervention 1: Relugolix intervention 2: Relugolix Placebo intervention 3: Leuprorelin intervention 4: Leuprorelin Placebo
Intervention descriptions: intervention 1: Relugolix tablets intervention 2: Relugolix placebo-matching tablets intervention 3: Leuprorelin injection intervention 4: Leuprorelin placebo-matching injections

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). 


 
PROTOCOL 
<Title> 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Phase 3 Study 
to Evaluate the Efficacy and Safety of Oral TAK-385 40 mg compared with Leuprorelin 
in the Treatment of Uterine Fibroids 
 
<Short Title> 
A Phase 3 Study to Evaluate the Efficacy and Safety of TAK-385 40 mg 
compared with Leuprorelin in the Treatment of Uterine Fibroids 
 
 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka 
Study Identifier: TAK-385/CCT-002 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
TAK-385 
Date: 
24 November 2015 
 
 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 


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1.0 ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 Contacts and Responsibilities of Study-Related Activities 
See the attachment 1. 
1.2 Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this 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. 
 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES
 .............................................................................................................................
 2
 
1.1 
Contacts and Responsibilities of Study-Related Activities 
........................................... 2 
1.2 
Principles of Clinical Studies ........................................................................................ 2 
2.0 
STUDY SUMMARY 
.......................................................................................................... 9 
3.0 
LIST OF ABBREVIATIONS ........................................................................................... 14 
4.0 
INTRODUCTION
 .............................................................................................................
 16 
4.1 
Background
 ..................................................................................................................
 16 
4.2 
Rationale for the Proposed Study 
................................................................................ 16 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 18 
5.1 
Objectives
 .................................................................................................................... 18
 
5.1.1 Primary
  Objective
 ..................................................................................................
 18 
5.1.2 Secondary Objectives 
............................................................................................ 18 
5.1.3 Additional Objectives 
............................................................................................ 18 
5.2 
Endpoints
 ..................................................................................................................... 18
 
5.2.1 Primary Endpoint 
................................................................................................... 18 
5.2.2 Secondary Endpoints 
............................................................................................. 18 
5.2.3 Additional Endpoints 
............................................................................................. 19 
6.0 
STUDY DESIGN AND DESCRIPTION 
.......................................................................... 20 
6.1 
Study Design 
................................................................................................................ 20 
6.1.1 Study Population and Design ................................................................................ 20 
6.1.2 Dose Level and Regimen 
....................................................................................... 21 
6.2 
Justification for Study Design, Dose, and Endpoints 
.................................................. 22 
6.2.1 Justification for Study Population and Design 
...................................................... 22 
6.2.2 Justification for Dose Level and Regimen ............................................................ 22 
6.2.3 Justification for Endpoints 
..................................................................................... 23 
6.2.3.1 Primary Endpoint 
............................................................................................. 23 
6.2.3.2 Secondary Endpoints 
....................................................................................... 24 
6.2.3.3 Additional Endpoints 
....................................................................................... 24 
6.3 
Premature Termination or Suspension of Study or Investigational Site ..................... 25
 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
........................... 25 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
.......... 25 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites 
..................................................................... 25 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
............... 26 


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7.1 
Inclusion Criteria 
......................................................................................................... 26 
7.1.1 Inclusion Criteria for Entering the Screening (at VISIT 1) 
................................... 26 
7.1.2 Inclusion Criteria for Entering the Run-in (at VISIT 2) 
........................................ 26 
7.1.3 Inclusion Criteria for Entering the Treatment (at VISIT 3) 
................................... 27 
7.2 
Exclusion Criteria 
........................................................................................................ 27 
7.3 
Excluded Medications and Treatments 
........................................................................ 29 
7.3.1 Excluded Medications ........................................................................................... 29 
7.3.1.1 Sex Hormone and Anti-hormone Preparations 
................................................ 29 
7.3.1.2 Anti-coagulants and Anti-platelets 
.................................................................. 29 
7.3.1.3 Anti-anemic agents 
.......................................................................................... 29 
7.3.1.4 Other Drugs That May Affect Efficacy, Safety, or Pharmacokinetics 
Assessment of TAK-385 ................................................................................. 30 
7.3.2 Drugs Permitted with Condition 
............................................................................ 31 
7.3.2.1 Iron Preparations 
.............................................................................................. 31 
7.3.2.2 Analgesics
 ........................................................................................................
 31 
7.3.3 Excluded Treatments 
............................................................................................. 32 
7.4 
Diet, Fluid and Activity Control 
.................................................................................. 32 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ............................................ 34
 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
....................................... 36
 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
........................................................ 37 
8.1 
Study Medication and Materials 
.................................................................................. 37 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
...................................... 37 
8.1.1.1 Investigational Drug 
........................................................................................ 37 
8.1.1.2 Packaging and Labeling 
................................................................................... 38 
8.1.2 Storage
 ...................................................................................................................
 39 
8.1.3 Dose and Regimen 
................................................................................................. 39 
8.1.4 Overdose
 ................................................................................................................
 40 
8.2 
Investigational Drug Assignment and Dispensing Procedures 
.................................... 41 
8.3 
Randomization Code Creation and Storage 
................................................................. 41
 
8.4 
Investigational Drug Blind Maintenance 
..................................................................... 41
 
8.5 
Unblinding
  Procedure
 ..................................................................................................
 42 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
...................................... 42 
9.0 
STUDY PLAN .................................................................................................................. 43 
9.1 
Study Procedures 
......................................................................................................... 43 
9.1.1 Informed Consent Procedure 
................................................................................. 43 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
............................................ 43 


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9.1.2 Demographics, Medical History, and Medication History Procedure 
................... 43 
9.1.3 Physical Examination Procedure 
........................................................................... 43 
9.1.4 Weight, Height and BMI 
....................................................................................... 44 
9.1.5 Vital Sign Procedure 
.............................................................................................. 44 
9.1.6 Documentation of Concomitant
  Medications
 ........................................................
 44
 
9.1.7 Documentation of Concurrent Medical Conditions 
............................................... 44
 
9.1.8 Procedures for Clinical Laboratory
  Samples
 .........................................................
 44 
9.1.9 Contraception and Pregnancy Avoidance Procedure ............................................ 46 
9.1.10 Pregnancy .............................................................................................................. 47 
9.1.11 ECG Procedure 
...................................................................................................... 47 
9.1.12 Pharmacogenomic Sample Collection 
................................................................... 47 
9.1.13 Pharmacodynamics Sample Collection 
................................................................. 47 
9.1.14 Documentation of Subjects Failure ....................................................................... 48 
9.1.15 Documentation of Randomization 
......................................................................... 48 
9.1.16 PBAC
 .....................................................................................................................
 48 
9.1.17 Transvaginal Ultrasound 
........................................................................................ 49 
9.1.18 Anemia-related Measurements 
.............................................................................. 50 
9.1.19 Pain Symptoms, Other Clinical Symptoms, and QOL 
.......................................... 50 
9.1.20 WPAI:GH
 ..............................................................................................................
 50 
9.1.21 Status of Menstruation Recovery .......................................................................... 50
 
9.1.22 BMD
 ......................................................................................................................
 51 
9.1.23 Biochemical Bone Metabolism Markers 
............................................................... 51 
9.2 
Monitoring Subject Treatment Compliance 
................................................................ 51 
9.3 
Schedule of Observations and Procedures 
................................................................... 51
 
9.3.1 Screening and Run-in ............................................................................................ 52 
9.3.1.1 VISIT 1 (Day -80 through Day -26) 
................................................................ 52 
9.3.1.2 VISIT 2 (Day -42 through Day -21) 
................................................................ 52 
9.3.2 Treatment
 ...............................................................................................................
 53 
9.3.2.1 VISIT 3 (Day 1) 
............................................................................................... 53 
9.3.2.2 VISIT 4 (Day 15) 
............................................................................................. 54 
9.3.2.3 VISIT 5 (Day 29) 
............................................................................................. 55 
9.3.2.4 VISIT 6 (Day 57) 
............................................................................................. 55 
9.3.2.5 VISIT 7 (Day 85) 
............................................................................................. 56 
9.3.2.6 VISIT 8 and 9 (Day 113 and 141) 
................................................................... 56 
9.3.3 Final Visit or Early Termination ........................................................................... 57 
9.3.3.1 VISIT 10 (Day 169) (or Early Termination) 
................................................... 57 


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9.3.4 Follow-up
 ...............................................................................................................
 58 
9.3.4.1 VISIT 11 (Final visit of the Follow-up, 28 days after last dose) 
..................... 58 
9.3.5 Post Study Care ..................................................................................................... 59 
9.4 
Biological Sample Retention and Destruction 
............................................................. 59
 
10.0 ADVERSE EVENTS ........................................................................................................ 60 
10.1 Definitions
 ................................................................................................................... 60
 
10.1.1 AEs ........................................................................................................................ 60 
10.1.2 Additional Points to Consider for AEs 
.................................................................. 60 
10.1.3 SAEs
 ......................................................................................................................
 62 
10.1.4 AEs of Special Interest 
.......................................................................................... 63 
10.1.4.1 LFT Abnormalities 
.................................................................................... 63 
10.1.5 Severity of AEs 
...................................................................................................... 63 
10.1.6 Causality of AEs to Study Medication(s) 
.............................................................. 64 
10.1.7 Causality of AEs to Study Procedures 
................................................................... 64 
10.1.8 Start Date 
............................................................................................................... 64 
10.1.9 End Date 
................................................................................................................ 64 
10.1.10 Pattern of Adverse Event 
................................................................................. 65 
10.1.11 Action Taken with Study Treatment ............................................................... 65 
10.1.12 Outcome
 ...........................................................................................................
 65 
10.2 Procedures ................................................................................................................... 66 
10.2.1 Collection and Reporting of AEs 
........................................................................... 66 
10.2.1.1 AE Collection Period 
................................................................................. 66 
10.2.1.2 AE Reporting 
............................................................................................. 66 
10.2.1.3 AE of Special Interest Reporting 
............................................................... 67 
10.2.2 Collection and Reporting of SAEs ........................................................................ 67 
10.2.3 Reporting of Abnormal LFTs 
................................................................................ 68 
10.3 Follow-up of SAEs 
...................................................................................................... 68 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities .................. 68 
11.0 STUDY-SPECIFIC COMMITTEES ................................................................................ 69 
12.0 DATA HANDLING AND RECORDKEEPING 
.............................................................. 70 
12.1 CRFs
 ............................................................................................................................
 70
 
12.2 Record Retention 
......................................................................................................... 71 
13.0 STATISTICAL METHODS 
.............................................................................................. 72 
13.1 Statistical and Analytical Plans ................................................................................... 72 
13.1.1 Analysis Sets 
.......................................................................................................... 72 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
............................ 72 


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13.1.3 Efficacy Analysis 
................................................................................................... 72 
13.1.4 Pharmacodynamic Analysis .................................................................................. 74 
13.1.5 Safety Analysis 
...................................................................................................... 74 
13.2 Interim Analysis and Criteria for Early Termination .................................................. 74 
13.3 Determination of Sample Size 
..................................................................................... 75 
14.0 QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 76 
14.1 Study-Site Monitoring Visits 
....................................................................................... 76 
14.2 Protocol Deviations ..................................................................................................... 76 
14.3 Quality Assurance Audits and Regulatory Agency Inspections 
.................................. 76 
15.0 ETHICAL ASPECTS OF THE STUDY 
........................................................................... 77 
15.1 IRB Approval .............................................................................................................. 77 
15.2 Subject Information, Informed Consent, and Subject Authorization 
.......................... 77 
15.3 Subject Confidentiality 
................................................................................................ 78 
15.4 Publication, Disclosure, and Clinical Trial Registration Policy 
.................................. 79 
15.4.1 Publication and Disclosure 
.................................................................................... 79 
15.4.2 Clinical Trial Registration 
..................................................................................... 79 
15.4.3 Clinical Trial Results Disclosure 
........................................................................... 79 
15.5 Insurance and Compensation for Injury ...................................................................... 80 
16.0 REFERENCES
 ..................................................................................................................
 81 
 
LIST OF IN-TEXT TABLES 
Table 8.a 
Dose and Regimen 
................................................................................................. 39 
Table 9.a 
Clinical Laboratory Tests ...................................................................................... 45 
Table 10.a 
Takeda Medically Significant AE List 
.................................................................. 63 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design 
.................................................................................... 21 
 
LIST OF APPENDICES 
 
 
 
 
 
 
 
 
 


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Study No. TAK-385/CCT-002 
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2.0 STUDY SUMMARY 
Clinical Study Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
TAK-385 
Study Title: A Multicenter, Randomized, Double-Blind, 
Parallel-Group, Phase 3 Study to Evaluate the Efficacy and 
Safety of Oral TAK-385 40 mg compared with Leuprorelin 
in the Treatment of Uterine Fibroids 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Identifier: TAK-385/CCT-002 
Phase: 3 
Study Design: 
This is a phase 3, multicenter, randomized, double-blind, parallel-group, non-inferiority study to evaluate the 
efficacy and safety of TAK-385 administered orally in daily dosing 40 mg for 24 weeks, compared with leuprorelin 
injection (once/4 weeks, 1.88 mg or 3.75 mg subcutaneous [SC]/time) in premenopausal subjects ≥ 20 years of age 
with symptomatic uterine fibroids. The primary objective of this study is to evaluate the efficacy of TAK-385 40 mg 
administered orally once daily for 12 weeks. 
Subjects must be diagnosed to have uterine fibroids as confirmed by transvaginal ultrasound or other methods, and 
have symptoms of menorrhagia. 
The total number of subjects to be randomized under double-blind conditions is 288 (144 subjects each for the TAK-
385 40 mg group or leuprorelin group). 
After signing the informed consent form, subjects will start recording in the patient diary from the day of VISIT 1. 
During the period between VISIT 2 and VISIT 3, in which subjects must experience 1 menstrual cycle, the baseline 
values for the efficacy evaluation, including pictorial blood loss assessment chart (PBAC) scores and pain 
symptoms, will be collected. Subjects should record in the patient diary every day until the end of study drug 
administration. VISIT 2 should be between the first and fifth day of the first menstruation after VISIT 1. The study 
drug (TAK-385 placebo and leuprorelin placebo) will be administered under single-blind conditions from the day of 
VISIT 2 to the day before VISIT 3. VISIT 3 should be between the first and fifth day of the second menstruation 
after VISIT 1. From VISIT 3 to 10, subjects should try to visit the study site during the morning in a fasted state and 
before taking the TAK-385 tablet. Subjects will be randomized in a 1:1 ratio to either TAK-385 40 mg group or 
leuprorelin group at VISIT 3. Subjects will be administered study drug (TAK-385 40 mg + leuprorelin placebo or 
TAK-385 placebo + leuprorelin) in a double-dummy method from the day of VISIT 3 to the day before VISIT 10 
(or until early termination) under double-blind conditions. The investigator or subinvestigator will decide the dosage 
of leuprorelin at VISIT 2 in accordance with the approved dosage and administration, considering the body weight 
and symptoms of the individual subject. The dosage of leuprorelin will not be changed throughout the Run-in and 
Treatment in each subject. TAK-385 (or TAK-385 placebo) will be administered daily as a single oral dose before 
breakfast. Leuprorelin (or leuprorelin placebo) will be administered SC (injection) once every 4 weeks. 
This study consists of Screening of approximately 1 to 6 weeks, a Run-in period of 3 to 6 weeks, a Treatment period 
of 24 weeks, and a Follow-up period of 4 weeks. The total period of study participation is approximately 32 to 40 
weeks. If the recovery of the first post-treatment menstruation is not observed by the visit at the end of the Follow-
up(VISIT 11), the subject will undergo further follow-up using possible means such as by telephone interview, until 
the recovery of the first post-treatment menstruation is observed. During the course of this study, subjects will visit 
the study site to undergo the designated examinations and evaluations at each visit, every 2 weeks for a month after 
the initiation of study drug administration (VISIT 3) under double-blind conditions, and monthly thereafter. 
Primary Objective: 
The primary objective of this study is to evaluate the efficacy of TAK-385 40 mg administered orally once daily for 
12 weeks, compared with leuprorelin injection (once/4 weeks, 1.88 mg or 3.75 mg SC/time) in subjects with uterine 
fibroids. 


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Secondary Objectives: 
The secondary objective of this study is to evaluate the efficacy and safety of TAK-385 40 mg administered orally 
once daily for 24 weeks, compared with leuprorelin injection (once/4 weeks, 1.88 mg or 3.75 mg SC/time) in 
subjects with uterine fibroids. 
Subject Population: Subjects aged 20 years or older inclusive, with uterine fibroids 
Planned Number of Subjects: 
The following number of subjects will be randomized: 
TAK-385 40 mg group : 144 subjects 
Leuprorelin group : 144 subjects 
Total : 288 subjects 
Planned Number of Sites: 
Approximately 40 sites 
Dose Levels: 
TAK-385 
Dose: 40 mg or placebo 
Regimen: Administered once daily before breakfast 
Leuprorelin 
Dose: 1.88 mg, 3.75 mg or placebo  
Regimen: Administered once every 4 weeks 
Route of Administration: 
TAK-385: Oral 
Leuprorelin: SC 
Duration of Treatment: 
24 weeks 
Study Length: 
Screening, Run-in, Treatment (24 weeks), Follow-up 
(4 weeks) 
Inclusion Criteria: 
Subject eligibility is determined according to the following criteria prior to entry into the study: 
Inclusion Criteria for Entering the Screening (at VISIT 1) 
1. In the opinion of the investigator or subinvestigator, the subject is capable of understanding and complying 
with protocol requirements. 
2. The subject signs and dates a written, informed consent form prior to the initiation of any study procedures. 
3. Prior to VISIT 1, the subject has a diagnosis of uterine fibroids confirmed by transvaginal ultrasound, 
abdominal ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or laparoscopy, and 
has never received surgical treatment for the myoma (measurable noncalcified myoma with a longest diameter 
of  3 cm). 
4. The subject is a premenopausal Japanese woman. 
5. The subject is aged 20 years or older on the day of signing and dating the informed consent form. 
6. The subject has 1 or more measurable noncalcified myomas with a longest diameter of  3 cm confirmed by 
transvaginal ultrasound. 
7. The subject has experienced 1 or more regular menstrual cycles (25 to 38 days) immediately prior to VISIT 1 
and that should include menstrual bleeding of at least 3 consecutive days. 
8. The subject who is sexually active with a nonsterilized male partner agrees to use routinely adequate 
contraception from signing of informed consent throughout the duration of the study. 
Inclusion Criteria for Entering the Run-in (at VISIT 2) 
9. The subject has experienced regular menstrual cycles (25 to 38 days) immediately prior to VISIT 2 that should 
include menstrual bleeding of at least 3 consecutive days (at least 2 regular menstruation cycles to be 
confirmed by Inclusion criteria #7 and #9). 
Inclusion Criteria for Entering the Treatment (at VISIT 3) 
10. The subject has 1 or more measurable noncalcified myomas, with a longest diameter of  3 cm confirmed by 


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transvaginal ultrasound (the same myoma should be measured as in Inclusion criterion #6). 
11. The subject has a diagnosis of menorrhagia with a total PBAC score of  120 in 1 menstrual cycle just before 
VISIT 3. 
12. The subject has experienced regular menstrual cycles (25 to 38 days) after VISIT 1 that should include 
menstrual bleeding of at least 3 consecutive days (at least 3 regular menstruation cycles to be confirmed by 
Inclusion criteria #7, #9 and #12). 
Exclusion Criteria: 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound within 24 weeks prior to the start of the administration 
of the study medication for the Run-in (VISIT 2).  
2. The subject has received TAK-385 (including placebo) in a previous clinical study. 
3. The subject is an immediate family member, study site employee, or is in a dependant relationship with a study 
site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under 
duress. 
4. The subject has a previous or current history of blood disorders (eg, thalassemia, sickle cells anemia, folic-acid 
deficiency, and coagulopathy), excluding (latent) iron-deficiency anemia. 
5. The subject has a known history of severe hypersensitivity or severe allergy to sanitary goods. 
6. The subject has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis. 
7. The subject has a current history of thyroid gland disorder with irregular menstruation, or has a potential for 
irregular menstruation due to thyroid gland disorder, as determined by the investigator or subinvestigator. 
8. The subject has a previous or current history of pelvic inflammatory disease within the 8 weeks prior to VISIT 
1. 
9. The subject has a positive Pap smear test result conducted within the 1 year prior to VISIT 1 (if there are no 
previous test results, those who were judged positive in the test conducted before VISIT 2). 
10. The subject has a history of panhysterectomy or bilateral oophorectomy. 
11. The subject has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the 
investigator or subinvestigator. 
12. The subject has a malignant tumor or a history of a malignant tumor within the 5 years prior to VISIT 1. 
13. The subject has been treated with any of the following drugs (excluding drugs for external use and dietary 
supplements) within the 4 weeks prior to VISIT 2: anti-coagulant drugs, anti-platelet drugs, tranexamic acid, 
selective estrogen receptor modulators (SERMs), activated vitamin D preparations, other vitamin D 
preparations, calcitonin, ipriflavone, steroid hormones, vitamin K preparations, teriparatide, or denosumab. 
14. The subject has been treated with any of the following drugs within the 8 weeks prior to VISIT 2: oral 
contraceptive or sex hormone preparations (norethindrone, norethisterone, medroxyprogesterone, estrogen, or 
other progestins), and within the 16 weeks prior to VISIT 2: gonadotropin-releasing hormone (GnRH) 
analogues, dienogest, danazol, or aromatase inhibitors (for 1- and 3-month sustained-release preparations, 
within the 20 and 28 weeks prior to VISIT 2, respectively). 
15. The subject has been treated with a bisphosphonate preparation within the 24 weeks prior to VISIT 2. 
16. The subject has a previous or current history of hypersensitivity or allergies to leuprorelin, synthetic GnRH, 
GnRH agonists or GnRH antagonists, or has a previous or current history of severe hypersensitivity or severe 
allergy to other drugs. 
17. The subject has nondiagnosable abnormal genital bleeding. 
18. Female subject who is pregnant, lactating, or intending to become pregnant or to donate ova prior to signing of 
informed consent, during the study period, or within 1 month after the end of the study. 
19. The subject has a previous or current history of osteoporosis, osteopenia, or other metabolic bone diseases. 
20. The subject has clinically significant cardiovascular disease (eg, myocardial infarction or unstable angina 


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pectoris within the 24 weeks prior to VISIT 1) or uncontrollable hypertension (eg, resting systolic blood 
pressure  180 mmHg or diastolic blood pressure  110 mmHg at Screening and Run-in). 
21. The subject is inappropriate for participation in this study based on standard 12-lead electrocardiogram (ECG) 
findings, as determined by the investigator or subinvestigator. 
22. The subject has active liver disease or jaundice, or with alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or bilirubin (total bilirubin) > 1.5 times the upper limit of normal (ULN) in the 
clinical laboratory tests at VISIT 1 and 2. 
23. The subject has previous or current history of diseases considered to be inappropriate for participation in this 
study, including severe hepatic impairment, jaundice, renal impairment, cardiovascular disease, endocrine 
system disease, metabolic disorder, pulmonary disease, gastrointestinal disease, neural disease, urological 
disease, immune disease, or mental disorder (especially depression-like symptoms) or suicide attempt resulting 
from a mental disorder. 
24. The subject has a previous or current history of drug abuse (defined as any illicit drug use) or alcohol abuse. 
25. The subject is inappropriate for participation in this study for other reasons, as determined by the investigator 
or subinvestigator. 
Main Criteria for Evaluation and Analyses: 
Primary Endpoint 
1) Efficacy: 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 
Secondary Endpoints 
1) Efficacy: 
• Proportion of subjects with a total PBAC score of < 10 (from Week 2 to 6, from Week 18 to 24, and for 6 
weeks before the final dose of study drug) 
• Myoma volumes (Week 2, 4, 8, 12 and 24) 
Note: Only the largest myoma among those measurable at VISIT 1 will be measured throughout the study. 
• Uterine volumes (Week 2, 4, 8, 12 and 24) 
• Hemoglobin (HGB) (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• Numerical rating scale (NRS) score (from Week 6 to 12, from Week 2 to 6, from Week 18 to 24, and for 6 
weeks before the final dose) 
• Uterine fibroid symptom and quality of life (UFS-QOL) score (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
2) Safety: 
• Adverse events (AEs), vital signs, weight, standard 12-lead ECG, clinical laboratory tests, bone mineral density 
(BMD), biochemical bone metabolism markers (serum N-telopeptide [NTELOP] and bone specific alkaline 
phosphatase [BAP]) 
Additional Endpoints 
1) Efficacy: 
• Hematocrit (HCT), serum iron (Fe), and serum ferritin (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• Use of analgesic medications during the Treatment (from Week 6 to 12, from Week 2 to 6, from Week 18 to 
24, and for 6 weeks before the final dose) 
• Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) (Week 2, 4, 8, 12 and 
24) 
2) Safety: 
• Period from the last dose of study drug to return of menstrual cycles 
3) Pharmacodynamic effects: 
• Luteinizing hormone (LH), follicle stimulation hormone (FSH), estradiol (E2), and progesterone (P) (Week 2, 


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4, 8, 12, 16, 20, 24 and Follow-up) 
Statistical Considerations: 
Primary analysis 
The following analyses will be performed based on the full analysis set (FAS): 
The proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 will be summarized by treatment 
group. The point estimate and 2-sided 95% confidence interval of the difference in the percentage will be calculated 
between TAK-385 40 mg group and leuprorelin group (TAK-385 40 mg group – leuprorelin group). In addition, 
non-inferiority test using Farrington and Manning method with a non-inferiority margin of 15% will be conducted 
for the comparison between TAK-385 40 mg group and leuprorelin group. 
Secondary analysis 
An analysis similar to the above “Primary analysis” will be performed using the per protocol set (PPS) to assess the 
robustness of the results (sensitivity analysis). 
Sample Size Justification: 
In a clinical study of ulipristal acetate (already approved in Europe) compared with leuprorelin conducted overseas, 
the proportion of subjects with a total PBAC score of < 75 for 28 days before Week 13 was 89.1% in the TAP-144-
SR (1M) 3.75 mg group, and the proportion of subjects with a total PBAC score of  2 for 28 days before Week 13 
was 80.4%. 
In TAK-385 phase 2 study in the treatment of uterine fibroids, the point estimate (and corresponding 2-sided 95% 
confidence interval) of the proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 was 83.6% 
(71.2%, 92.2%) in the TAK-385 40 mg group. 
Based on the results of the above 2 studies, the proportions of subjects with a total PBAC score of < 10 from Week 6 
to 12 in both TAK-385 40 mg group and leuprorelin group are estimated to be 83.6%. 
Under this assumption, a sample size of at least 129 subjects per group will provide  90% power to demonstrate 
non-inferiority at 1-sided 0.025 level of significance, using a non-inferiority margin of 15% (nQuery Advisor 6.01). 
Based on the above, a sample size of 129 subjects per group (258 subjects in total) is planned as the number of 
evaluable subjects. Assuming that approximately 10% of subjects will not be evaluable for the primary endpoint, 
144 subjects are to be randomized to each group, for a total of 288 subjects. 
 


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3.0 LIST OF ABBREVIATIONS 
AE
 adverse
 
event
 
AESI 
adverse event of special interest 
ALP
 alkaline
 
phosphatase
 
ALT
 alanine
 
aminotransferase
 
AST
 aspartate
 
aminotransferase
 
AUC 
area under the blood concentration-time curve 
BAP 
bone specific alkaline phosphatase 
BMD
 bone
 
mineral
 
density
 
BMI
 body
 
mass
 
index
 
BUN 
blood urea nitrogen 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CT
 computed
 
tomography
 
DXA 
dual-energy x-ray absorptiometry 
E2 estradiol
 
ECG
 electrocardiogram
 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
Fe
 iron
 
FSH
 follicle-stimulating
 
hormone
 
GCP 
Good Clinical Practice 
GGT
 gamma
 
glutamyl
 
transferase
 
GLDH
 glutamate
 
dehydrogenase
 
GnRH
 gonadotropin-releasing
 
hormone
 
hCG
 human
 
chorionic
 
gonadotropin
 
HCT
 hematocrit
 
HDL 
high density lipoprotein 
HGB
 hemoglobin
 
ICH 
International Conference on Harmonisation 
INN 
international non-proprietary name 
INR
 international
 
normalized
 
ratio
 
IRB 
institutional review board 
IUD
 intrauterine
 
device
 
LDH
 lactate
 
dehydrogenase
 
LDL
 low
 
density
 
lipoprotein
 
LFT 
liver function test 
LH
 luteinizing
 
hormone
 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NILM 
negative for intraepithelial lesion or malignancy 
NRS
 numerical
 
rating
 
scale
 
NSAIDs 
non-steroidal anti-inflammatory drugs 
NTELOP 
N-telopeptide 
P
 progesterone
 
PBAC 
pictorial blood loss assessment chart 
P-gp
 P-glycoprotein
 
PGx
 pharmacogenomics
 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per protocol set 
PT
 preferred
 
term
 
QOL 
quality of life 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC
 subcutaneous(ly)
 
SERM 
selective estrogen receptor modulator 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TBA 
total bile acid 
TEAE 
treatment-emergent adverse event 
TPC
 Takeda
 
Pharmaceutical
 
Company
 
Limited
 
UFS-QOL 
uterine fibroid symptom and quality of life 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire:General Health 
 


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4.0 INTRODUCTION 
4.1 Background 
Uterine fibroid is a benign sex hormone-dependent gynecological disease affecting 1 in every 3 
to 4 women. Most uterine fibroids are asymptomatic, but clinical symptoms such as increase in 
menstrual blood loss and anemia due to menorrhagia as well as compression and pain in the 
bladder and pelvis due to large myoma are seen in about 10% to 20% of patients. In particular, 
menorrhagia is considered to be caused by the combination of an increase in surface area of the 
uterine cavity; poor uterine contraction due to myoma; and increased circulation, congestion, or 
impaired hemostasis due to hypertrophy of the endometrium in the vicinity of the myoma. 
Persistent menorrhagia is known to induce iron-deficiency anemia. Therefore, menorrhagia is a 
primary factor that deteriorates the quality of life (QOL) of patients with uterine fibroids. 
Gonadotropin-releasing hormone (GnRH) agonists, such as leuprorelin are commonly used for 
the treatment of benign sex hormone-dependent gynecological diseases, such as endometriosis 
and uterine fibroids. It is considered that continuous use of a GnRH agonist induces a transient 
increase in the secretion of gonadotropins (flare up), followed by pituitary and gonadal 
desensitization that decreases sex hormone secretion. Therefore, GnRH agonists exert 
therapeutic effects against these diseases by reducing secretion of sex hormones. However, 
GnRH agonists often cause flare up (temporary worsening of symptoms) and may typically take 
about 3 to 4 weeks before therapeutic effects begin to emerge. They also cannot be orally 
administered because they are peptides. For these reasons, the development of a new oral drug 
that is not associated with temporal worsening of symptoms is awaited for the treatment of these 
diseases. 
TAK-385 has been synthesized at Takeda Pharmaceutical Company Limited (TPC) and is an 
orally active, nonpeptide, GnRH antagonist with a novel structure. TAK-385 antagonizes GnRH 
on the GnRH receptors that are present in the pituitary anterior lobe basophiles (secretory cells), 
and inhibits the GnRH-stimulated secretion of luteinizing hormone (LH) and follicle-stimulating 
hormone (FSH) from these cells. As a result, the drug decreases blood concentrations of 
hormones, including estradiol (E2) and progesterone (P), and induces amenorrhea. Therefore, 
TAK-385 is expected to improve the clinical symptoms observed in patients with uterine fibroids. 
As TAK-385 is a GnRH antagonist, it causes no flare up and has a faster onset of action than 
GnRH agonists. Unlike GnRH agonists, which are given either subcutaneously (SC) or 
intranasally, TAK-385 is a nonpeptide preparation and can be administered orally. 
For the above reasons, the development of TAK-385 for the treatment of benign sex hormone-
dependent gynecological diseases such as endometriosis and uterine fibroids, has been 
progressing in Japan and overseas. 
4.2 Rationale for the Proposed Study 
A phase 1 study
 
 


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The efficacy and safety of TAK-385 were investigated when orally administered to patients with 
uterine fibroids at dose levels of 10, 20, and 40 mg for 12 weeks, compared to placebo in the 
Phase 2 study (TAK-385/CCT-001). 
In the efficacy evaluation, a statistically significant difference in proportion of subjects with a 
total pictorial blood loss assessment chart (PBAC) score of < 10 from Week 6 to 12, as the 
primary endpoint in the Phase 2 study, was observed between each TAK-385 group and placebo 
group. The proportion was highest in TAK-385 40 mg group, suggesting a dose-response 
relationship. The decrease in menstrual blood loss, and achievement of amenorrhea, being ones 
of the secondary endpoints in this study, was seen in higher proportion of subjects at the higher 
dose levels of TAK-385 evaluated. 
In the safety evaluation, the common treatment-emergent adverse events (TEAEs) reported 
during the study period were nasopharyngitis, headache, metrorrhagia, menorrhagia (among the 
35 subjects in which the symptoms were categorized as menorrhagia, 34 subjects were actually 
diagnosed with menostaxis [lowest level term].), genital hemorrhage, menstruation irregular and 
hot flush. As for the TEAEs relevant to the pharmacological activity of TAK-385, such as hot 
flush, headache, menstruation irregular, and metrorrhagia, the incidence was higher in 
accordance with the dose levels among the 10, 20, and 40 mg groups of TAK-385, but there were 
no clinically significant TEAEs related to the study drug. The percent change of bone mineral 
density (BMD) in this study was considered to be the same level compared to the percent change 
of BMD that has previously been reported with the use of leuprorelin 3.75 mg. 
Based on the above, a Phase 3 confirmatory study in uterine fibroid patients was planned to 
investigate the efficacy and safety of TAK-385 40 mg compared to leuprorelin which is widely 
used for the treatment of uterine fibroids. 
Pharmacogenomics (PGx) analysis may be conducted to investigate the contribution of genetic 
variance on drug response, eg, its efficacy and safety. Participation of study subjects in PGx 
sample collection is optional. 
As PGx is an evolving science, numerous genes and the corresponding functions are currently 
not yet fully understood. Future data may suggest a role of some of these genes in drug responses 
or diseases, which may lead to additional hypothesis-generating exploratory research on stored 
samples. 


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5.0 STUDY OBJECTIVES AND ENDPOINTS 
5.1 Objectives 
5.1.1 Primary Objective 
The primary objective of this study is to evaluate the efficacy of TAK-385 40 mg administered 
orally once daily for 12 weeks, compared with leuprorelin injection (once/4 weeks, 1.88 mg or 
3.75 mg SC/time) in subjects with uterine fibroids. 
5.1.2 Secondary Objectives 
The secondary objective of this study is to evaluate the efficacy and safety of TAK-385 40 mg 
administered orally once daily for 24 weeks, compared with leuprorelin injection (once/4 weeks, 
1.88 mg or 3.75 mg SC/time) in subjects with uterine fibroids. 
5.1.3 Additional Objectives 
An additional objective of this study is to evaluate the pharmacodynamic effect, which is blood 
concentrations of LH, FSH, E
2, and P. 
5.2 Endpoints 
5.2.1 Primary Endpoint 
1) Efficacy: 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 
5.2.2 Secondary Endpoints 
1) Efficacy: 
• Proportion of subjects with a total PBAC score of < 10 (from Week 2 to 6, from Week 18 to 
24, and for 6 weeks before the final dose of study drug) 
• Myoma volumes (Week 2, 4, 8, 12 and 24) 
Note: Only the largest myoma among those measurable at VISIT 1 will be measured 
throughout the study. 
• Uterine volumes (Week 2, 4, 8, 12 and 24) 
• Hemoglobin (HGB) (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• Numerical Rating Scale (NRS) score (from Week 6 to 12, from Week 2 to 6, from Week 18 
to 24, and for 6 weeks before the final dose) 
• Uterine fibroid symptom and QOL (UFS-QOL) score (Week 4, 8, 12, 16, 20, 24 and Follow-
up) 


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2) Safety: 
• Adverse events (AEs), vital signs, weight, standard 12-lead electrocardiogram (ECG), 
clinical laboratory tests, BMD, biochemical bone metabolism markers (serum N-telopeptide 
[NTELOP] and bone specific alkaline phosphatase [BAP]) 
5.2.3 Additional Endpoints 
1) Efficacy: 
• Hematocrit (HCT), serum iron (Fe), and serum ferritin (Week 4, 8, 12, 16, 20, 24 and 
Follow-up) 
• Use of analgesic medications during the Treatment (from Week 6 to 12, from Week 2 to 6, 
from Week 18 to 24, and for 6 weeks before the final dose) 
• Work Productivity and Activity Impairment Questionnaire:General Health (WPAI:GH) 
(Week 2, 4, 8, 12 and 24) 
2) Safety: 
• Period from the last dose of study drug to return of menstrual cycles 
3) Pharmacodynamic effects: 
• LH, FSH, E2 and P (Week 2, 4, 8, 12, 16, 20, 24 and Follow-up) 


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6.0 STUDY DESIGN AND DESCRIPTION 
6.1 Study Design 
An overview of the study design is shown in Figure 6.a. See Appendix A for details of the 
schedule of tests, observations, and evaluations. 
6.1.1 Study Population and Design 
This is a phase 3, multicenter, randomized, double-blind, parallel-group, non-inferiority study to 
evaluate the efficacy and safety of TAK-385 compared with leuprorelin injection (once/4 weeks, 
1.88 mg or 3.75 mg SC/time) in premenopausal subjects ≥ 20 years of age with symptomatic 
uterine fibroids. The primary objective is to evaluate the efficacy of TAK-385 40 mg 
administered orally once daily for 12 weeks. The secondary objective is to evaluate the efficacy 
and safety of TAK-385 40 mg administered orally once daily for 24 weeks. In addition, the 
pharmacodynamics of continuous oral administration of TAK-385 40 mg for 24 weeks is to be 
assessed. 
Subjects must be diagnosed to have uterine fibroids as confirmed by transvaginal ultrasound or 
other methods, and have symptoms of menorrhagia (the total PBAC score of ≥ 120 for the entire 
menstrual cycle immediately before VISIT 3). The total number of subjects to be randomized 
under double-blind conditions is 288 (144 subjects each for the TAK-385 40 mg group or 
leuprorelin group). 
After signing the informed consent form, subjects will start recording in the patient diary from 
the day of VISIT 1. During the period between VISIT 2 and VISIT 3, in which subjects must 
experience 1 menstrual cycle, the baseline values for the efficacy evaluation, including PBAC 
scores and pain symptoms (baseline PBAC score: the total PBAC score for the entire menstrual 
cycle immediately before VISIT 3) will be collected. Subjects should record in the patient diary 
every day until the end of study drug administration. VISIT 2 should be between the first and 
fifth day of the first menstruation after VISIT 1. The study drug (TAK-385 placebo and 
leuprorelin placebo) will be administered under single-blind conditions from the day of VISIT 2 
to the day before VISIT 3. VISIT 3 should be between the first and fifth day of the second 
menstruation after VISIT 1. From VISIT 3 to 10, subjects will receive study drug (TAK-385 and 
leuprorelin placebo, or TAK-385 placebo and leuprorelin) in a double blind manner. Subjects 
should try to visit the study site during the morning in a fasted state and before taking the TAK-
385 tablet.  
The study consists of Screening of approximately 1 to 6 weeks, a Run-in period of 3 to 6 weeks, 
a Treatment period of 24 weeks, and a Follow-up period of 4 weeks. The total period of study 
participation is approximately 32 to 40 weeks. If the recovery of the first post-treatment 
menstruation is not observed by the visit at the end of the Follow-up (VISIT 11), the subject will 
undergo further follow-up using possible means such as by telephone interview, until the 
recovery of the first post-treatment menstruation is observed. During the course of this study, 
subjects will visit the study site to undergo the designated examinations and evaluations at each 
visit, every 2 weeks for a month after the initiation of study drug administration (VISIT 3) under 
double-blind conditions, and monthly thereafter. 


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6.1.2 Dose Level and Regimen 
At VISIT 3, subjects will be randomized in a 1:1 ratio to either the TAK-385 40 mg group or 
leuprorelin group. Study drug (TAK-385 40 mg + leuprorelin placebo or TAK-385 placebo + 
leuprorelin) will be administered in a double-dummy method from the day of VISIT 3 to the day 
before VISIT 10 (or until early termination) under double-blind conditions. 
The investigator or subinvestigator will decide the dosage of leuprorelin at VISIT 2 in 
accordance with the approved dosage and administration, considering the body weight and 
symptoms of the individual subject. Leuprorelin (or leuprorelin placebo) should be administered 
SC (injection) once every 4 weeks using the same dose throughout the Run-in and Treatment. 
TAK-385 (or TAK-385 placebo) will be administered daily as a single oral dose before breakfast. 
 
Figure 6.a  Schematic of Study Design 
 
VISIT
Day
F o
 
l
lo w-
up
Screening 
Run-in
Treatment
Fol
low-up
Leuprorel
in group
Informed
consent*
Ini
tia
 
tion o 
f
adm
inistration
Ini
tiatio n o 
f
treatment
End of
treatment
(24 weeks)
(4 weeks)
(12 weeks)
TAK-385 40 mg
 group
Placebo
1 
2** 
3** 4
9 
10 
11
-80~-26 -42~-21 
1 
29
TAK-385 40 mg 
tablet
TAK-385 placebo tablet
Leuprorel
in
  acetate (1.88
 mg
 
or 3.75 mg) injection
Leuprorel
in
  acetate (1.88
 mg
 
or 3.75 mg) placebo injection
Tablet
(once/day, before
 breakfast)
Injec 
tion
(once/4 wks, at site
 visit)
*  In
 addi
tion to Day
  
-80~-26, informed  consent  may
  be obtained  before  Day
  
-80.
**VISIT
  2 and 3:
 On
 Days 1 to 5 of
  
the menstrual
  cycle
8
7
6
5
15
57 
85 
113 
141 
169 
197


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6.2 Justification for Study Design, Dose, and Endpoints 
6.2.1 Justification for Study Population and Design 
Menorrhagia is the most frequent symptom seen in patients with uterine fibroids. Patients with 
menorrhagia have to frequently replace sanitary products. In addition, prolonged menorrhagia 
can induce iron-deficiency anemia. Therefore, menorrhagia is the main cause of QOL 
deterioration1. Surgery is performed for radical treatment of uterine fibroids. Drug therapy is 
used before surgery to alleviate anemia and to reduce the size of myoma2, 3. TAK-385 is thought 
to overcome the shortcomings of GnRH agonists commonly used in preoperative therapy. In this 
study, the improvement in the bleeding profile is examined for evaluation of improvement of 
QOL and efficacy of TAK-385 in patients with uterine fibroids. 
The study is designed as a double-blind, parallel-group study to demonstrate the non-inferiority 
of TAK-385 compared with leuprorelin which is commonly used for the treatment of uterine 
fibroids. Since the period of general presurgical treatment for uterine fibroids is 3 months, which 
is stated to be a period for decreasing the size of myoma and improving anemia in some reports
3, 
the evaluation period of drug efficacy for the primary endpoint is to be set as 3 months. However, 
since medication for more than 3 months may sometimes be needed as a maintenance therapy, 
evaluation of drug efficacy and safety for up to 6 months are to be set as secondary endpoints. In 
benign indications GnRH agonist administration exceeding more than 6 months is generally not 
permitted because it may cause BMD loss resulting from a decrease in estrogen level. 
The Treatment for this study is set at 6 months to evaluate the safety of TAK-385 and the 
potential effect of TAK-385 on BMD compared to GnRH agonists in subjects with uterine 
fibroids and menorrhagia. A single-blind treatment period (with placebo) is also included to 
investigate if there is any potential placebo effect on baseline blood loss and pain assessment. In 
addition, the Follow-up is included for safety assessment, including assessment of the recovery 
of menstruation after discontinuation of active treatment. 
6.2.2 Justification for Dose Level and Regimen 
1. TAK-385 
The efficacy, safety, pharmacokinetics, and pharmacodynamics of TAK-385 10, 20, and 40 mg 
were evaluated in study TAK-385/CCT-001. For the primary endpoint (proportion of subjects 
with a total PBAC score of < 10 from Week 6 to 12), statistically significant differences were 
observed in all TAK-385 treatment groups compared to placebo group. The proportion was 
higher in the TAK-385 40 mg group compared to the other treatment arms, suggesting a dose-
response relationship. Similarly, the trend toward improvement with increasing dose was also 
observed in the secondary endpoints, change in myoma and uterine volumes and blood 
concentration of HGB. The common TEAEs were considered to be caused by the 
pharmacological effect of TAK-385, and their incidence was higher in the TAK-385 treatment 
groups compared to placebo group. Most of the TEAEs were mild or moderate, and no serious 
TEAEs considered related to the study drug were observed. A trend toward a decrease in BMD 
was observed with increasing dose. However, the type, frequency, and intensity of TEAEs and 
the percent change of BMD were expected to be at a comparable level as that of GnRH agonists; 


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CONFIDENTIAL 
therefore, there seemed to be no clinically serious problem on safety. For these reasons, the dose 
of 40 mg is considered appropriate for use as the clinical dose of TAK-385 to evaluate the 
efficacy and safety in subjects with uterine fibroids. 
With regard to pharmacokinetics,
 
 
 
 TAK-385 will be administered once daily before breakfast. 
2. Leuprorelin 
Leuprorelin is the first-line drug for the treatment of uterine fibroids. In the package insert, the 
“dosage and administration” section states the follows: 
Usually, for adults, 1.88 mg of Leuprorelin Acetate is SC administered once every 4 weeks. 
However, for patients with heavy weight or those with markedly enlarged uterus, 3.75 mg is 
administered. The administration of this drug should be initiated on the first to fifth day after the 
start of menstrual period. 
In this study, the dosage of leuprorelin (either 1.88 mg or 3.75 mg) is to be determined by the 
investigator or subinvestigator at VISIT 2 in accordance with the approved dosage and 
administration, considering the body weight and symptoms of the individual subject. Leuprorelin 
should be administered once every 4 weeks using the same dose throughout the Run-in and 
Treatment. Also, a double dummy is used to conduct this study under double blind conditions. 
6.2.3 Justification for Endpoints 
6.2.3.1 Primary Endpoint 
Measuring menstrual blood loss is considered appropriate for the assessment of the bleeding 
profile in subjects with uterine fibroids having menorrhagia. In order to accurately assess the 
efficacy of TAK-385, the “proportion of subjects with a total PBAC score of < 10 from Week 6 
to 12” is the primary endpoint. The evaluation period is set as 6 weeks, which is long enough to 
cover the subject’s maximum menstrual cycle (38 days, which is the upper limit of normal 
[ULN] menstrual cycle). 
The PBAC score was used for the measurement of menstrual blood loss in the Phase 2 Study, 
TAK-385/CCT-001, as overseas literature has reported its usefulness
4. No collection of used 
sanitary products was necessary by using the PBAC score. In the result of TAK-385/CCT-001, 
the baseline values of PBAC score were higher in order of the subjects with submucosal fibroid, 
intramural fibroid, and subserosal fibroid, showing blood loss depends on the type of myoma. In 
addition, the correlation between the total PBAC score from Week 6 to 12 and the change in 
myoma and uterine volumes from baseline after Week 12 was relatively high. This result 
suggested that PBAC could be a tool for assessing the clinical symptoms of uterine fibroids. For 
these reasons, PBAC was considered an appropriate method for assessing the symptoms of 
uterine fibroids. 


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As the blood E2 concentration decreases due to pharmacological effect after the administration of 
TAK-385, amenorrheic state is expected to be induced. However, the possibility of occurrence of 
metrorrhagia cannot be denied. Therefore, for the study TAK-385/CCT-001, the cut-off value of 
total PBAC score was set at 10 based on the cut-off value in other clinical studies and on the 
medical expert’ s opinion. In order to assess the appropriateness of the cut-off value, the 
agreement between total PBAC score and the number of menstruations (0,  1) was assessed 
using the cut-off value of 2, 10, and 75, and as a result, the cut-off value of 10 produced the 
greatest  coefficient. Therefore, the primary endpoint of this study was defined as the proportion 
of subjects with a total PBAC score of < 10 from Week 6 to 12. 
6.2.3.2 Secondary Endpoints 
A decrease in menstrual blood loss is to be assessed to demonstrate whether or not the decrease 
in menstrual blood loss can be maintained after administration for up to 6 months. Blood 
concentration of HGB is selected as a secondary endpoint as it is an important parameter of the 
bleeding profile, as described above. Myoma and uterine reduction prior to surgery is one of the 
most important goals of drug therapy. For this reason, myoma and uterine volumes are assessed 
using transvaginal ultrasound. Clinical symptoms unrelated to menorrhagia but associated with 
uterine fibroids, and also QOL are assessed using the NRS and UFS-QOL. 
With regard to safety assessment, the hypoestrogenic state associated with long-term use of 
GnRH agonists has been reported to reduce BMD. For this reason, the effect of TAK-385 on 
BMD is to be assessed using dual-energy x-ray absorptiometry (DXA). In addition to the 
assessment of BMD, biochemical bone metabolism markers (serum NTELOP and BAP) are also 
to be assessed as a supplementary parameter of BMD. Other commonly used safety endpoints, 
such as AEs and vital signs, are also included. 
6.2.3.3 Additional Endpoints 
In addition to blood concentration of HGB, HCT and serum concentrations of Fe and ferritin are 
also measured for the assessment of anemia during the Treatment. As analgesics are permitted in 
this study under specific conditions, information on analgesic use is incorporated into the 
efficacy assessment. Also, WPAI:GH, validated questionnaire to measure impairments in work 
and activities
5, is used to evaluate the effects of TAK-385 on the QOL of patients with uterine 
fibroids. 
Amenorrhea is induced due to the pharmacological effect of TAK-385. Therefore, in order to 
assess the time until menstruation returns after the end of treatment, the period from the last dose 
of study drug to return of menstrual cycles was selected as one of the other endpoints for 
additional assessment of the safety of TAK-385. 
For the additional evaluation of the safety and efficacy of TAK-385 and pharmacodynamics of 
TAK-385 (LH, FSH, E2, and P concentrations) in subjects with uterine fibroids are also to be 
evaluated. 


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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 medication 
that indicates a change in the known risk/benefit profile for the compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of 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 entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study. 
7.1.1 Inclusion Criteria for Entering the Screening (at VISIT 1) 
1. In the opinion of the investigator or subinvestigator, the subject is capable of 
understanding and complying with protocol requirements. 
2. The subject signs and dates a written, informed consent form prior to the initiation of any 
study procedures. 
3. Prior to VISIT 1, the subject has a diagnosis of uterine fibroids confirmed by 
transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging (MRI), 
computed tomography (CT), or laparoscopy, and has never received surgical treatment 
for the myoma (measurable noncalcified myoma with a longest diameter of ≥ 3 cm). 
4. The subject is a premenopausal Japanese woman. 
5. The subject is aged 20 years or older on the day of signing and dating the informed 
consent form. 
6. The subject has 1 or more measurable noncalcified myomas with a longest diameter of 
≥3 cm confirmed by transvaginal ultrasound. 
7. The subject has experienced 1 or more regular menstrual cycles (25 to 38 days) 
immediately prior to VISIT 1 and that should include menstrual bleeding of at least 
3 consecutive days. 
8. The subject who is sexually active with a nonsterilized* male partner agrees to use 
routinely adequate contraception from signing of informed consent throughout the 
duration of the study. 
*Definitions and acceptable methods of contraception are defined in 
Section 9.1.9 Contraception and Pregnancy Avoidance Procedure and 
reporting responsibilities are defined in Section 9.1.10 Pregnancy. 
 
7.1.2 Inclusion Criteria for Entering the Run-in (at VISIT 2) 
9. The subject has experienced regular menstrual cycles (25 to 38 days) immediately prior 
to VISIT 2 that should include menstrual bleeding of at least 3 consecutive days (at least 
2 regular menstruation cycles to be confirmed by Inclusion criteria #7 and #9). 


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7.1.3 Inclusion Criteria for Entering the Treatment (at VISIT 3) 
10. The subject has 1 or more measurable noncalcified myomas, with a longest diameter of 
 3 cm confirmed by transvaginal ultrasound (the same myoma should be measured as in 
Inclusion criterion #6). 
11. The subject has a diagnosis of menorrhagia with a total PBAC score of  120 in 1 
menstrual cycle just before VISIT 3. 
12. The subject has experienced regular menstrual cycles (25 to 38 days) after VISIT 1 that 
should include menstrual bleeding of at least 3 consecutive days (at least 3 regular 
menstruation cycles to be confirmed by Inclusion criteria #7, #9 and #12). 
7.2 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study. 
1. The subject has received any investigational compound within 24 weeks prior to the start 
of the administration of the study medication for the Run-in (VISIT 2). 
2. The subject has received TAK-385 (including placebo) in a previous clinical study. 
3. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in conduct of this study (eg, 
spouse, parent, child, sibling) or may consent under duress. 
4. The subject has a previous or current history of blood disorders (eg, thalassemia, sickle 
cells anemia, folic-acid deficiency, and coagulopathy), excluding (latent) iron-deficiency 
anemia. 
5. The subject has a known history of severe hypersensitivity or severe allergy to sanitary 
goods. 
6. The subject has lower abdominal pain due to irritable bowel syndrome or severe 
interstitial cystitis. 
7. The subject has a current history of thyroid gland disorder with irregular menstruation, 
or has a potential for irregular menstruation due to thyroid gland disorder, as determined 
by the investigator or subinvestigator. 
8. The subject has a previous or current history of pelvic inflammatory disease within the 
8 weeks prior to VISIT 1. 
9. The subject has a positive Pap smear test result conducted within the 1 year prior to 
VISIT 1 (if there are no previous test results, those who were judged positive in the test 
conducted before VISIT 2). 
Note: “Positive” is defined as the result that falls in classes other than I or II in the 
Nichibo Classification or any result other than negative for intraepithelial lesion or 
malignancy (NILM) in the Bethesda System. 
10. The subject has a history of panhysterectomy or bilateral oophorectomy. 


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11. The subject has had markedly abnormal uterine bleeding or anovulatory bleeding, as 
determined by the investigator or subinvestigator. 
12. The subject has a malignant tumor or a history of a malignant tumor within the 5 years 
prior to VISIT 1. 
13. The subject has been treated with any of the following drugs (excluding drugs for 
external use and dietary supplements) within the 4 weeks prior to VISIT 2: anti-
coagulant drugs, anti-platelet drugs, tranexamic acid, selective estrogen receptor 
modulators (SERMs), activated vitamin D preparations, other vitamin D preparations, 
calcitonin, ipriflavone, steroid hormones, vitamin K preparations, teriparatide, or 
denosumab. 
14. The subject has been treated with any of the following drugs within the 8 weeks prior to 
VISIT 2: oral contraceptive or sex hormone preparations (norethindrone, norethisterone, 
medroxyprogesterone, estrogen, or other progestins), and within the 16 weeks prior to 
VISIT 2: GnRH analogues, dienogest, danazol, or aromatase inhibitors (for 1- and 3-
month sustained-release preparations, within the 20 and 28 weeks prior to VISIT 2, 
respectively). 
15. The subject has been treated with a bisphosphonate preparation within the 24 weeks 
prior to VISIT 2. 
16. The subject has a previous or current history of hypersensitivity or allergies to 
leuprorelin, synthetic GnRH, GnRH agonists or GnRH antagonists, or has a previous or 
current history of severe hypersensitivity or severe allergy to other drugs. 
17. The subject has nondiagnosable abnormal genital bleeding. 
18. Female subject who is pregnant, lactating, or intending to become pregnant or to donate 
ova prior to signing of informed consent, during the study period, or within 1 month 
after the end of the study. 
19. The subject has a previous or current history of osteoporosis, osteopenia, or other 
metabolic bone diseases. 
20. The subject has clinically significant cardiovascular disease (eg, myocardial infarction or 
unstable angina pectoris within the 24 weeks prior to VISIT 1) or uncontrollable 
hypertension (eg, resting systolic blood pressure  180 mmHg or diastolic blood 
pressure  110 mmHg at Screening and Run-in). 
21. The subject is inappropriate for participation in this study based on standard 12-lead 
ECG findings, as determined by the investigator or subinvestigator. 
22. The subject has active liver disease or jaundice, or with alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or bilirubin (total bilirubin) > 1.5 times the upper limit 
of normal (ULN) in the clinical laboratory tests at VISIT 1 and 2. 
23. The subject has previous or current history of diseases considered to be inappropriate for 
participation in this study, including severe hepatic impairment, jaundice, renal 
impairment, cardiovascular disease, endocrine system disease, metabolic disorder, 


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pulmonary disease, gastrointestinal disease, neural disease, urological disease, immune 
disease, or mental disorder (especially depression-like symptoms) or suicide attempt 
resulting from a mental disorder. 
24. The subject has a previous or current history of drug abuse (defined as any illicit drug 
use) or alcohol abuse. 
25. The subject is inappropriate for participation in this study for other reasons, as 
determined by the investigator or subinvestigator. 
7.3 Excluded Medications and Treatments 
7.3.1 Excluded Medications 
Use of the following drugs is prohibited in this study. 
7.3.1.1 Sex Hormone and Anti-hormone Preparations 
Use of the following drugs is prohibited from VISIT 1 to 11 (or until early termination) to avoid 
confounding of the assessment of safety, efficacy and pharmacodynamics. 
• Danazol 
• GnRH analogues (except for leuprorelin provided by the sponsor for this study) 
• Dienogest 
• Oral contraceptives and other sex hormone preparations (norethindrone, norethisterone, 
medroxyprogesterone, estrogen, and other progestins) 
• Aromatase inhibitors 
• Herbal medicines with indications related to menstruation (eg, Tokishakuyakusan and 
Keishi-bukuryogan) 
7.3.1.2 Anti-coagulants and Anti-platelets 
Use of the following drugs (excluding drugs for external use and dietary supplements) is 
prohibited from VISIT 1 to 10 (or until early termination). 
• Anti-coagulants (warfarin, heparin, anti-thrombin agent, urokinase, tisokinase, alteplase, 
nateplase, monteplase, nasaruplase) 
• Anti-platelets (prostaglandin preparation, thromboxane synthetase inhibitor, ticlopidine 
hydrochloride, clopidogrel, cilostazol, sarpogrelate hydrochloride, ethyl icosapentate, 
beraprost sodium, dipyridamole, batroxobin) 
7.3.1.3 Anti-anemic agents 
Use of the following drugs (excluding drugs for external use and dietary supplements) is 
prohibited from VISIT 1 to 10 (or until early termination). 


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• Vitamin B12 
• Vitamin B6 
• Folic acid 
• Iron preparations (injection) 
7.3.1.4 Other Drugs That May Affect Efficacy, Safety, or Pharmacokinetics Assessment of 
TAK-385 
Use of the following drugs (excluding drugs for external use and dietary supplements) is 
prohibited from VISIT 1 to 10 (or until early termination). 
• Tranexamic acid 
• Steroid hormones 
• Anti-epileptic drugs 
• Anti-convulsants 
• Anti-depressants 
• Anti-psychotics (major tranquilizers) 
• Ergot alkaloids 
• St. John’s wort (Hypericum perforatum) 
• P-glycoprotein (P-gp) inhibitors 
• P-gp inducers 
• Cytochrome P450 inducers 
• SERMs 
• Bisphosphonates 
• Active and other vitamin D preparations 
• Calcium preparations 
• Calcitonins 
• Ipriflavones 
• Vitamin K preparations 
• Teriparatide 
• Denosumab 


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7.3.2 Drugs Permitted with Condition 
7.3.2.1 Iron Preparations 
An oral iron preparation is administered from VISIT 2 as specified below in subjects with blood 
HGB of < 10.0 g/dL at VISIT 1. Once started, the dose and regimen may not be changed up to 
VISIT 10 (or until early termination). 
1) Dose and regimen of iron preparations: Iron 100 mg/day orally given 
2) Criteria for use: 
• HGB is < 10.0 g/dL: 100 mg/day 
• HGB is  10.0 g/dL: Do not use 
Only oral preparations may be used. No injection may be given. 
Oral iron preparations are continued without changing the dose or regimen up to VISIT 10 (or 
until early termination) in patients who have been using them before entering into the study 
(prior to VISIT 1). 
Regardless of with or without iron preparations administration, the subjects must be withdrawn 
immediately when their HGB concentrations at VISIT 2 or later decrease to < 8.0 g/dL. 
Use of an iron preparation may be interrupted when an AE occurs due to its use or when the 
investigator or subinvestigator makes an overall decision that the subject no longer needs it based 
on anemia-related and other parameters. 
7.3.2.2 Analgesics 
Use of analgesics is ONLY permitted under the following conditions from VISIT 1 to 10 (or 
until early termination). This restriction was set because it is likely to have an impact on the 
evaluation of secondary and additional endpoints. Analgesics refer to drugs containing 
compounds that have indications for pain symptoms in the package inserts and antispasmodic 
drugs which possess indications for gynecological or urological disease in the package inserts. 
• For severe pain associated with uterine fibroids; Loxoprofen can be used as the first choice 
medicine. If loxoprofen cannot be used for various reasons, other non-steroidal anti-
inflammatory drugs (NSAIDs) can be used. 
• For treatment of AE, etc. NOT associated with uterine fibroids (eg, common cold); 
Acetaminophen can be used as the first choice medicine. If acetaminophen cannot be used 
for various reasons, other NSAIDs can be used. In addition to acetaminophen and NSAIDs, 
analgesics for external use are also permitted to be used. 
Analgesics for pain associated with uterine fibroids will be provided by the site in accordance 
with the approved package labeling. 
The investigator or subinvestigator should instruct subjects to take analgesics as directed and to 
avoid using them under a fasted state. The investigator or subinvestigator should instruct subjects 
not to casually use analgesics for prophylactic purposes. The investigator or subinvestigator 


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should also instruct subjects to record their maximum pain symptoms during the past 24 hours, 
considering pain symptoms before taking analgesics, in the patient diary (NRS). Subjects must 
record the use of analgesics to relieve pain from uterine fibroids every day in the patient diary. 
In addition, analgesics can be used in the cases as follows.  
• When the reason for use is other than AE, concurrent condition or target disease (eg, 
scopolamine butylbromide for MRI preparation) 
• Codeine which is not intended to relieve pain associated with uterine fibroids (eg, codeine 
phosphate in a combination cold remedy) 
7.3.3 Excluded Treatments 
Surgical treatment of uterine fibroids, use of intrauterine device (IUD), and transfusions are 
prohibited from VISIT 1 to VISIT 11 (or until early termination). 
7.4 Diet, Fluid and Activity Control 
The investigator, subinvestigator, and study collaborator should advise subjects to comply with 
the following instructions: 
1. Make the scheduled visits on time, and undergo examinations and tests as requested. If 
the subject cannot make a scheduled visit, she should inform the study site as soon as 
possible. 
2. Report the subjective symptom and objective symptom at each visit, including its 
contents, the date of occurrence, intensity, outcome, and date of outcome. 
3. If any abnormality has occurred between visits, such as worsening of a bleeding 
symptom, the subject should immediately report to the investigator, subinvestigator, or 
study collaborator by telephone or other means, and ask for instructions. 
4. If the subject visits another medical institution during the study period, she should 
inform the investigator or subinvestigator about the reasons for the visit and treatment 
received. 
5. If the subject takes any drugs other than those prescribed by the investigator or 
subinvestigator (including over-the-counter medications), she should report this at the 
next visit. 
6. The subject should record in the patient diary every day (it is very important for the 
evaluation of TAK-385 in this study to keep a daily record of menstrual blood loss and 
entering information on the use of study drugs and analgesics). 
7. The subjects are instructed to use adequate contraception during the study period. 
8. The subjects will be asked to avoid excessive exercise and activities, and maintain a 
normal daily routine during the study period. In particular, subjects must avoid drinking 
and eating excessively on the day before each visit, and should also avoid drinking 
grapefruit juice to any extent possible during the study period. 


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9. The subject should bring all unused study drugs, empty blister card(s) of study drug, and 
the patient diary to each visit. 
10. The subject should start taking the TAK-385 tablet for the Run-in from the day of VISIT 
2, and start taking the TAK-385 tablet for the Treatment from the day of VISIT 3. The 
subject should take the TAK-385 tablet every day as instructed by the investigator or 
subinvestigator. Taking the TAK-385 tablet every day is very important for the drug to 
show its expected effects. 
11. The subject should take the TAK-385 tablet every day before breakfast during the Run-
in and the Treatment, and should try to take the TAK-385 tablet at approximately the 
same time each day. If the subject forgets to take the TAK-385 tablet before breakfast, 
she should take it before lunch on the same day. If the subject forgets to take the 
TAK-385 tablet in both cases (ie, before breakfast and before lunch), she should take it 
before dinner on the same day. The subject should avoid carrying over the missed dose 
to other day and taking multiple doses together on the same day. The date of 
administration and whether the drug was taken before a meal should be properly 
recorded in the patient diary. 
For the scheduled study site visit from VISIT 2 through 10, follow the instructions 
below: 
<VISIT 2> 
The subject should try to visit the study site during the morning and undergo the 
designated study procedures as far as possible. 
<VISITS 3 and 10> 
On the days of the scheduled study site visit, the subject should try to visit the study site 
without taking the TAK-385 tablet in the morning and undergo the designated study 
procedures as far as possible. Even if the subject cannot visit the study site in the 
morning, she should still come to the study site without taking the TAK-385 tablet. 
<VISITS 4, 5, 6, 7, 8 and 9> 
On the days of the scheduled study site visit, the subject should try to visit the study site 
without taking the TAK-385 tablet in the morning and undergo the designated study 
procedures as far as possible. If the subject cannot visit the study site in the morning, she 
must take the TAK-385 tablet before breakfast, and report to the investigator or 
subinvestigator that she has taken the drug. 
12. On VISIT 2, 7 and 10 (or early termination), the subject should try to visit the study site 
at the same time and undergo the designated study procedures to the maximum extent 
possible. 
13. The subject should always use the designated sanitary products provided by the study 
site during the study period (see section 9.1.16 for details on sanitary products). If it 
becomes difficult to continue to use the designated sanitary products during the study 
period, for reasons such as the onset of AEs, she should stop using the designated 


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sanitary products, report that fact to the investigator, subinvestigator, or study 
collaborator by telephone or other appropriate means, and ask for further instructions. 
14. During the study period, the subject should always use the sanitary products provided by 
the study site, except in cases as stated in the instruction No.13. The subject must not use 
the sanitary products that the subject has been using before entering this study. The 
subject should avoid wearing the same product for long hours, except during sleeping 
hours, and change the product frequently so that the area in contact with the product is 
kept clean. Even during sleeping hours, the subject should try to avoid wearing the same 
product for more than 8 hours. Except during the menstruation period, the subject may 
use other sanitary products for preventing staining of underwear, but must switch to the 
sanitary product provided by the study site as soon as possible when bleeding is 
confirmed. 
15. When the subject needs to take analgesic drugs due to severe pain associated with 
uterine fibroids, the subject should comply with the investigator’s or subinvestigator’s 
instructions before taking the analgesic drug, and try to avoid taking it in a fasted state as 
far as possible. The subject should also not take the analgesic drug casually or for 
prophylactic purposes. In cases where the subject has to take an analgesic drug, she is 
required to properly record her pain symptoms which occur before taking analgesics in 
the patient diary (NRS) and to record analgesic use in the patient diary. 
16. The subject may use acetaminophen as the first choice medicine in certain circumstances, 
such as occurrence of an AE, that requires an analgesic for purposes other than to relieve 
pain from uterine fibroids. In this case, avoid casually using it for prophylactic purposes. 
7.5 Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the electronic case report form (eCRF) using the following 
categories. For subject failure, refer to Section 9.1.14. 
1. Death. The subject died on study and caused early termination of study treatment. 
Note: If the subject dies on study, the event will be considered as serious adverse event 
(SAE). Refer to Section 10.2.2 for the reporting procedures. 
2. Adverse event (AE). The subject has experienced an 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 AE. 
• Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status, see Section 9.1.8), if the following circumstances occur at any time 
during study medication treatment: 
– ALT or AST > 8 × ULN, or 


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– ALT or AST > 5 × ULN and persists for more than 2 weeks, or 
– ALT or AST > 3 × ULN in conjunction with elevated total bilirubin > 2 × ULN or 
international normalized ratio (INR) > 1.5, or 
– ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
• Hypoestrogenic symptoms 
The investigator or subinvestigator makes an overall risk-benefit assessment for the subject 
when any of the following events that can be considered related to the pharmacological 
effect of TAK-385 occur, and decides whether to stop the drug administration based on the 
intensity and frequency of the event: 
– Hot flush, feeling hot, flushed face, shoulder stiffness, headache, insomnia, dizziness, 
perspiration, menopausal depression, decreased libido, feeling cold, visual disturbance, 
emotional lability, etc. 
• ECG abnormality 
The subject judged by the investigator or subinvestigator to be inappropriate for 
continuation of the study based on standard 12-lead ECG findings. 
3. Protocol deviation. The discovery after randomization that the subject failed to meet 
protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health. 
4. Lost to follow-up. The subject did not return to the clinic and attempts to contact the 
subject were unsuccessful. Attempts to contact the subject must be documented. 
5. Withdrawal by subject. 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 (withdrawal due to an AE 
or lack of efficacy should not be recorded in the “Withdrawal by subject” category). If 
subject wishes to withdraw from the study to proceed to surgery, the category No.9 
“Recovery leading to surgery” should be recorded. 
6. Study terminated by sponsor. The sponsor terminates the study. 
7. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
8. Lack of efficacy. The investigator or subinvestigator judges TAK-385 shows no efficacy 
based on the menstrual blood loss, menstrual status, and use of analgesics (eg, a notable 
increase in menstrual blood loss after start of study drug administration) and judges 
continued participation in the study would pose an unacceptable risk to the subject. 


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9. Bone mineral density loss. The subjects with BMD measured by DXA at VISIT 7 is 
< 90% of baseline (or subjects with BMD changes from baseline > 10%), or the 
investigator or subinvestigator makes an overall risk-benefit assessment for the subject 
and decides to stop the study drug administration, even if the subject’s BMD maintains  
90% of baseline (or with a BMD change from baseline  10%). 
10. Recovery leading to surgery. The subject who does not apply to any of the above 
category 1 to 8 and has a favorable outcome (eg, the improvement in the bleeding profile, 
the reduction in myoma and uterine volumes, and improvement in anemia) leading to the 
proceeding to surgery, and the investigator or subinvestigator judges that it is appropriate 
to proceed to surgery and not ethically desirable for the subject to be administered the 
study drug any longer. 
11. Reduction of HGB concentration. Regardless of with or without iron preparations 
administration, HGB concentration of subject at VISIT 2 or later decreases to < 8.0 g/dL. 
12. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or subinvestigator may discontinue a subject’s study participation at any time 
during the study when the subject meets the study termination criteria described in Section 7.5. 
In addition, a subject may discontinue her participation without giving a reason at any time 
during the study. Should a subject’s participation be discontinued, the primary criterion for 
termination must be recorded by the investigator or subinvestigator. In addition, efforts should be 
made to perform all procedures scheduled for the Early Termination Visit. Discontinued or 
withdrawn subjects will not be replaced. 


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8.0 CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1 Study Medication and Materials 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Investigational Drug 
1. TAK-385 
Study drug name: TAK-385 
Nonproprietary name: relugolix (international non-proprietary name [INN]) 
Chemical name: 
Urea,N-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-3-(6-
methoxy-3-pyridazinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-N’-methoxy- 
Dosage form and content: 
Name
 Content
 
TAK-385 40 mg tablet 
Contains 40 mg of TAK-385 per tablet 
TAK-385 placebo tablet 
Contains no TAK-385 per tablet 
 
Appearance: both the TAK-385 40 mg tablet and TAK-385 placebo tablet are light yellow red, 
film-coated tablets and are indistinguishable in appearance from each other. 
2. Leuprorelin 
Study drug name: leuprorelin acetate 
Nonproprietary name: leuprorelin (INN) 
Chemical name: 
5-Oxo-prolyl-histidyl-tryptophyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-N-ethyl-prolinamide 
monoacetate 
Dosage form and content: 
Name
 Content
 
Leuprorelin acetate 1.88 mg injection 
Contains 1.88 mg of leuprorelin per vial 
Leuprorelin acetate 3.75 mg injection 
Contains 3.75 mg of leuprorelin per vial 
Leuprorelin acetate 1.88 mg placebo injection  
Contains no leuprorelin per vial 
Leuprorelin acetate 3.75 mg placebo injection  
Contains no leuprorelin per vial 
 


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Appearance: the powder for both of the leuprorelin acetate 1.88 mg injection and the 
corresponding placebo injection, and the powder for both of the leuprorelin acetate 3.75 mg 
injection and the corresponding placebo injection are indistinguishable in appearance from each 
other. The vials filled with them are also indistinguishable from each other. 
3. Vehicle for suspension 
An ampule (1 mL) contains water for injection, and 50 mg of D-mannitol, 5 mg of carmellose 
sodium, and 1 mg of polysorbate 80 as excipients. 
8.1.1.2 Packaging and Labeling 
1. Packaging of study drugs for the Run-in (single-blind) 
1) TAK-385 
TAK-385 placebo tablets are packaged in blister cards containing 14 tablets (for 14 days) per 
sheet. Three blister cards are sealed in an aluminum pouch with desiccant. Three aluminum 
pouches, each containing 3 blister cards, are placed in an outer case. One pouch is allocated to 
each subject. 
The outer case indicates that it contains a study drug and includes the name of the drug, quantity, 
protocol number, sponsor’s name and address, serial number, and storage conditions. 
2) Leuprorelin 
One vial of leuprorelin acetate 1.88 mg placebo injection or leuprorelin acetate 3.75 mg placebo 
injection and an ampule of vehicle for suspension (for one injection) are contained in a small box. 
One small box is allocated to each subject. 
The small box indicates that it contains a study drug and includes the name of the drug, protocol 
number, sponsor’s name and address, serial number, and storage conditions. 
2. Packaging of study drugs for the Treatment (double-blind) 
1) TAK-385 
TAK-385 40 mg tablets or TAK-385 placebo tablets are packaged in blister cards containing 14 
tablets (for 14 days) per sheet. Three blister cards are sealed in an aluminum pouch with 
desiccant. Six aluminum pouches, each containing 3 blister cards, are placed in an outer case. 
One outer case is allocated to each subject. All packaging materials for TAK-385 40 mg tablets 
and TAK-385 placebo tablets are indistinguishable from each other. 
The outer case indicates that it contains a study drug, and includes the name of the drug, quantity, 
protocol number, sponsor’s name and address, serial number, and storage conditions. 
2) Leuprorelin 
One vial of leuprorelin acetate (1.88 mg, 3.75 mg, 1.88 mg placebo, or 3.75 mg placebo) 
injection and an ampule of vehicle for suspension (for one injection) are contained in a small box. 
One vial of leuprorelin acetate (1.88 mg, 3.75 mg, 1.88 mg placebo, or 3.75 mg placebo) 
injection and 3 ampules of vehicle for suspension are contained in a small box as a spare. Eight 


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small boxes (6 boxes for scheduled once-use and 2 boxes for spare use) are placed in an outer 
case. One outer case is allocated to each subject. All packaging materials for leuprorelin are 
indistinguishable from each other. 
The outer case indicates that it contains a study drug and includes the name of the drug, quantity, 
protocol number, sponsor’s name and address, serial number, and storage conditions. 
8.1.2 Storage 
All investigational drugs referred in 8.1.1.1 are to be kept at room temperature (1°C to 30°C). A 
daily temperature log of the drug storage area must be maintained every working day. 
Investigational drugs must be kept in an appropriate, limited-access, secure place until it is used 
or returned to the sponsor or designee for destruction. Investigational drugs must be stored under 
the conditions specified on the label, and remain in the original container until dispensed. 
Leuprorelin acetate (1.88 mg or 3.75 mg) injection, leuprorelin acetate (1.88 mg or 3.75 mg) 
placebo injection and their vehicle for suspension are to be kept in the original containers until 
use. 
8.1.3 Dose and Regimen 
Table 8.a describes the dose and tablet count that will be provided to each group. 
Table 8.a  
Dose and Regimen 
Period 
Group 
Dose and Regimen 
Run-in
 All
 
group
 
• One TAK-385 placebo tablet per day 
• One leuprorelin acetate (1.88 mg or 3.75 mg) placebo 
injection once/4 weeks 
Treatment 
TAK-385 40 mg group 
• One TAK-385 40 mg tablet per day 
• One leuprorelin acetate (1.88 mg or 3.75 mg) placebo 
injection once/4 weeks 
Leuprorelin group 
• One TAK-385 placebo tablet per day 
• One leuprorelin acetate (1.88 mg or 3.75 mg)  
injection once/4 weeks 
 
1. TAK-385 
1) Run-in 
Administration of TAK-385 placebo tablets should be started on the day of VISIT 2. Until the 
day before VISIT 3, subjects take 1 tablet once daily before breakfast. The investigator or 
designee must instruct the subject to bring each of the study drug containers (blister cards) to 
each visit, regardless of whether the study drugs are empty. 
2) Treatment 
Administration of TAK-385 40 mg tablets or TAK-385 placebo tablets should be started on the 
day of VISIT 3. Until the day before VISIT 10, subjects take 1 tablet once daily before breakfast. 


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During the Treatment, subjects should try to make each scheduled visit to the study site in the 
morning and take the TAK-385 (40 mg or placebo) tablet for the day after completing the 
scheduled tests (see Section 7.4). However, if unable to visit the study site in the morning of 
VISIT 4, 5, 6, 7, 8 or 9, subjects should take the morning dose before breakfast and report to the 
investigator or subinvestigator that the morning dose has been taken (see Section 7.4). 
2. Leuprorelin 
1) Run-in 
The investigator or subinvestigator will decide the dosage of leuprorelin acetate (1.88 mg or 
3.75 mg) injection for individual subjects at VISIT 2 (see Section6.1.2 for details). Leuprorelin 
acetate (1.88 mg or 3.75 mg) placebo injection should be administered SC on the day of VISIT 2. 
2) Treatment 
Leuprorelin acetate (1.88 mg, 3.75 mg, 1.88 mg placebo, or 3.75 mg placebo) injection are 
administered SC once every 4 weeks on the day of visiting the study sites. At VISIT 4, 
leuprorelin acetate (1.88 mg, 3.75 mg, 1.88 mg placebo, or 3.75 mg placebo) injection should 
NOT be administered. 
For dosing, powder in a vial should be sufficiently suspended with the vehicle for suspension 
(1 mL). A needle for injection of 23 Gauge or larger should be used. For optimal SC injection, 
need to follow the following instructions. 
• The site for SC injection should be the brachial, abdominal or gluteal region. 
• The injection site should be changed each time. Repeated injection should not be given at the 
same site. 
• Confirmation should be made to see that the needle is not piercing a blood vessel. 
• The patients should be instructed not to massage the injection site. 
Instructions for preparing method of leuprorelin acetate (1.88 mg or 3.75 mg) injection and 
leuprorelin acetate (1.88 mg or 3.75 mg) placebo injections are as follows. 
• The injectable solution should be prepared at the time of use and be used immediately after 
preparing the suspension. 
• If any sedimentation is noticed in the suspension of vial product, such suspension should be 
used after swirling the vial gently, avoiding formation of bubbles, to resuspend the particles 
uniformly. 
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 overdosing study drugs during the treatment period (with or without associated AEs) 
will be documented on an Overdose page of the eCRF, in order to capture this important safety 


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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 
CRFs according to Section 10.0, ADVERSE EVENTS. 
SAEs associated with overdose should be reported according to the procedure outlined in Section 
10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 Investigational Drug Assignment and Dispensing Procedures 
At VISIT 2, the investigator or subinvestigator will decide the dosage of leuprorelin acetate 
(1.88 mg or 3.75 mg) injection for individual subjects (see Section 6.1.2 for details). The 
investigator or his/her designee checks each subject’s eligibility for the Treatment at VISIT 3, 
and register via website the subject on registration/randomization center of the subject’s 
qualification for randomization to the treatment groups (a unique number designating each study 
drug [TAK-385 tablet and leuprorelin acetate injection] for 1 subject is issued). When the subject 
registration/randomization center shows drug numbers, the study drug set with the number is 
dispensed to the subject. The investigator or his/her designee enters the study drug number in the 
eCRF. The subject will be registered at subject registration/randomization center even if the 
subject is ineligible for randomization. 
8.3 Randomization Code Creation and Storage 
The supervisor on randomization personnel generates a randomization schedule. All 
randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
At VISIT 3, subjects will be randomized in a 1:1 ratio to either the TAK-385 40 mg group or 
leuprorelin group. 
8.4 Investigational Drug Blind Maintenance 
The emergency key control center will keep the emergency key until it needs to be accessed in 
an emergency or the database for all subjects is locked. 
Blind maintenance may become difficult in this study depending on the results of 
pharmacodynamic testing. For blind maintenance, the laboratory conducting the analysis should 
conceal the test results from any outside party until the randomization code is opened. The 
laboratory reports the results to the investigator via the sponsor after the randomization code is 
opened. If the test results need to be reported before the randomization code is opened, the 
necessary steps for of blind maintenance must be taken not to be identified the subject by a 
person appointed at the laboratory, such as changing the drug numbers. The test results may then 
be reported to the sponsor via the randomization personnel of the sponsor or the designee. 
During the period between VISIT 2 and 3, all subjects will receive the placebo treatment 
(TAK-385 placebo tablets and leuprorelin acetate [1.88 mg or 3.75 mg] placebo injection) in a 
single-blind manner. Subjects must not be informed of their treatment allocation (placebo) 
during this time as it may compromise study data. 


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8.5 Unblinding Procedure  
The investigational drug blind should not be broken by the investigator or subinvestigator unless 
information concerning the investigational drug is necessary for the medical treatment of the 
subject. 
The investigator or subinvestigator may obtain the randomization information to break the 
blinding by contacting the emergency key control center (see the contact information in the 
attachment). 
The sponsor must be notified as soon as possible if the investigational drug blind is broken. The 
date, time, and reason the blind is broken must be recorded in the document called Record of 
Early Blind-Breaking and the same information (except the time) must be recorded on the eCRF. 
If any site personnel is unblinded, investigational drug must be stopped immediately and the 
subject must be withdrawn from the study. 
8.6 Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of 
investigational medicines created by the sponsor, according to which the site designee will 
appropriately manage the sponsor-supplied drug (TAK-385 placebo tablet, leuprorelin acetate 
[1.88 mg or 3.75 mg] placebo injection for the Run-in, TAK-385 40 mg tablet or TAK-385 
placebo tablet, leuprorelin acetate [1.88 mg or 3.75 mg] injection, and leuprorelin acetate 
[1.88 mg or 3.75  mg] placebo injection for the Treatment). The investigator will also receive 
those procedures from the sponsor. The procedures include those for ensuring appropriate receipt, 
handling, storage, management, dispensation of the sponsor-supplied drug, and collection of 
unused medications from the subject as well as return of them to the sponsor or destruction of 
them. 
The site designee will immediately return unused medications to the sponsor after the study is 
closed at the site. 


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9.0 STUDY PLAN 
9.1 Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator and subinvestigator whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is explained; this subject number will be used throughout the study. 
9.1.1.1 Pharmacogenomic Informed Consent Procedure 
A separate informed consent form pertaining to storage of the sample must be obtained prior to 
collecting a blood sample for PGx research for this study. 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 Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, birth history, 
classification of uterine fibroids, first defined diagnosis date of uterine fibroids, treatment history 
of uterine fibroids and smoking classification of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases that stopped within one year prior to signing of informed consent. All 
events related to the exclusion criteria must be surveyed regardless of the time of resolution or 
disappearance. Ongoing conditions are considered concurrent medical conditions (see Section 
9.1.7).  
Medication history information to be obtained includes any medication that was stopped at or 
within 4 weeks (28 days) prior to signing of informed consent. 
9.1.3 Physical Examination Procedure 
The following body systems will be examined. 
(1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; 
(5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; 
(9) nervous system; (10) lymph nodes; (11) genitourinary system; and (12) other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination. 


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9.1.4 Weight, Height and BMI 
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The body mass index (BMI) is calculated by the sponsor from the weight and height 
recorded in the eCRF using metric units with the formula provided below. The Takeda standard 
for collecting height is centimeters without decimal places and for weight it is kilograms (kg) 
with 1 decimal place. BMI should be derived as: 
Metric: BMI = weight (kg)/height (m)2 
Example: 
Height = 176 cm, Weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m
2 
9.1.5 Vital Sign Procedure 
Vital signs will include body temperature (axilla measurement), sitting blood pressure (resting 
 5 minutes), and pulse (beats per minute). 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through 
VISIT 11 [or early termination]), and all medication including vitamin supplements, over-the-
counter medications, and oral herbal preparations, must be recorded in the eCRF. 
9.1.7 Documentation of 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, standard 
12-lead ECG, or physical examination abnormalities noted at screening examination. The 
condition (ie, diagnosis) should be described. 
9.1.8 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 23 mL (including PGx sample 
collection), and the approximate total volume of blood for the study is 170 mL (including PGx 
sample collection). 
The samples collected for clinical laboratory tests are listed in Table 9.a. 


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Table 9.a  
Clinical Laboratory Tests 
Hematology
 Chemistry
 
Urinalysis
 
Red blood cells (RBC) 
White blood cells (WBC) 
with differential 
HGB (a) 
HCT (a) 
Platelets 
ALT 
AST 
Lactate dehydrogenase (LDH) 
Gamma glutamyl transferase (GGT) 
Albumin 
Alkaline phosphatase (ALP) 
Bilirubin (Total bilirubin) 
Protein (Total protein) 
Cholesterol (Total cholesterol) 
High density lipoprotein (HDL) cholesterol 
Low density lipoprotein (LDL) cholesterol 
Triglycerides 
Glucose 
HGB A1C 
Creatinine 
Blood urea nitrogen (BUN) 
Creatine kinase 
Urate 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphate 
Magnesium 
Ferritin (a) 
Fe (a) 
Bile acid (total bile acid [TBA]) 
Glutamate dehydrogenase (GLDH) 
Qualitative (protein, glucose, occult 
blood, urobilinogen, bilirubin) 
Pregnancy test (human chorionic 
gonadotropin [hCG]) 
Hormone 
Biochemical bone metabolism markers 
LH 
FSH 
E2 
P 
NTELOP 
BAP 
(a) Anemia-related measurement (see Section 9.1.18) 
 
The central laboratory (see the attachment 1) will perform laboratory tests for hematology, 
chemistries, urinalysis (excluding pregnancy tests), hormone, biochemical bone metabolism 
markers. 


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Each study site will conduct urine pregnancy tests (hCG). 
The results of laboratory tests will be returned to the investigator or subinvestigator, who is 
responsible for reviewing and filing these results. 
If subjects experience ALT or AST > 3 ×ULN, follow-up laboratory tests (at a minimum, ALP, 
ALT, AST, total bilirubin, GGT, and INR) should be performed within a maximum of 7 days 
and preferably within 48-72 hours after the abnormality was noted. In this case, “LFT 
Abnormalities” are to be reported as AEs of special interest (AESI)s. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory used. 
(Please see Section 7.5 for discontinuation criteria, and Section 10.2.3 for the appropriate 
guidance on Reporting of Abnormal LFTs in relation to ALT or AST > 3 ×ULN in conjunction 
with total bilirubin > 2 ×ULN.) 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent, throughout the duration of the study, and until the recovery of 
menstruation after last dose of study medication, subjects who are sexually active with a 
nonsterilized male partner (sterilized males should be at least 1 year postvasectomy and have 
confirmed that they have obtained documentation of the absence of sperm in the ejaculate) must 
use adequate contraception. In addition they must be advised not to donate ova during this period.  
An acceptable method of contraception is defined as one that has no higher than a 1% failure rate. 
In this study, where medications and devices containing hormones are excluded, the only 
acceptable methods of contraception are: 
Barrier methods (each time the subject has intercourse): 
• Male condom PLUS spermicide. 
• Cap (plus spermicidal cream or jelly) PLUS male condom and spermicide. 
• Diaphragm (plus spermicidal cream or jelly) PLUS male condom and spermicide. 
 
Subjects will be provided with information on acceptable methods of contraception as part of the 
subject informed consent process and will be asked to sign a consent form stating that they 
understand the requirements for avoidance of pregnancy and donation of ova during the course 
of the study. 
During the course of the study, regular urine hCG pregnancy tests will be performed, and 
subjects will receive continued guidance with respect to the avoidance of pregnancy as part of 
the study procedures (Appendix A). 
In addition to a negative urine hCG pregnancy test at Screening (VISIT 1), subjects also must 
have a negative urine hCG pregnancy test at VISIT 2 and VISIT 3. 


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9.1.10 Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. 
If the pregnancy occurs during administration of active study medication, eg, after VISIT 3 or 
within 28 days of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in the attachment 1. 
Should the pregnancy occur during or after administration of blinded drug, the investigator or 
subinvestigator must inform the subject of their right to receive treatment information. If the 
subject chooses to receive unblinded treatment information, the individual blind should be 
broken by the investigator or subinvestigator.  
If the female subject agrees to the primary care physician (obstetrician or gynecologist, etc.) 
being informed, the investigator or subinvestigator should notify the primary care physician that 
the subject was participating in a clinical study at the time she became pregnant and provide 
details of treatment the subject received (blinded or unblinded, as applicable). 
All pregnancies in subjects on active study drug including comparator will be followed up to 
final outcome, using the pregnancy form. Pregnancies will remain blinded to the study team. The 
outcome, including any premature termination, must be reported to the sponsor. An evaluation 
after the birth of the child will also be conducted. 
9.1.11 ECG Procedure 
A standard 12-lead ECG will be recorded. The investigator or subinvestigator (or a qualified 
observer at the investigational site) will interpret the ECG using 1 of the following categories: 
normal or abnormal. The investigator or subinvestigator will judge if it is clinically significant. 
9.1.12 Pharmacogenomic Sample Collection 
For possible exploratory investigation of markers enabling the prediction of drug response, one 
5 mL whole blood sample for PGx should be collected at the earliest time possible between 
VISIT 3 and VISIT 11 (or early termination) from consenting subject after investigational drug 
was assigned. 
PGx sample should not be collected from any subject who has received comparable bone marrow 
transplant or whole blood transfusion within 6 months before any sample collection. 
See the separately created procedure for directions on collecting, handling, and storage of PGx 
samples. 
9.1.13 Pharmacodynamics Sample Collection 
LH, FSH, E2, and P concentrations are used in the pharmacodynamic evaluation. These sex 
hormone concentrations are determined using samples collected at each visit from VISIT 3 to 11 
(or early termination). To maintain blinding, sex hormone concentrations should be reported to 
the investigator and sponsor after unblinding. 


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9.1.14 Documentation of Subjects Failure 
An eCRF is completed for each subject who signs informed consent and discontinues study 
before randomization. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
• Death 
• Adverse Event 
• Screen Failure (failed inclusion criteria or did meet exclusion criteria) 
• Protocol deviation 
• Lost to follow-up 
• Withdrawal by subject <specify reason> 
• Study terminated by sponsor 
• Pregnancy 
• Other <specify reason> 
Subject numbers assigned to subjects who fail screening should not be reused. 
9.1.15 Documentation of Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the treatment phase. 
If the subject is found to be not eligible for randomization, the investigator or subinvestigator 
should record the primary reason for failure on the applicable eCRF. 
9.1.16 PBAC 
The volume of menstrual blood loss is measured using the PBAC score. The investigator or 
subinvestigator distributes the patient diary to consented subjects. Subjects fill out the patient 
diary every day from VISIT 1 to the day before VISIT 10 (or until early termination). 
From VISIT 1, subjects are required to use only the sanitary products designated by the sponsor. 
The products supplied by the study site are shown below: 
• Sanitary towel (pad): 
 
• Tampon:
 
Products other than those supplied by the study site may only be used outside the menstruation 
period to prevent staining of the underwear. However, those sanitary products supplied by the 
study site must be immediately used when bleeding is observed. 
Subjects should check the sanitary product after use, and record the number of used products that 
look similar to each of the diagrams of the sanitary towel or tampon in the PBAC sheet every day. 


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The investigator or subinvestigator should check the recorded PBAC scores at each subject’s 
visit. Additionally, the start/end date of menstruation must be recorded in CRF in reference to the 
PBAC score. If there is anything unclear or insufficient description in the patient diary, queries 
may be made to the subject, and corrections to the patient diary are recorded by the subject in an 
change history that captures the old information, the new information, identification of the 
person making the correction and the date the correction. If it is impossible to make queries to 
the subject at site visits, queries will be made to the subject with telephone calls or other means, 
and corrections to the patient diary are recorded by the investigator or subinvestigator in a 
change history that captures the old information, the new information, identification of the 
person making the correction and the date of the correction. 
Three diagrams each for the sanitary towel and tampon are shown in the PBAC score sheet. Each 
diagram represents a lightly stained, moderately stained, or completely saturated pad or tampon. 
The following scores are assigned to these categories: 
• Add 1, 5, or 20 points for each lightly stained, moderately stained, or completely saturated 
pad, respectively. 
• Add 1, 5, or 10 points for each lightly stained, moderately stained, or completely saturated 
tampon, respectively. 
• Add 1 or 5 points for each blood clot of smaller than 1 cm or for each blood clot of 1 cm or 
larger in the longest diameter, respectively. 
• Add 5 points for each episode of flooding. 
A total PBAC score is calculated by summing the points for the number of used sanitary towels 
and used tampons, the number of blood clots, and the number of flooding per designated period. 
9.1.17 Transvaginal Ultrasound 
Transvaginal ultrasound is performed for diagnosis of uterine fibroids, and to determine uterine 
and myoma volumes. To avoid interobserver and interdevice variations, 1 physician (investigator 
or subinvestigator) will be assigned to a subject and perform all the transvaginal ultrasound scans 
using the same device as far as possible. Only the largest myoma among those measurable at 
VISIT 1 will be measured throughout the study. 
On the assumption that the uterus and myoma are spheroids, uterine and myoma volumes are 
calculated using 3 diameters (D1, D2, and D3) measured as shown below: 
• D1: the longest diameter of the myoma or uterus (unit of length: cm) 
• D2: the longest diameter of the myoma or uterus which is perpendicular to D1 (unit of 
length: cm) 
• D3: the diameter of the myoma or uterus which crosses the intersection of D1 and D2 
(intersection “Z”) and is perpendicular to D1/D2 plane (unit of length: cm) 
[Formula] Uterine or myoma volume = D1 × D2 × D3 ×  / 6 


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The investigator or subinvestigator records the D1, D2, and D3 values for the uterus and myoma 
in the eCRF. With regard to measurement of myoma at VISIT 1, the longest diameter (D1) of the 
largest myoma is determined and recorded in the eCRF. 
See the separate procedure manual regarding details of the transvaginal ultrasound. 
9.1.18 Anemia-related Measurements 
Anemia-related measurements consist of HGB, HCT, Fe, and ferritin concentrations. These are 
determined at the central laboratory (see the attachment 1). 
9.1.19 Pain Symptoms, Other Clinical Symptoms, and QOL 
Pain symptoms are evaluated using the NRS score. The investigator or subinvestigator 
distributes the patient diary to consented subjects. Subjects fill out the patient diary every day 
from VISIT 1 to the day before VISIT 10 (or until early termination). Subjects record pain 
symptoms within 24 hours associated with uterine fibroids (NRS score), menstruation, and use of 
analgesics. If subjects use any analgesics for pain associated with uterine fibroids, they should 
record this fact in the patient diary along with the accompanying pain symptoms before use of 
analgesics. If there is anything unclear or insufficient description in the patient diary, queries 
may be made to the subject, and corrections to the patient diary are recorded by the subject in a 
change history that captures the old information, the new information, identification of the 
person making the correction and the date of the correction. If it is impossible to make queries to 
the subject at site visits, queries will be made to the subject with telephone calls or other means, 
and corrections to the patient diary are recorded by the investigator or subinvestigator in an 
change history that captures the old information, the new information, identification of the 
person making the correction and the date of the correction. 
UFS-QOL score is used to evaluate other clinical symptoms and the QOL of subjects. The 
investigator or subinvestigator distributes the UFS-QOL questionnaire at VISITS 3, 5, 6, 7, 8, 9, 
10 and 11 and has subjects fill it out before physical examination at site visit. 
9.1.20 WPAI:GH 
WPAI:GH (see Appendix C) is a questionnaire about the past 7 days to measure the effects of 
health in general and specific symptoms on work productivity and outside of work consisting of 
6 questions. WPAI:GH should be assessed before physical examination at site visit. At the visit 
that UFS-QOL is scheduled, WPAI:GH should be assessed after UFS-QOL assessment. 
9.1.21 Status of Menstruation Recovery 
If the first menstruation after the end of study drug administration is observed before the 
VISIT 11 in the Follow-up, the date of onset of the first menstruation is recorded in the eCRF. If 
menstruation recovery is not observed by the VISIT 11 in the Follow-up, follow-up will be 
continued as far as possible through telephone calls or other means until the recovery of the first 
menstruation. If menstruation recovery is observed during continued follow-up, the date of 
recovery should be recorded in the eCRF. The status at the end of menstruation follow-up will be 
recorded in the eCRF regarding menstruation recovery. After the Follow-up, follow-up will not 


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be continued in subjects who undergo surgery or receive hormone therapy for the treatment of 
uterine fibroids before the recovery of menstruation. 
9.1.22 BMD 
BMD is determined using DXA. Throughout the study, the same apparatus is used and operated 
in the same scan mode for all scans for an individual subject. The investigator or subinvestigator 
records the date of each scan and the following results of the scan in the eCRF: 
Measurement Site: 2nd to 4
th lumbar vertebrae (L2 to L4) 
Parameters: mean BMD (g/cm2) of L2 to L4, and T-score (standard deviations from a young, 
sex-specific reference mean BMD) of L2 to L4 
9.1.23 Biochemical Bone Metabolism Markers 
Biochemical bone metabolism markers are determined at the contract laboratory organization at 
the time points specified in the “Schedule of Study Procedures” (Appendix A). Blood is drawn 
roughly at the same time each day (as far as possible) in each subject. 
Venous blood is collected into the container distributed to the study sites. Serum is placed into 
the tubes that are also distributed to the sites. The samples are kept frozen at or below -20°C until 
analysis. 
Parameters: Serum NTELOP and BAP 
9.2 Monitoring Subject Treatment Compliance 
Subjects will be required to bring all remaining study medication and the blister card to each site 
visit. The investigator or subinvestigator records the following information in the eCRF. 
Run-in period 
• TAK-385 placebo: the start/end date of dosing 
• Leuprorelin placebo: the date of dosing 
Treatment period 
• TAK-385 blinded: the start/end date of dose, and the date of non-dosing 
• Leuprorelin blinded: the date of dosing 
If a subject is persistently noncompliant with the study medication (TAK-385 40 mg tablet or 
TAK-385 placebo tablet) (eg, failure to take 10% or more of the scheduled doses after the last 
visit), it may be appropriate to withdraw the subject from the study. All subjects should be 
reinstructed about the dosing requirement during study contacts. The authorized study personnel 
conducting the re-education must document the process in the subject source records. 
9.3 Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points. 


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9.3.1 Screening and Run-in 
9.3.1.1 VISIT 1 (Day -80 through Day -26) 
Subjects undergo examinations and tests for eligibility assessment at VISIT 1 (between 80 and 
26 days prior to the initial dose of the study drug for the Treatment). Subject eligibility is 
determined based on the inclusion and exclusion criteria as described in Section 7.0. See Section 
9.1.14 for procedures for documenting the records of subjects withdrawn before study drug 
administration in the Screening and Run-in. 
The following procedures should be performed at VISIT 1: 
• Informed consent 
• Inclusion and exclusion criteria 
• Pap smear test (if a subject has no test result obtained within 1 year before VISIT 1, perform 
pap smear test between VISIT 1 and VISIT 2) 
• Demographics and concurrent medical conditions 
• Medical history and medication history 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs, height and weight 
• Patient diary (distributed) 
• Transvaginal ultrasound (see Section 9.1.17. If it cannot be performed at VISIT 1, it may be 
delayed up to the day before VISIT 2 [but should be done as early as possible]) 
• Anemia-related measurements 
• Clinical laboratory tests 
• Standard 12-lead ECG 
• AE 
• Concomitant medications 
9.3.1.2 VISIT 2 (Day -42 through Day -21) 
The subject visits the study site between the first and fifth day of their first menstruation after 
VISIT 1. The subject should be screened in accordance with the inclusion and exclusion criteria 
as described in Section 7.0, including confirmation of the description in the patient diary. See 
Section 9.1.14 for procedures for documenting the records of subjects withdrawn in the 
Screening and Run-in. Study drugs for the Run-in are started in a single-blind fashion on the day 
of VISIT 2. If a dose is missed before breakfast, subjects may take the drug before lunch on the 


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same day. If a dose is missed before breakfast and lunch, subjects may take the drug before 
dinner on the same day. 
The following procedures should be performed at VISIT 2: 
• Inclusion and exclusion criteria 
• Pap smear test (if a subject has no test result obtained within 1 year before VISIT 1, perform 
pap smear test between VISIT 1 and VISIT 2) 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• BMD (perform between VISIT 2 and VISIT 3 so that the results can be reviewed at VISIT 3) 
• Anemia-related measurements 
• Clinical laboratory tests 
• Biochemical bone metabolism markers 
• AE 
• Concomitant medications 
• Deciding the dosage of leuprorelin 
• Dispensing of study drugs for the Run-in 
9.3.2 Treatment 
9.3.2.1 VISIT 3 (Day 1) 
The subject visits the study site between the first and fifth day of the second menstration after 
VISIT 1, without taking the TAK-385 tablet for the Run-in in the morning. 
Subjects who satisfy all of the inclusion criteria and do not meet the exclusion criteria are 
randomized in the manner described in Section 8.2. Study drugs for the Treatment are started on 
the day of VISIT 3. If a dose is missed before breakfast, subjects may take the TAK-385 tablet 
before lunch on the same day. If a dose is missed before breakfast and lunch, subjects may take 
the TAK-385 tablet before dinner on the same day. The procedure for documenting the records 
of subjects withdrawn before randomization is provided in Section 9.1.14. Subjects are 
randomized after eligibility assessment on Day 1 (VISIT 3). 
The following procedures should be performed at VISIT 3: 
• Inclusion and exclusion criteria 
• Pregnancy test (urine) 


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• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• Transvaginal ultrasound (see Section 9.1.17. If it cannot be performed at VISIT 3, it is 
performed between VISIT 2 and VISIT 3 [but should be done at nearest point to VISIT 3]) 
• BMD (perform between VISIT 2 and VISIT 3 so that the results can be reviewed at VISIT 3) 
• UFS-QOL 
• WPAI:GH 
• Anemia-related measurements 
• Clinical laboratory tests 
• Pharmacodynamic measurements 
• Standard 12-lead ECG 
• AE 
• Concomitant medications 
• Dispensing of study drugs for the Treatment 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent to participate in PGx research 
[see Section 9.1.12]) 
9.3.2.2 VISIT 4 (Day 15) 
The following procedures should be performed at VISIT 4: 
• Pregnancy test (urine) 
• Physical examination 
• Patient diary (collected and distributed) 
• Transvaginal ultrasound (see Section 9.1.17) 
• WPAI:GH 
• Clinical laboratory test (only TBA and GLDH are assessed) 
• Pharmacodynamic measurements 
• AE 
• Concomitant medications 
• Compliance of study drug administration 


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• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
9.3.2.3 VISIT 5 (Day 29) 
The following procedures should be performed at VISIT 5: 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• Transvaginal ultrasound (see Section 9.1.17) 
• UFS-QOL 
• WPAI:GH 
• Anemia-related measurements 
• Clinical laboratory tests 
• Pharmacodynamic measurements 
• AE 
• Concomitant medications 
• Dispensing of study drugs for the Treatment 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
9.3.2.4 VISIT 6 (Day 57) 
The following procedures should be performed at VISIT 6: 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• Transvaginal ultrasound (see Section 9.1.17) 
• UFS-QOL 
• WPAI:GH 
• Anemia-related measurements 


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• Clinical laboratory tests 
• Pharmacodynamic measurements 
• AE 
• Concomitant medications 
• Dispensing of study drugs for the Treatment 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
9.3.2.5 VISIT 7 (Day 85) 
The following procedures should be performed at VISIT 7: 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• Transvaginal ultrasound (see Section 9.1.17). 
• BMD 
• UFS-QOL 
• WPAI:GH 
• Anemia-related measurements 
• Clinical laboratory tests 
• Pharmacodynamic measurements 
• Biochemical bone metabolism markers 
• AE 
• Concomitant medications 
• Dispensing of study drugs for the Treatment 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
9.3.2.6 VISIT 8 and 9 (Day 113 and 141) 
The following procedures should be performed at VISIT 8 and 9: 


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• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected and distributed) 
• UFS-QOL 
• Anemia-related measurements 
• Clinical laboratory tests 
• Pharmacodynamic measurements 
• AE 
• Concomitant medications 
• Dispensing of study drugs for the Treatment 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
9.3.3 Final Visit or Early Termination 
9.3.3.1 VISIT 10 (Day 169) (or Early Termination) 
The final visit during the Treatment will be performed on VISIT 10 (169 days after the initial 
dose of the study medication for the Treatment). The following procedures should be performed. 
If early termination occurs during the Treatment, the same procedures scheduled at VISIT 10 
should be performed. 
• Pregnancy test (urine) 
• Physical examination 
• Vital signs and weight 
• Patient diary (collected) 
• Transvaginal ultrasound (see Section 9.1.17). 
• BMD 
• UFS-QOL 
• WPAI:GH 
• Anemia-related measurements 
• Clinical laboratory tests 


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• Pharmacodynamic measurements 
• Biochemical bone metabolism markers 
• Standard 12-lead ECG 
• AE 
• Concomitant medications 
• Compliance of study drug administration 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 
For all subjects receiving study medication, the investigator or subinvestigator must complete the 
Subject Status eCRF page. 
9.3.4 Follow-up 
9.3.4.1 VISIT 11 (Final visit of the Follow-up, 28 days after last dose) 
The Follow-up lasts for 4 weeks (28 days) from the day after the final dose of study drug. The 
following procedures should be performed at the final visit of the Follow-up (VISIT 11). If early 
termination occurs during the Treatment, the same procedures scheduled at VISIT 11 should be 
performed 4 weeks (28 days) after the end of treatment. If study termination occurs during the 
Follow-up, the same procedures scheduled at VISIT 11 should be performed. 
• Pregnancy test (urine) 
• Physical examination 
• Vital sign and weight 
• Status of menstruation recovery 
• UFS-QOL 
• Anemia-related measurement 
• Clinical laboratory test 
• Pharmacodynamic measurement 
• Standard 12-lead ECG 
• AE 
• Concomitant medications 
• PGx sample collection (perform only in subjects who consent and from whom the sample has 
not been collected [see Section 9.1.12]) 


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9.3.5 Post Study Care 
The study medication will not be available upon completion of the subject’s participation in the 
study. The subject should be returned to the care of a physician and standard therapies as 
required. 
If the recovery of the first post-treatment menstruation is not observed by the visit at the end of 
the Follow-up (VISIT 11), the subject will undergo further follow-up using possible means such 
as by telephone interview, until the recovery of the first post-treatment menstruation is observed. 
9.4 Biological Sample Retention and Destruction 
Samples of 5 mL whole blood collected for PGx will be stored frozen at 
 
 (See the attachment 1). 
The collected samples will be retained at specimen storage agency up to 15 years after the 
completion of the study. 
When subjects request disposal of a stored sample during the retention period, or the sponsor 
discontinues the application aimed at obtaining approval from the Ministry of Health, Labour 
and Welfare, the site will ask
 to destroy the sample via the sponsor 
according to the procedure. The 
 will destroy the sample in 
accordance with the procedure, and notify the site and sponsor. However, any samples should 
not be destroyed if all the documents (including medical records) have been destroyed which 
could identify the subject and it is impossible to link the sample to the subject.  
Even if the sample can be linked to the subject, when PGx investigation has been conducted, the 
remaining samples will be destroyed and the results of PGx investigation of anonymized subject 
will be retained by the sponsor. 
The sponsor will build a management system required for protection of the subject’s personal 
information, define standards for collecting, store and destruction of samples, and prepare 
appropriate procedures. 


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


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Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as AEs. Baseline evaluations (eg, 
laboratory tests, ECG, X-rays etc.) should NOT be recorded as AEs unless related to study 
procedures. However, if the subject experiences a worsening or complication of such a 
concurrent condition after informed consent is signed, the worsening or complication should 
be recorded appropriately as an AE. Investigator or subinvestigator should ensure that the 
event term recorded captures the change in the condition (eg, “worsening of…”). 
• If a subject has a pre-existing episodic condition (eg, asthma, epilepsy) any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious or 
severe in nature, that is, investigator or subinvestigator should ensure that the AE term 
recorded captures the change in the condition from Baseline (eg, “worsening of…”). 
• If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
to that which would be expected. Again, investigator or subinvestigator should ensure that 
the AE term recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as a 
new AE. Investigator or subinvestigator should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigator or 
subinvestigator should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
Changes in severity of AEs: 
• If the subject experiences changes in severity of an AE that are not related to starting or 
changing the study medication, the event should be captured once with the maximum 
severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening 
of the condition should be captured appropriately as an AE. Complications resulting from 
any planned surgery should be reported as AEs. 


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Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator or subinvestigator must make the distinction between exacerbation 
of pre-existing illness and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented 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. 
Worsening of the target disease: 
• Worsening of expected conditions (measured by the primary efficacy and other endpoints) 
within the normal course will not be recorded as AEs. 
10.1.3 SAEs 
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who 
has signed informed consent to participate in a study: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/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). 


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Table 10.a  Takeda Medically Significant AE List 
Term 
Acute respiratory failure/acute respiratory distress 
syndrome 
Acute liver failure 
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
Anaphylactic shock 
Acute renal failure 
Malignant hypertension 
Pulmonary hypertension 
Convulsive seizure (including convulsion and epilepsia)  Pulmonary fibrosis (including interstitial pneumonia) 
Agranulocytosis 
Confirmed or suspected endotoxin shock 
Aplastic anemia 
Confirmed or suspected transmission of infectious agent 
by a medicinal product 
Toxic epidermal necrolysis/ Stevens-Johnson syndrome  Neuroleptic malignant syndrome / malignant 
hyperthermia 
Hepatic necrosis 
Spontaneous abortion / stillbirth and fetal death 
 
10.1.4 AEs of Special Interest 
An adverse event of special interest (treatment-emergent only, serious or non-serious) is one of 
scientific and medical concern specific to the compound or program, for which ongoing 
monitoring and rapid communication by the investigator or subinvestigator to Takeda may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them and would be described in protocols and instructions provided for investigators 
or subinvestigator as to how and when they should be reported to Takeda (see Section 10.2.1.3). 
10.1.4.1  LFT Abnormalities 
A nonclinical study in monkeys reported abnormal LFT results. A clinical study of an oral GnRH 
antagonist having the same structure as TAK-385 also reported increased ALT and AST, which 
were relevant to the study medication. Therefore, LFT abnormalities are handled as AESIs. 
Section 9.1.8 describes how to handle LFT abnormalities. 
When LFT abnormalities meet the criteria specified in Section 7.5, the investigator or 
subinvestigator must immediately discontinue study medication and perform follow-up. 
10.1.5 Severity of AEs 
The different categories of severity are characterized as follows: 
Mild:  
The event is transient and easily tolerated by the subject. 
Moderate:  
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe:  
The event causes considerable interference with the subject’s usual activities. 
 


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10.1.6 Causality of AEs to Study Medication(s) 
The causality of each AE to study medication(s) will be assessed using the following categories: 
Related:  
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not related:  
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments. 
 
10.1.7 Causality of AEs to Study Procedures 
The causality of each AE to study procedures will be assessed. 
The causality should be assessed as Related if the investigator or subinvestigator considers that 
there is reasonable possibility that an event is due to a study procedure. Otherwise, the causality 
should be assessed as Not related. 
10.1.8 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator or subinvestigator. The start date of the AE is defined as follows: 
AE 
Definition of Onset 
Sign, Symptom, disease 
(diagnosed) 
The date when a subject or the investigator/subinvestigator first noticed the sign or 
symptom. 
Asymptomatic disease  
The date when the diagnosis was confirmed; even if the finding suggests that this is 
asymptomatic disease persisting for a long time with diagnosis being confirmed with 
examination/test results (but no information of the start date). 
Complication or worsening 
of an AE that occurs prior to 
the first exposure to study 
drug 
The date when a subject or the investigator/subinvestigator first noticed worsening of 
the sign or symptom. 
Abnormal laboratory value 
which was within normal 
limit at screening 
The date of an examination where clinically significant abnormality was detected. 
Abnormal laboratory value 
which was out of normal 
limit at screening and then 
deteriorate 
The date of an examination where apparent increase/decrease or elevation/reduction 
is observed based on the course of laboratory test result. 
 
10.1.9 End Date  
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. If the outcome of recovered/resolved cannot be confirmed at the 
study end, it should be recorded as an ongoing AE. 


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10.1.10 Pattern of Adverse Event  
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous. 
10.1.11 Action Taken with Study Treatment  
• Drug withdrawn – a study medication is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study medication. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not Applicable – a study medication was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study medication was already 
stopped before the onset of the AE, the AE that occured before the study medication 
administration. 
• Drug Interrupted – the dose was interrupted due to the particular AE and the dose was 
restarted at subsequent day. 
10.1.12 Outcome  
• Recovered/Resolved – Subject returned to first assessment status with respect to the AE. 
• Recovering/Resolving – the intensity is lowered by one or more stages; the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”. 
• Recovered/Resolved with sequelae – the subject recovered from an acute AE but was left 
with permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis). 
• Fatal – the AEs which are considered as the cause of death. 
• Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study. 


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10.2 Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 AE Collection Period 
Collection of AEs will commence from the time the subject signs the informed consent. Routine 
collection of AEs will continue until VISIT 11 (or early termination). 
10.2.1.2 AE Reporting 
At each study visit, the investigator or subinvestigator will assess whether any subjective AEs 
have occurred. A neutral question, such as “How have you been feeling since your last visit?” 
may be asked. Subjects may report AEs occurring at any other time during the study. Subjects 
experiencing a serious AE that occurs prior to the first exposure to study drug must be monitored 
until the symptoms subside and any clinically relevant changes in laboratory values have 
returned to baseline or there is a satisfactory explanation for the change. Non-serious AEs that 
occur prior to the first exposure to study drug, related or unrelated to the study procedure, need 
not to be followed-up for the purposes of the protocol. 
All subjects experiencing AEs that occur after the first exposure to study drug, whether 
considered associated with the use of the study medication or not, must be monitored until the 
symptoms subside and any clinically relevant changes in laboratory values have returned to 
baseline or until there is a satisfactory explanation for the changes observed. All AEs will be 
documented in the AE page of the eCRF, whether or not the investigator or subinvestigator 
concludes that the event is related to the drug treatment. The following information will be 
documented for each event: 
1. Event term. 
2. Start and end date. 
3. Pattern. 
4. Severity. 
5. Investigator’s opinion of the causality between the event and administration of study 
medication(s). 
6. Investigator’s opinion of the causality to study procedure(s), including the details of the 
suspected procedure. 
7. Action taken with study treatment. (not applicable for the AE that occured before the 
study medication administration) 
8. Outcome of event. 
9. Seriousness. 
10. After administration of study drug 
11. Treatment emergent 


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The patient diary, UFS-QOL and WPAI:GH will not be used as a primary means to collect AEs. 
However, should the investigator or subinvestigator become aware of a potential AE through the 
information collected with these instruments, proper follow-up with the patient for medical 
evaluation should be undertaken. Through this follow-up if it is determined that an AE not 
previously reported has been identified, normal reporting requirements should be applied. 
10.2.1.3 AE of Special Interest Reporting 
If this abnormality, which occurs during the Run-in, the treatment period or the follow-up period, 
is considered to be clinically significant based on the criteria below, it should be reported to the 
sponsor (described in the separate contact information list) immediately or within 1 business day 
of first onset or subject’s notification of the event. An AESI name Form or an SAE Form should 
be completed, signed and/or sealed by the principal investigator, and reported to appropriate 
personnel in the separate contact information list within 10 business days.  
• Laboratory value threshold if applicable. 
• Premature termination for the AE of special interest, if applicable. 
• Any other specific criteria. 
Investigator shall refer to the “Checklist for Reporting Liver Function Test Abnormalities” 
(Appendix D), when writing the report. 
The criterion for a LFT abnormality is: 
• ALT or AST > 3 × ULN 
When a subject is noted to have ALT or AST > 3 × ULN and total bilirubin > 2 × ULN, the 
event should be handled as an SAE if the investigator concludes from the results of retesting (see 
Section 9.1.8 for procedures) that no factors, other than the study drugs, can account for it. The 
steps specified in Section 10.2.2 are followed to collect and report the event. 
The AESIs have to be recorded as AEs in the eCRF. An evaluation form along with all other 
required documentation must be submitted to the sponsor. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
An SAE should be reported to the sponsor (described in the separate contact information list) 
within 1 business day of first onset or subject’s notification of the event. The principal 
investigator should submit the completed SAE form within 10 calendar days. The information 
should be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s or subinvestigator’s name. 


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• Name of the study medication(s) 
• Causality assessment. 
Any SAE spontaneously reported to the investigator or subinvestigator following the AE 
collection period should be reported to the sponsor if considered related to study participation. 
10.2.3 Reporting of Abnormal LFTs 
If a subject is noted to have ALT or AST elevated > 3 ×ULN, the abnormality should be handled 
as an AESI (see Section 10.2.1.3). The investigator or subinvestigator should report the event to 
the sponsor, promptly conduct examinations and tests to obtain more information from the 
subject, and explore possible causes of the event other than the study drug (eg, acute Type A, B, 
C, or E viral hepatitis, other acute hepatic disorders, general medical history, or concurrent 
conditions). Follow-up laboratory tests as described in Section 9.1.8 must also be performed.  
If a subject is noted to have ALT or AST > 3 ×ULN and bilirubin (total bilirubin) > 2 ×ULN for 
which an alternative etiology has not been identified, the event should be recorded as an SAE 
and reported as per Section 10.2.2. The investigator or subinvestigator must contact the sponsor 
for discussion of the relevant subject details and possible alternative etiologies, such as acute 
viral hepatitis A, B, C or E or other acute liver disease or medical history/concurrent medical 
conditions. 
If the abnormality meets the criteria listed in Section 7.5 (Liver function test abnormalities), the 
study drug should be discontinued immediately. 
10.3 Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator or subinvestigator should complete a follow-up SAE form or provide other written 
documentation and fax it immediately. Copies of any relevant data from the hospital notes (eg, 
ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the addressee, 
if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, the investigators, IRBs, and 
the head of the study site. Relative to the first awareness of the event by/or further provision to 
the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal products administration or in the overall conduct of the 
trial. 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 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 


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12.0 DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, and medical history including concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 CRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate study collaborator in the use of the eCRF. These 
forms are used to transmit the information collected in the performance of this study to the 
sponsor and regulatory authorities. eCRFs must be completed in English. Data are transcribed 
directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change.  
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded into the eCRFs: 
1) Results of clinical laboratory tests conducted at the central laboratory 
2) Results of pharmacodynamic tests 
After the lock of the clinical study database, any change of, modification of or addition to the 
data on the eCRFs should be made by the investigator or subinvestigator with use of change and 
modification records of the eCRFs (Data Clarification Form) provided by the sponsor. The 
principal investigator must review the data change for completeness and accuracy, and must sign, 
or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 


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12.2 Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in Section 
12.1 and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 
signed and dated informed consent forms, electronic copy of eCRFs, including the audit trail, 
and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. 
The investigator and the head of the institution are required to retain essential relevant 
documents until the day specified as 1) or 2) below, whichever comes later. However, if the 
sponsor requests a longer time period for retention, the head of the institution should discuss how 
long and how to retain those documents with the sponsor.  
1) The day on which marketing approval of the 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. 
In addition, the investigator and the head of the institution should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required. 


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13.0 STATISTICAL METHODS 
13.1 Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, three kinds of analysis sets are defined: full analysis set (FAS), per protocol set 
(PPS) and safety analysis set. The FAS, the main analysis set used for primary efficacy analysis, 
will be defined as “all subjects who were randomized and received at least one dose of the study 
drug.” The definition of each analysis set will be described in the Handling Rules for Analysis 
Data. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, consulting a medical expert as needed. If necessary, the Handling Rules for 
Analysis Data will be supplemented with new handling rules that were not discussed at the 
planning stage. The Handling Rules for Analysis Data must be finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized overall and by treatment 
group using the randomized set. 
13.1.3 Efficacy Analysis 
(1) Primary endpoint and analytical methods 
Primary endpoint 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 
Primary analysis 
The following analyses will be performed based on the FAS: 
The proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 will be 
summarized by treatment group. The point estimate and 2-sided 95% confidence interval of the 
difference in the percentage will be calculated between TAK-385 40 mg group and leuprorelin 
group (TAK-385 40 mg group – leuprorelin group). In addition, non-inferiority test using 
Farrington and Manning method with a non-inferiority margin of 15% will be conducted for the 
comparison between TAK-385 40 mg group and leuprorelin group. 


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Secondary analysis 
An analysis similar to the above “Primary analysis” will be performed using the PPS to assess 
the robustness of the results (sensitivity analysis). 
(2) Secondary endpoints and analytical methods 
Secondary endpoints 
• Proportion of subjects with a total PBAC score of < 10 (from Week 2 to 6, from Week 18 to 
24, and for 6 weeks before the final dose of study drug) 
• Myoma volumes (Week 2, 4, 8, 12 and 24) 
• Uterine volumes (Week 2, 4, 8, 12 and 24) 
• HGB (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• NRS score (from Week 6 to 12, from Week 2 to 6, from Week 18 to 24, and for 6 weeks 
before the final dose) 
• UFS-QOL score (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
Analytical methods 
1. Proportion of subjects with a total PBAC score of < 10 
Frequency will be summarized by treatment group. The point estimate and 2-sided 95% 
confidence interval of the difference in the percentage will be calculated between TAK-385 
40 mg group and leuprorelin group. 
2. Myoma and uterine volumes, HGB, NRS score and UFS-QOL scores 
For each variable, summary statistics will be provided by treatment group for each visit. Two-
sided 95% confidence interval of the difference will be calculated between TAK-385 40 mg and 
leuprorelin group. 
(3) Additional efficacy endpoints 
Additional endpoints 
• HCT, serum Fe, and serum ferritin (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• Use of analgesic medications during the Treatment (from Week 6 to 12, from Week 2 to 6, 
from Week 18 to 24, and for 6 weeks before the final dose) 
• WPAI:GH during the Treatment (Week 2, 4, 8, 12 and 24) 
(4) Methods of data transformation and handling of missing data 
Details will be described in the SAP. 
(5) Significance level and confidence coefficient 
Significance Level: 2.5% (one-sided, non-inferiority test) 
Confidence coefficient: 95% (two-sided) 


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13.1.4 Pharmacodynamic Analysis 
Additional endpoints 
LH, FSH, E2, and P (Week 2, 4, 8, 12, 16, 20, 24 and Follow-up) 
13.1.5 Safety Analysis 
The following analyses will be based on the safety analysis set. 
(1) Secondary endpoint 
Treatment-emergent adverse events 
A TEAE is defined as an AE whose date of onset occurs on or after the start of study drugs for 
the Treatment. 
TEAEs will be coded using the MedDRA dictionary. The frequency distribution will be provided 
using the system organ class (SOC) and the preferred term (PT) for each treatment group as 
follows: 
• All TEAEs 
• Drug-related TEAEs 
• Intensity of TEAEs 
• Intensity of drug-related TEAEs 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
• TEAEs over time 
Laboratory test results, standard 12-lead ECGs, vital signs, weight, BMD and biochemical bone 
metabolism markers (serum NTELOP and BAP) 
For continuous variables except BMD, the observed values and the changes from baseline will 
be summarized by treatment group for each visit using descriptive statistics. For BMD, the 
observed values and the percent changes from baseline will be summarized by treatment group 
for each visit using descriptive statistics. Case plots will also be presented for the observed 
values. 
For categorical variables, shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided for each treatment group. 
(2) Additional endpoint 
• Period from the last dose of study drug to return of menstrual cycles. 
13.2 Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 


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13.3 Determination of Sample Size 
Justification of Sample size 
In a clinical study of ulipristal acetate (already approved in Europe) compared with leuprorelin 
conducted overseas, the proportion of subjects with a total PBAC score of < 75 for 28 days 
before Week 13 was 89.1% in the TAP-144-SR (1M) 3.75 mg group, and the proportion of 
subjects with a total PBAC score of  2 for 28 days before Week 13 was 80.4%. 
In TAK-385 phase 2 study in the treatment of uterine fibroids, the point estimate (and 
corresponding 2-sided 95% confidence interval) of the proportion of subjects with a total PBAC 
score of < 10 from Week 6 to 12 was 83.6% (71.2%, 92.2%) in the TAK-385 40 mg group. 
Based on the results of the above 2 studies, the proportions of subjects with a total PBAC score 
of < 10 from Week 6 to 12 in both TAK-385 40 mg group and leuprorelin group are estimated to 
be 83.6%. 
Under this assumption, a sample size of at least 129 subjects per group will provide  90% 
power to demonstrate non-inferiority at 1-sided 0.025 level of significance, using a non-
inferiority margin of 15% (nQuery Advisor 6.01). 
Based on the above, a sample size of 129 subjects per group (258 subjects in total) is planned as 
the number of evaluable subjects. Assuming that approximately 10% of subjects will not be 
evaluable for the primary endpoint, 144 subjects are to be randomized to each group, for a total 
of 288 subjects. 
Justification of non-inferiority margin 
As the result of the TAK-385 phase 2 study in the treatment of uterine fibroids, the point 
estimate (and corresponding 2-sided 95% confidence interval) of the difference in the proportion 
of subjects with a total PBAC score of < 10 from Week 6 to 12 was 83.6% (73.9%, 93.4%) 
between the TAK-385 40 mg group and Placebo group. Assuming that leuprorelin has 
comparable effect to TAK-385 40 mg, the non-inferiority margin of 15% is considered smaller 
than the smallest effect size that leuprorelin would be reliably expected to have. 


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


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15.0 ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix 
E. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities. 
15.1 IRB Approval 
IRBs must be constituted according to the applicable local requirements. The sponsor or 
designee will require documentation noting all names and titles of members who make up the 
respective IRB. If any member of the IRB has direct participation in this study, written 
notification regarding his or her abstinence from voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB for approval. The IRB’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB approval must refer to the study by exact protocol title, number, and 
version date; identify versions of other documents (eg, informed consent form) reviewed; and 
state the approval date. The sponsor will notify site once the sponsor has confirmed the adequacy 
of site regulatory documentation. Until the site receives notification no protocol activities, 
including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
Regarding PGx investigation using collected and stored specimens, analysis will be carried out at 
the time when detail is determined. The sponsor will create a research protocol for PGx 
investigations and a research protocol will require prior approval of the company IRB in Japan. 
15.2 Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 


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applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is 
given. The informed consent form will detail the requirements of the participant and the fact that 
she is free to withdraw at any time without giving a reason and without prejudice to her further 
medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form. The informed consent form must be approved by the IRB prior to use. 
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the investigator or subinvestigator to explain the 
detailed elements of the informed consent form to the subject. Information should be given in 
both oral and written form whenever possible and in the manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject determines she will participate in 
the study, then the informed consent form must be signed and dated by the subject at the time of 
consent and prior to the subject entering into the study. The subject should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator or 
subinvestigator must also sign and date the informed consent form at the time of consent and 
prior to subject entering into the study.  
Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator or subinvestigator must document the date the subject signs the informed consent in 
the subject’s medical record. Copies of the signed informed consent form shall be given to the 
subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in the 
same manner as the original informed consent. The date the revised consent was obtained should 
be recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form. 
PGx research should be explained to the subject using “Informed Consent Form for PGx 
Research of TAK-385” after explanation about the study using the informed consent form has 
been given. Specimens for PGx research should be collected from subjects who consented to 
participate in the study and PGx research. 
The procedure specified in Section 9.4 should be followed when a subject requests disposal of 
her PGx samples. 
15.3 Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age or 


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date of birth may be used to verify the subject and accuracy of the subject’s unique 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 (eg, FDA, MHRA,PMDA), the sponsor’s designated auditors, and 
the appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, the protocol 
or study results are the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator.  
The investigator and subinvestigator need to obtain a prior written approval from the sponsor to 
publish any information from the study externally such as to a professional association. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, country, and recruiting status will be 
registered and available for public viewing. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 


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


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16.0 REFERENCES 
1. Tsutsui A. Uterine fibroids and anemia: treatment. Obstetrics and Gynecology Mook. 
Kanehara & Co., Ltd. 1986;35:36-49. 
2. Sugiyama Y. Precautions before and after surgery for uterine fibroids. Obstetrics and 
Gynecology Mook. Kanehara & Co., Ltd. 1986;35:167-73. 
3. Lefebvre G, Vilos G, Allaire C, et al. The management of uterine leiomyomas. J Obstet 
Gynaecol Can. 2003;25:396-418;quiz 419-22. 
4. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a 
pictorial chart. Br J Obstet Gynaecol. 1990;97:734-9. 
5. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproductibility of a work 
productivity and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-
365. 

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). 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: TAK-385/CCT-002 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Phase 3 Study to Evaluate the 
Efficacy and Safety of Oral TAK-385 40 mg compared with Leuprorelin in the Treatment 
of Uterine Fibroids 
PHASE 3 
Version: Final 
Date: 1 AUG 2017 
 
Prepared by:  
  
 
 
 
 
 
 
 
 
Based on: 
Protocol Version: Original  
Protocol Date: 24 November 2015 
 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 


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1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 


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2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .......................................................................................................................1 
1.1 
Approval Signatures.......................................................................................................2 
2.0 
TABLE OF CONTENTS .....................................................................................................3 
List of In-Text Figures ...............................................................................................................4 
3.0 
LIST OF ABBREVIATIONS ..............................................................................................5 
4.0 
OBJECTIVES ......................................................................................................................7 
4.1 
Primary Objectives.........................................................................................................7 
4.2 
Secondary Objectives.....................................................................................................7 
4.3 
Additional Objectives ....................................................................................................7 
4.4 
Study Design ..................................................................................................................7 
4.4.1 
Study Population and Design ...................................................................................7 
4.4.2 
Dose Level and Regimen .........................................................................................8 
5.0 
ANALYSIS ENDPOINTS ................................................................................................10 
5.1 
Primary Endpoint .........................................................................................................10 
5.2 
Secondary Endpoints ...................................................................................................10 
5.3 
Additional Endpoints ...................................................................................................10 
6.0 
DETERMINATION OF SAMPLE SIZE ..........................................................................12 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .....................................................13 
7.1 
General Principles ........................................................................................................13 
7.1.1 Study Definitions ............................................................................................................13 
7.1.2 Definition of Study Days ................................................................................................15 
7.1.3 Definition of Study Visit Windows ................................................................................15 
7.1.4 Methods for Handling Missing Data...............................................................................18 
7.2 
Analysis Sets ................................................................................................................18 
7.3 
Disposition of Subjects ................................................................................................18 
7.3.1 
Study Information ..................................................................................................18 
7.3.2 
Screen Failures .......................................................................................................19 
7.3.3 
Subject Eligibility ..................................................................................................19 
7.3.4 
Number of Subjects Randomized by Site and Treatment Group ...........................19 
7.3.5 
Disposition of Subjects ..........................................................................................20 
7.3.6 
Protocol Deviations ................................................................................................21 
7.3.7 
Analysis Sets ..........................................................................................................22 
7.4 
Demographic and Other Baseline Characteristics .......................................................22 
7.5 
Medical History and Concurrent Medical Conditions .................................................24 


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7.6 
Medication History and Concomitant Medications .....................................................25 
7.7 
Study Drug Exposure and Compliance ........................................................................25 
7.8 
Efficacy Analysis .........................................................................................................26 
7.8.1 
Primary Efficacy Endpoint(s) ................................................................................26 
7.8.2 
Secondary Efficacy Endpoint(s) ............................................................................28 
7.8.3 
Additional Efficacy Endpoint(s) ............................................................................30 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis .............................................................32 
7.9.1 
Pharmacokinetic Analysis ......................................................................................32 
7.9.2 
Pharmacodynamic Analysis ...................................................................................32 
7.10 
Other Outcomes ...........................................................................................................33 
7.11 
Safety Analysis ............................................................................................................33 
7.11.1 Adverse Events ......................................................................................................33 
7.11.2 Clinical Laboratory Evaluations ............................................................................38 
7.11.3 Vital Signs ..............................................................................................................40 
7.11.4 12-Lead ECGs ........................................................................................................41 
7.11.5 Other Observations Related to Safety ....................................................................41 
7.12 
Interim Analysis ...........................................................................................................43 
7.13 
Changes in the Statistical Analysis Plan ......................................................................43 
8.0 
REFERENCES ..................................................................................................................48 
 
LIST OF IN-TEXT FIGURES 
Figure 4 
Schematic of Study Design ......................................................................................9 
 
 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the blood concentration-time curve 
BAP 
bone specific alkaline phosphatase 
BMD 
bone mineral density 
BMI 
body mass index 
BUN 
blood urea nitrogen 
Cmax 
maximum observed plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
DXA 
dual-energy x-ray absorptiometry 
E2 
estradiol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
Fe 
iron 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GLDH 
glutamate dehydrogenase 
GnRH 
gonadotropin-releasing hormone 
hCG 
human chorionic gonadotropin 
HCT 
hematocrit 
HDL 
high density lipoprotein 
HGB 
hemoglobin 
ICH 
International Conference on Harmonisation 
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
IUD 
intrauterine device 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LFT 
liver function test 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NILM 
negative for intraepithelial lesion or malignancy 
NRS 
numerical rating scale 
NSAIDs 
non-steroidal anti-inflammatory drugs 
NTELOP 
N-telopeptide 
P 
progesterone 
PBAC 
pictorial blood loss assessment chart 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPS 
per protocol set 
PT 
preferred term 
PTE 
Pretreatment event 
QOL 
quality of life 
Run-in AE 
run-in  adverse event 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SERM 
selective estrogen receptor modulator 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
TBA 
total bile acid 
TEAE 
treatment-emergent adverse event 
TPC 
Takeda Pharmaceutical Company Limited 
UFS-QOL 
uterine fibroid symptom and quality of life 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 
WPAI:GH 
Work Productivity and Activity Impairment Questionnaire:General Health 
 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
The primary objective of this study is to evaluate the efficacy of TAK-385 40 mg administered 
orally once daily for 12 weeks, compared with leuprorelin injection (once/4 weeks, 1.88 mg or 
3.75 mg subcutaneously [SC]/time) in subjects with uterine fibroids. 
4.2 
Secondary Objectives 
The secondary objective of this study is to evaluate the efficacy and safety of TAK-385 40 mg 
administered orally once daily for 24 weeks, compared with leuprorelin injection (once/4 weeks, 
1.88 mg or 3.75 mg SC/time) in subjects with uterine fibroids. 
4.3 
Additional Objectives 
An additional objective of this study is to evaluate the pharmacodynamic effect, which is blood 
concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), 
and progesterone (P). 
4.4 
Study Design 
An overview of the study design is shown in Figure 4 
4.4.1 
Study Population and Design 
This is a phase 3, multicenter, randomized, double-blind, parallel-group, non-inferiority study to 
evaluate the efficacy and safety of TAK-385 compared with leuprorelin injection (once/4 weeks, 
1.88 mg or 3.75 mg SC/time) in premenopausal subjects ≥ 20 years of age with symptomatic 
uterine fibroids. The primary objective is to evaluate the efficacy of TAK-385 40 mg 
administered orally once daily for 12 weeks. The secondary objective is to evaluate the efficacy 
and safety of TAK-385 40 mg administered orally once daily for 24 weeks. In addition, the 
pharmacodynamics of continuous oral administration of TAK-385 40 mg for 24 weeks is to be 
assessed. 
Subjects must be diagnosed to have uterine fibroids as confirmed by transvaginal ultrasound or 
other methods, and have symptoms of menorrhagia (the total pictorial blood loss assessment 
chart [PBAC] score of ≥ 120 for the entire menstrual cycle immediately before VISIT 3). The 
total number of subjects to be randomized under double-blind conditions is 288 (144 subjects 
each for the TAK-385 40 mg group or leuprorelin group). 
After signing the informed consent form, subjects will start recording in the patient diary from 
the day of VISIT 1. During the period between VISIT 2 and VISIT 3, in which subjects must 
experience 1 menstrual cycle, the baseline values for the efficacy evaluation, including PBAC 
scores and pain symptoms (baseline PBAC score: the total PBAC score for the entire menstrual 
cycle immediately before VISIT 3) will be collected. Subjects should record in the patient diary 
every day until the end of study drug administration. VISIT 2 should be between the first and 


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fifth day of the first menstruation after VISIT 1. The study drug (TAK-385 placebo and 
leuprorelin placebo) will be administered under single-blind conditions from the day of VISIT 2 
to the day before VISIT 3. VISIT 3 should be between the first and fifth day of the second 
menstruation after VISIT 1. From VISIT 3 to 10, subjects will receive study drug (TAK-385 and 
leuprorelin placebo, or TAK-385 placebo and leuprorelin) in a double blind manner. Subjects 
should try to visit the study site during the morning in a fasted state and before taking the TAK-
385 tablet.  
The study consists of Screening of approximately 1 to 6 weeks, a Run-in period of 3 to 6 weeks, 
a Treatment period of 24 weeks, and a Follow-up period of 4 weeks. The total period of study 
participation is approximately 32 to 40 weeks. If the recovery of the first post-treatment 
menstruation is not observed by the visit at the end of the Follow-up (VISIT 11), the subject will 
undergo further follow-up using possible means such as by telephone interview, until the 
recovery of the first post-treatment menstruation is observed. During the course of this study, 
subjects will visit the study site to undergo the designated examinations and evaluations at each 
visit, every 2 weeks for a month after the initiation of study drug administration (VISIT 3) under 
double-blind conditions, and monthly thereafter. 
4.4.2 
Dose Level and Regimen 
At VISIT 3, subjects will be randomized in a 1:1 ratio to either the TAK-385 40 mg group or 
leuprorelin group. Study drug (TAK-385 40 mg + leuprorelin placebo or TAK-385 placebo + 
leuprorelin) will be administered in a double-dummy method from the day of VISIT 3 to the day 
before VISIT 10 (or until early termination) under double-blind conditions. 
The investigator or subinvestigator will decide the dosage of leuprorelin at VISIT 2 in 
accordance with the approved dosage and administration, considering the body weight and 
symptoms of the individual subject. Leuprorelin (or leuprorelin placebo) should be administered 
SC (injection) once every 4 weeks using the same dose throughout the Run-in and Treatment. 
TAK-385 (or TAK-385 placebo) will be administered daily as a single oral dose before breakfast. 
 
 
 
 
 
 
 
 
 
 


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Figure 4 
Schematic of Study Design 
 
VISIT
Day
Follow-
up
Screening
Run-in
Treatment
Follow-up
Leuprorelin group
Informed
consent*
Initiation of
administration
Initiation of
treatment
End of
treatment
(24 weeks)
(4 weeks)
(12 weeks)
TAK-385 40 mg group
Placebo
1
2**
3**
4
9
10
11
-80~-26
-42~-21
1
29
TAK-385 40 mg tablet
TAK-385 placebo tablet
Leuprorelin acetate (1.88 mg 
or 3.75 mg) injection
Leuprorelin acetate (1.88 mg 
or 3.75 mg) placebo injection
Tablet
(once/day, before breakfast)
Injection
(once/4 wks, at site visit)
*  In addition to Day -80~-26, informed consent may be obtained before Day -80.
**VISIT 2 and 3: On Days 1 to 5 of the menstrual cycle
8
7
6
5
15
57
85
113
141
169
197


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5.0 
ANALYSIS ENDPOINTS 
5.1 
Primary Endpoint 
1) Efficacy: 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 12 
5.2 
Secondary Endpoints 
1) Efficacy: 
• Proportion of subjects with a total PBAC score of < 10 (from Week 2 to 6, from Week 18 to 
24, and for 6 weeks before the final dose of study drug) 
• Myoma volumes (Week 2, 4, 8, 12 and 24) 
Note: Only the largest myoma among those measurable at VISIT 1 will be measured 
throughout the study. 
• Uterine volumes (Week 2, 4, 8, 12 and 24) 
• Hemoglobin (HGB) (Week 4, 8, 12, 16, 20, 24 and Follow-up) 
• Numerical Rating Scale (NRS) score (from Week 6 to 12, from Week 2 to 6, from Week 18 
to 24, and for 6 weeks before the final dose) 
• Uterine fibroid symptom and QOL (UFS-QOL) score (Week 4, 8, 12, 16, 20, 24 and Follow-
up) 
2) Safety: 
• Adverse events (AEs), vital signs, weight, standard 12-lead electrocardiogram (ECG), 
clinical laboratory tests, bone mineral density (BMD), biochemical bone metabolism markers 
(serum N-telopeptide [NTELOP] and bone specific alkaline phosphatase [BAP]) 
5.3 
Additional Endpoints 
1) Efficacy: 
• Hematocrit (HCT), serum iron (Fe), and serum ferritin (Week 4, 8, 12, 16, 20, 24 and 
Follow-up) 
• Use of analgesic medications during the Treatment (from Week 6 to 12, from Week 2 to 6, 
from Week 18 to 24, and for 6 weeks before the final dose) 
• Work Productivity and Activity Impairment Questionnaire:General Health (WPAI:GH) 
(Week 2, 4, 8, 12 and 24) 
2) Safety: 
• Period from the last dose of study drug to return of menstrual cycles 


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3) Pharmacodynamic effects: 
LH, FSH, E2 and P (Week 2, 4, 8, 12, 16, 20, 24 and Follow-up) 


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6.0 
DETERMINATION OF SAMPLE SIZE 
Justification of Sample size 
In a clinical study of ulipristal acetate (already approved in Europe) compared with leuprorelin 
conducted overseas, the proportion of subjects with a total PBAC score of < 75 for 28 days 
before Week 13 was 89.1% in the TAP-144-SR (1M) 3.75 mg group, and the proportion of 
subjects with a total PBAC score of ≤ 2 for 28 days before Week 13 was 80.4%. 
In TAK-385 phase 2 study in the treatment of uterine fibroids, the point estimate (and 
corresponding 2-sided 95% confidence interval) of the proportion of subjects with a total PBAC 
score of < 10 from Week 6 to 12 was 83.6% (71.2%, 92.2%) in the TAK-385 40 mg group. 
Based on the results of the above 2 studies, the proportions of subjects with a total PBAC score 
of < 10 from Week 6 to 12 in both TAK-385 40 mg group and leuprorelin group are estimated to 
be 83.6%. 
Under this assumption, a sample size of at least 129 subjects per group will provide ≥ 90% 
power to demonstrate non-inferiority at 1-sided 0.025 level of significance, using a non-
inferiority margin of 15% (nQuery Advisor 6.01). 
Based on the above, a sample size of 129 subjects per group (258 subjects in total) is planned as 
the number of evaluable subjects. Assuming that approximately 10% of subjects will not be 
evaluable for the primary endpoint, 144 subjects are to be randomized to each group, for a total 
of 288 subjects. 
Justification of non-inferiority margin 
As the result of the TAK-385 phase 2 study in the treatment of uterine fibroids, the point 
estimate (and corresponding 2-sided 95% confidence interval) of the difference in the proportion 
of subjects with a total PBAC score of < 10 from Week 6 to 12 was 83.6% (73.9%, 93.4%) 
between the TAK-385 40 mg group and Placebo group. Assuming that leuprorelin has 
comparable effect to TAK-385 40 mg, the non-inferiority margin of 15% is considered smaller 
than the smallest effect size that leuprorelin would be reliably expected to have. 


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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
All statistical analyses will be conducted using SAS® Version 9.2, or higher. 
A statistical test for the primary endpoint will be reported as 1-sided and will be assessed at 
α=0.025 significance level and all confidence intervals will be reported as 2-sided unless 
otherwise stated. P-values will be rounded to 4 decimal places prior to assessment of statistical 
significance. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate. 
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated. 
Confidence intervals for continuous variables will be calculated based on t-statistics and ones for 
categorical variables will be based on Wald confidence intervals without using any model, unless 
otherwise stated. 
7.1.1 Study Definitions 
Duration of exposure to double-blind study drug (days) : 
Date of last dose of double-blind study drug - date of first dose of double-blind study drug + 
1 
Double-blind study drug compliance (%) : 
Number of TAK-385 blinded drugs taken/duration of exposure to TAK-385 blinded drug * 
100 (rounded to 1 decimal places ) 
Disease duration (years): 
((year of informed consent*12 + month of informed consent) –(year of first defined diagnosis 
of uterine fibroids*12 + month of first defined diagnosis of uterine fibroids))/12  (rounded to 
1 decimal places ) 
Maximum drug holidays (days): 
Maximum number of consecutive days on which the subject does not take the TAK-385 
blinded drug for the treatment period 
Total PBAC score from Week 6 to 12 
Total PBAC score from Day 43 to earlier of Day 84 or Follow-up Day 3. 
Similarly, Total PBAC score from Week 2 to 6 and from Week 18 to 24 will be defined as 


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those from Day 15 to earlier of Day 42 or Follow-up Day 3 and from Day 127 to earlier of 
Day 168 or Follow-up Day 3, respectively. 
Total PBAC score for 6 weeks before the final dose of study drug 
Total PBAC score for the last 42 days of the treatment 
NRS score from Week 6 to 12 
Average NRS score from Day 43 to earlier of Day 84 or Follow-up Day 3. 
Similarly, NRS score from Week 2 to 6 and from Week 18 to 24 will be defined as average 
NRS score from Day 15 to earlier of Day 42 or Follow-up Day 3 and from Day 127 to earlier 
of Day 168 or Follow-up Day 3, respectively. 
NRS score for 6 weeks before the final dose 
Average NRS score for the last 42 days of the treatment 
Total PBAC at baseline  
Total PBAC score from first day of menstrual period confirmed at Visit 2 to a day prior to 
menstrual period confirmed at Visit 3 
NRS score at baseline 
Average NRS score from first day of menstrual period confirmed at Visit 2 to a day prior to 
menstrual period confirmed at Visit 3 
Use of analgesic medications during the treatment from Week 6 to 12 
((number of days with analgesic medications use between Day 43 and earlier of Day 84 or 
Follow-up Day 3)/(number of days with available data between Day 43 and earlier of Day 84 
or Follow-up Day 3))*100 (rounded to 1 decimal places) 
Similarly, use of analgesic medications during the treatment from Week 2 to 6 and from 
Week 18 to 24 will be defined as proportion of days with analgesic use between Day 15 and 
earlier of Day 42 or Follow-up Day 3 and between Day 127 and earlier of Day 168 or 
Follow-up Day 3, respectively.  
Use of analgesic medications during the Treatment for 6 weeks before the final dose 
((number of days with analgesic medications use for the last 42 days of the 
treatment)/(number of days with available data for the last 42 days of the treatment))*100 
(rounded to 1 decimal places) 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 12: 
((number of subjects with a total PBAC score of less than 10 from Week 6 to 12)/( number of 
subjects with available PBAC score from Week 6 to 12))*100 (rounded to 1 decimal places) 
Myoma volumes 
D1*D2*D3*π/6 (cm3) 
Uterine volumes will be similarly calculated.   
Definitions of D1, D2 and D3 are shown in protocol. 
Duration of Menstruation Recovery 
Date of menstruation recovery - date of last dose of double-blind study drug  
Oral iron preparation  


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The drug with the following drug code of WHODD: 
00023503001, 00023505001, 00023520001, 00023550009, 00023550074, 90059601001 
7.1.2 Definition of Study Days 
When calculating Study Day relative to a reference date (ie, date of first dose of double-blind 
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 Follow-up Day relative to a reference date (ie, date of last dose of double-blind 
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. 
 
7.1.3 Definition of Study Visit Windows 
All evaluable data (ie, 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 to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used.  
 
Transvaginal ultrasound and WPAI 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 2 
Study Day: 15 
2 - 22 
< 4 
Week 4 
Study Day: 29 
23 - 43 
< 4 
Week 8 
Study Day: 57 
44 - 71 
< 4 
Week 12 
Study Day: 85 
72 - 127 
< 4 
Week 24 
Study Day: 169 
128 – 183 
< 4 
 
Anemia-related measurements (Hemoglobin [HGB], Hematocrit [HCT], Serum Fe, and Serum 
Ferritin) and UFS-QOL score 
Visit 
Scheduled Study Day 
Time Interval (days)  


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(days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 4 
Study Day: 29 
2 – 43 
< 4 
Week 8 
Study Day: 57 
44 – 71 
< 4 
Week 12 
Study Day: 85 
72 – 99 
< 4 
Week 16 
Study Day: 113 
100 – 127 
< 4 
Week 20 
Study Day: 141 
128 – 155 
< 4 
Week 24 
Study Day: 169 
156 – 183 
< 4 
Follow-up 
Follow-up Day: 28 
2 <= 
4 – 42 
 
Clinical laboratory tests (except bile acid (total bile acid [TBA]) and glutamate dehydrogenase 
(GLDH))  and vital sign and weight 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 4 
Study Day: 29 
2 – 43 
< 15 
Week 8 
Study Day: 57 
44 – 71 
< 15 
Week 12 
Study Day: 85 
72 – 99 
< 15 
Week 16 
Study Day: 113 
100 – 127 
< 15 
Week 20 
Study Day: 141 
128 – 155 
< 15 
Week 24 
Study Day: 169 
156 – 183 
< 15 
Follow-up 
Follow-up Day: 28 
2 <= 
15 – 42 
 
Pharmacodynamic measurements 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 2 
Study Day: 15 
2 – 22 
< 4 
Week 4 
Study Day: 29 
23 – 43 
< 4 
Week 8 
Study Day: 57 
44 – 71 
< 4 
Week 12 
Study Day: 85 
72 – 99 
< 4 
Week 16 
Study Day: 113 
100 – 127 
< 4 


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Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Week 20 
Study Day: 141 
128 – 155 
< 4 
Week 24 
Study Day: 169 
156 – 183 
< 4 
Follow-up 
Follow-up Day: 28 
2 <= 
4 – 42 
 
Clinical laboratory tests (TBA and GLDH) 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 2 
Study Day: 15 
2 – 22 
< 15 
Week 4 
Study Day: 29 
23 – 43 
< 15 
Week 8 
Study Day: 57 
44 – 71 
< 15 
Week 12 
Study Day: 85 
72 – 99 
< 15 
Week 16 
Study Day: 113 
100 – 127 
< 15 
Week 20 
Study Day: 141 
128 – 155 
< 15 
Week 24 
Study Day: 169 
156 – 183 
< 15 
Follow-up 
Follow-up Day: 28 
2 <= 
15 – 42 
 
 
12-lead ECG 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 
Week 24 
Study Day: 169 
2 – 183 
< 15 
Follow-up 
Follow-up Day: 28 
2 <= 
15 – 42 
 
Biochemical bone metabolism markers and BMD 
Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Baseline  
Study Day: 1 
-80 - 1 
 


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Visit 
Scheduled Study Day 
(days)  
Time Interval (days)  
Study Day 
Follow-up Day 
Week 12 
Study Day: 85 
2 – 127 
< 15 
Week 24 
Study Day: 169 
128 – 183 
< 15 
 
7.1.4 Methods for Handling Missing Data 
All available efficacy and safety data will be included in data listing and tabulations. No 
imputation of values for missing data will be performed unless otherwise specified.  
• For UFS-QoL and WPAI, published scoring manuals and guidelines will be used to 
calculate UFS-QoL and WPAI scale scores and handle missing data (see Appendix 3 and 
4, respectively). 
• For myoma or uterus volume, if D1 and D2 of the myoma or uterus are present but D3 is 
missing, then the volume will be calculated as D1*D2*D2*π/6 (cm3). 
• For LH, FSH, E2, P and clinical laboratory tests, values less than the lower limit of 
quantification will be treated as zero when calculating the descriptive statistics. 
• Disease duration with first diagnosis date of uterine fibroid that are completely or 
partially missing will be derived as follows: 
1. If the year is missing, then the disease duration will be treated as missing. 
2. If the year is present but the month is missing, then the month will be treated as 
January for the calculation. 
7.2 
Analysis Sets 
Refer to the Handling Rules for Analysis Data. 
7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Date first subject signed informed consent form 
 
Date of last subject’s last visit/contact 
 
MedDRA version 
 
WHO Drug version 
 
SAS version used for creating the datasets 
Analytical 
 


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Method(s) : 
(1) Study Information 
Study information shown in the analysis variables section will be 
provided. 
 
7.3.2 Screen Failures 
Analysis Set: All Subjects Who Were Not Randomized  
Analysis 
Variable(s) : 
 
Age (years)  
 
[20<= - <30, 30<= - <40, 40<= - 
<50, 50<= - <=Max]  
Analytical 
Method(s) : 
 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive 
statistics for continuous variables will be provided. 
 
7.3.3 Subject Eligibility 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Eligibility status 
 
[Eligible for Randomization, Not 
Eligible for Randomization] 
 
Primary Reason for Subject Not 
Being Eligible 
[Death, Adverse Event, Screen 
Failure, Protocol Deviation, Lost to 
Follow-up, Withdrawal by Subject, 
Study Terminated by Sponsor, 
Pregnancy, 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. 
 
7.3.4 Number of Subjects Randomized by Site and Treatment Group 
Analysis Set: Randomized Set 


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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. 
 
7.3.5 Disposition of Subjects 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
Double-blind study drug 
administration status 
 
[Randomized but Not Treated] 
 
Reason for not being treated 
[Death, Adverse Event, Protocol 
Deviation, Lost to Follow-up, 
Withdrawal by Subject, Study 
Terminated by Sponsor, 
Pregnancy, Lack of Efficacy, Bone 
Mineral Density Loss, Recovery 
Leading to Surgery, Reduction of 
HGB Concentration, Other] 
 
Double-Blind Study Drug 
Completion Status 
[Completed Study Drug, 
Prematurely Discontinued Study 
Drug] 
 
Reason for Discontinuation of 
Study Drug 
[Death, Adverse Event, Protocol 
Deviation, Lost to Follow-up, 
Withdrawal by Subject, Study 
Terminated by Sponsor, 
Pregnancy, Lack of Efficacy, Bone 
Mineral Density Loss, Recovery 
Leading to Surgery, Reduction of 
HGB Concentration, Other] 
 
Completion Status of the Follow-
[Completed Follow-up Period, 


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up Period  
Prematurely Discontinued Follow-
up Period] 
 
Reason for Discontinuation of 
the Follow-up Period 
[Death, Adverse Event, Protocol 
Deviation, Lost to Follow-up, 
Withdrawal by Subject, Study 
Terminated by Sponsor, 
Pregnancy, Lack of Efficacy, Bone 
Mineral Density Loss, Recovery 
Leading to Surgery, Reduction of 
HGB Concentration, 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, the total number of subjects who prematurely 
discontinued will be used as the denominator. 
 
7.3.6 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 


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deviations that can be classified into the same category will be counted 
only once. 
 
7.3.7 Analysis Sets 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
 
Handling of Subjects and Subject 
Data 
 
[Categories are based on the 
specifications in Handling Rules 
for Analysis Data] 
 
Analysis Sets 
Full Analysis Set 
Per Protocol Set  
Safety Analysis Set 
 
[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. 
 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: Randomized Set 
Analysis 
Variable(s) : 
 
Age (years) 
 
[20<= - <30, 30<= - <40, 
 40<= - <50, 50<= - <=Max] 
 
Height (cm) 
[Min<= - <150, 150<= - <160, 
160<= - <170, 170<= - <=Max] 
 
Weight (kg) at Baseline 
[Min<= - <50, 50<= - <60,  
60<= - <70, 70<= - <80,  


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80<= - <=Max] 
 
BMI (kg/m2) at Baseline 
[Min<= - <18.5, 18.5<= - <25.0, 
25.0<= - <=Max] 
 
Smoking Classification 
[The subject has never smoked,  
The subject is a current smoker,  
The subject is an ex-smoker] 
 
Birth Experience 
[Yes, No]  
 
Disease Duration (years) 
[Min<= - <=1, 1< - <=3, 3< - <=5, 
5< - <=10, 10< - <=Max] 
 
Type of Uterine Fibroid 
  Subserosal Fibroid 
  Intramural Fibroid 
  Submucosal Fibroid 
  Cervical Fibroid 
 
[Yes, No] 
[Yes, No] 
[Yes, No] 
[Yes, No] 
 
Stopped Any Medications for 
Uterine Fibroids 
 
[Yes, No] 
 
Type of Medication for Uterine 
Fibroid 
  GnRH Agonist 
  Herbal Medicine 
  Other Medicines for Uterine 
Fibroids 
 
 
[Yes] 
[Yes] 
 
[Yes] 
 
Any Surgery for Uterine Fibroids 
[Yes, No] 
 
Volume of Myoma at Baseline 
(cm3 ) 
[Min<= - <=28, 28< - <=170,  
170< - <=700, 700< - <=Max] 
 
Volume of Uterus at Baseline 
(cm3 ) 
[Min<= - <=28, 28< - <=170,  
170< - <=700, 700< - <=Max] 
 
PBAC Score at Baseline 
[120<= - <200, 200<= - <500, 
500<= - <=Max] 
 
NRS Score at Baseline 
[Min<= - <4, 4<= - <7, 7<= - 
<=Max] 
 
UFS-QOL Score at Baseline 
Symptom Severity 
 
Concern 
 
 Activities 
 
 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 


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Energy/Mood 
 
Control 
 
Self-consciousness 
 
Sexual Function 
 
HRQL Total 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max] 
[Min<= - <=25, 25< - <=50,  
50< - <=75, 75< - <=Max]  
 
HGB at Baseline (g/dL) 
[Min<= - <10, 10<= - <12, 12<= - 
<=Max] 
 
HCT at Baseline (%) 
 
 
Serum Fe at Baseline (µg/dL) 
 
 
Serum Ferritin at Baseline (ng/mL)  
 
Dosage of leuprorelin vial 
[1.88 mg, 3.75 mg] 
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. 
 
7.5 
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. 
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.  


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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. 
 
7.6 
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 Preferred 
Medication Name 
Frequency distributions will be provided for each treatment group. WHO 
Drug dictionary will be used for coding. Summaries will be provided 
using preferred medication names and 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. 
 
7.7 
Study Drug Exposure and Compliance 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
Duration of Exposure to Double-
Blind Study Drug (days)  
[1<= - <=14, 15<= - <=42,  
43<= - <=84, 85<= - <=168 
169<= - <=Max] 
 
Double-Blind Study Drug 
Compliance (%) 
[Min<= - <80, 80<= - <90, 90<= - 
<=Max] 
 
Maximum Drug Holidays (days) 
[0, 1<= - <4, 4<= - <=Max] 
 
Exposure to Double-Blind 
leuprorelin vial (times) 
[0, 1, 2, 3, 4, 5, 6] 


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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. 
 
7.8 
Efficacy Analysis 
7.8.1 Primary Efficacy Endpoint(s) 
7.8.1.1 Primary Analysis 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 
12 
Analytical 
Method(s): 
The point estimate and 2-sided 95% confidence interval of the proportion 
of subjects with a total PBAC score of < 10 from Week 6 to 12 will be 
summarized by treatment group. The point estimate and 2-sided 95% 
confidence interval of the difference in the percentage will be calculated 
between TAK-385 40 mg group and leuprorelin group (TAK-385 40 mg 
group – leuprorelin group), using Farrington and Manning (FM) method. 
In addition, non-inferiority test using FM method with a non-inferiority 
margin of 15% will be conducted for the comparison between TAK-385 
40 mg group and leuprorelin group. If the lower bound of the 95%CI is 
greater or equal to the non-inferiority margin of -15%, then non-
inferiority of TAK-385 40mg to leuprorelin will be concluded.  
7.8.1.2 Secondary Analysis 
Analysis Set: Per Protocol Set 
Analysis 
Variable(s): 
 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 
12 
Analytical 
Method(s): 
 
An analysis similar to the above “Primary analysis” will be performed 


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using the PPS to assess the robustness of the results. 
7.8.1.3 Adjustments for Covariates 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 
12 
Covariate(s): PBAC Score at Baseline 
[120<= - <200, 200<= - <500, 
500<= - <=Max] 
Analytical 
Method(s): 
 
The difference between groups in the proportion of subjects with a total 
PBAC score of < 10 from Week 6 to 12 will be analyzed using binomial 
regression with the identity link that includes treatment group and PBAC 
score at baseline as independent categorical variable.  
7.8.1.4 Examination of Subgroups 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Proportion of subjects with a total PBAC score of < 10 from Week 6 to 
12 
Subgroup(s): Age (years) 
[20<= - <30, 30<= - <40, 
 40<= - <50, 50<= - <=Max] 
 
BMI (kg/m2) at Baseline 
[Min<= - <18.5, 18.5<= - <25.0, 
25.0<= - <=Max] 
 
PBAC Score at Baseline 
[120<= - <200, 200<= - <500, 
500<= - <=Max] 
 
Birth Experience 
[Yes, No]  
 
Volume of Uterus at Baseline 
(cm3 ) 
[Min<= - <=28, 28< - <=170,  
170< - <=700, 700< - <=Max ] 
 
Type of Uterine Fibroid 
 
 
Subserosal Fibroid 
[Yes, No] 
 
Intramural Fibroid 
[Yes, No] 
 
Submucosal Fibroid 
[Yes, No] 


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Analytical 
Method(s): 
 
(1) Descriptive Statistics 
The point estimate and 2-sided 95% confidence interval of the proportion 
of subjects with a total PBAC score of < 10 from Week 6 to 12 will be 
summarized for above each subgroup by treatment group. 
 
7.8.2 Secondary Efficacy Endpoint(s) 
7.8.2.1 PBAC Score 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Proportion of subjects with a total PBAC score of < 10 from Week 2 to 6 
 
Proportion of subjects with a total PBAC score of < 10 from Week 18 to 
24 
 
Proportion of subjects with a total PBAC score of < 10 for 6 weeks 
before the final dose of study drug 
Analytical 
Method(s): 
 
For each variable, frequency will be summarized by treatment group. 
The point estimate and 2-sided 95% confidence interval of the difference 
in the percentage will be calculated between TAK-385 40 mg group and 
leuprorelin group, using FM method with the non-inferiority margin of -
15%. The confidence interval will be presented in a descriptive manner 
and not for the purpose of statistical inference. 
7.8.2.2 Myoma Volumes and Uterine Volumes 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Myoma volumes 
 
Uterine volumes 
Visit: 
Baseline, Week 2, 4, 8, 12 and 24 
Analytical 
Method(s): 
 
For each variable, descriptive statistics will be provided for the observed 
values and the percent changes from baseline by treatment group for 


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each visit.  
The mean differences in the percent changes from baseline between 
TAK-385 40 mg and leuprorelin group and the two-sided 95% 
confidence intervals will be provided.  
7.8.2.3 Hemoglobin 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
HGB (g/dL) 
 
[Min<= - <12, 12<= - <=Max] 
 
 
Change from baseline on HGB 
(g/dL) 
[Min<= - <1, 1<= - <=Max] 
 
Subgroup(s): Oral iron preparation use at 
baseline 
[Yes, No] 
 
HGB at Baseline (g/dL) 
[Min<= - <12, 12<= - <=Max] 
Visit: 
Baseline, Week 4, 8, 12, 16, 20, 24 and Follow-up 
Analytical 
Method(s): 
 
Summary statistics will be provided for the observed values and the 
changes from baseline by treatment group for each visit.  
The mean differences in the change from baseline between TAK-385 
40 mg and leuprorelin groups and the two-sided 95% confidence 
intervals will be provided for each visit. 
For categorical variables, frequency will be summarized by treatment 
group for each visit. The differences in the percentage between TAK-385 
40 mg and leuprorelin groups and the two-sided 95% confidence 
intervals will be provided for each visit. 
Additionally, the above mentioned analysis will also be conducted for 
each subgroup. 
7.8.2.4 NRS Score 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
NRS score from Week 6 to 12 


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NRS score from Week 2 to 6 
 
NRS score from Week 18 to 24 
 
NRS score for 6 weeks before the final dose 
Analytical 
Method(s): 
 
For each variable, summary statistics will be provided by treatment 
group. Two-sided 95% confidence interval of the difference will be 
calculated between TAK-385 40 mg and leuprorelin group. 
7.8.2.5 UFS-QOL Score 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Symptom Severity 
 
Concern 
 
Activities 
 
Energy/Mood 
 
Control 
 
Self-consciousness 
 
Sexual Function 
 
HRQL Total 
Visit: 
Baseline , Week 4, 8, 12, 16, 20, 24 and Follow-up 
Analytical 
Method(s): 
 
For each variable, descriptive statistics will be provided for the observed 
values and the changes from baseline by treatment group for each visit.  
The mean differences in the observed values between TAK-385 40 mg 
and leuprorelin group and the two-sided 95% confidence intervals will 
be provided for each visit. 
 
7.8.3 Additional Efficacy Endpoint(s) 
7.8.3.1 Hematocrit, Serum Fe, and Serum Ferritin 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
HCT 


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Serum Fe 
 
Serum ferritin 
Visit: 
Baseline , Week 4, 8, 12, 16, 20, 24 and Follow-up 
Analytical 
Method(s): 
 
For each variable, summary statistics will be provided for the observed 
values and the changes from baseline by treatment group for each visit.  
7.8.3.2 Use of Analgesic Medications During the Treatment 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Use of analgesic medications during the Treatment from Week 6 to 12 
 
Use of analgesic medications during the Treatment from Week 2 to 6 
 
Use of analgesic medications during the Treatment from Week 18 to 24 
 
Use of analgesic medications during the Treatment for 6 weeks before 
the final dose 
Analytical 
Method(s): 
 
For each variable, summary statistics will be provided by treatment 
group.  
7.8.3.3 WPAI:GH During the Treatment 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
 
Absenteeism 
 
Presenteeism 
 
Work productivity loss 
 
Activity impairment 
Visit: 
Baseline , Week 2, 4, 8, 12 and 24 
Analytical 
Method(s): 
 
For each variable, summary statistics will be provided for the observed 
values and the changes from baseline by treatment group for each visit.  
The mean differences in the observed values between TAK-385 40 mg 
and leuprorelin group and the two-sided 95% confidence intervals will 
be provided for each visit.  
 


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7.8.3.4 Amenorrhea (The subject with a total PBAC score of 0) 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s): 
  
Proportion of subjects with a total PBAC score of 0 from Week 6 to 12  
 
Proportion of subjects with a total PBAC score of 0 from Week 2 to 6 
 
Proportion of subjects with a total PBAC score of 0 from Week 18 to 24 
 
Proportion of subjects with a total PBAC score of 0 for 6 weeks before 
the final dose of study drug 
Analytical 
Method(s): 
 
For each variable, frequency will be summarized by treatment group. 
The point estimate and 2-sided 95% confidence interval of the difference 
in the percentage will be calculated between TAK-385 40 mg group and 
leuprorelin group, using FM method with the non-inferiority margin of -
15%. The confidence interval will be presented in a descriptive manner 
and not for the purpose of statistical inference. 
 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
Not applicable  
7.9.2 Pharmacodynamic Analysis 
7.9.2.1 LH, FSH, E2, and P 
Analysis Set: Full Analysis Set 
Analysis 
Variable(s) : 
 
LH  
 
FSH 
 
E2 
 
P 
Visit: 
Baseline , Week 2, 4, 8, 12, 16, 20, 24 and Follow-up 
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment 
group. 


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(1) Summary of each variable and Change from Baseline by Visit 
Descriptive statistics for observed values for each visit and changes 
from baseline will be provided. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
 
7.10 
Other Outcomes 
Not applicable 
7.11 
Safety Analysis 
7.11.1 Adverse Events  
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Treatment-emergent adverse event (TEAE) 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analytical 
Method(s) : 
 
The following summaries will be provided for each treatment group. 
 
(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 


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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 (ie, Related 
and Not Related) will be counted once in the Related category. 
• Summary for 3)  
A subject with multiple occurrences of TEAE will be counted once 
for the TEAE with the maximum intensity. 
• Summaries other than 2) , 3) , and 6)  
A subject with multiple occurrences of TEAE will be counted only 
once. 
Number of events 
For each summary, the total number of events will be calculated. 
 
7.11.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
TEAE 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of Onset (day)  
[1<= - <=28, 29<= - <=56, 57<= - 
<=84, 85<= - <=112, 113<= - 
<=140, 141<= - <=168, 169<= - 
<=Max] 
Analytical 
Method(s) : 
 
The following summaries will be provided using frequency distribution 


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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. 
 
(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) Intensity of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(6) Intensity of Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class, and Preferred Term 
 
(7) Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation by System Organ Class and Preferred Term 
 
(8) Serious Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
 
(9) Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term Over Time 
 
(10) Most Frequent Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
 
(11) Most Frequent Non-Serious 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 (5), (6) and (9) 
A subject with multiple occurrences of TEAE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences 
of TEAE within a PT will be counted only once in that PT. 


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Percentages will be based on the number of subjects in the safety 
analysis set. 
• Summary tables for (5) and (6)  
A subject with multiple occurrences of TEAE within a SOC or a PT 
will be counted only once for the TEAE with the maximum intensity. 
Percentages will be based on the number of subjects in the safety 
analysis set. 
• Summary table for (9)  
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each time 
interval, a subject with multiple occurrences of TEAE within a SOC 
or a PT will be counted only once in that SOC or PT. 
When calculating percentages for each time interval, the number of 
subjects at risk (ie, 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. 
• Summary table for (10)  
Most frequent TEAEs refer to PTs whose percentages are at least 
5.0% in any one of the treatment groups. 
• Summary table for (11)  
Most frequent Non-Serious TEAEs refer to PTs whose percentages 
are at least 5.0% in any one of the treatment groups. If no Non-
Serious TEAEs exceed a frequency of 5.0%, the frequency cutoff of 
2.0% will be used instead. Percentages will be based on the number of 
subjects in the safety analysis set. 
7.11.1.3 Displays of Pretreatment Events 
Analysis Set: All Subjects Who Signed the Informed Consent Form 
Analysis 
Variable(s) : 
 
Pretreatment event (PTE) 
Analytical 
The following summaries will be provided using frequency distribution. 


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Method(s) : 
PTEs will be coded using the MedDRA and will be summarized using 
SOC and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency. 
 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events 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 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. 
 
7.11.1.4 Displays of Run-in Adverse Events 
Analysis Set: All Subjects Who Received Run-in Study Drug 
Analysis 
Variable(s) : 
 
Run-in AE 
Analytical 
Method(s) : 
The following summaries will be provided using frequency distribution. 
Run-in AEs 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) Run-in Adverse Events by System Organ Class and Preferred Term 
(2) Drug-Related Run-in Adverse Events by System Organ Class and 
Preferred Term 
(3) Serious Run-in Adverse Events 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 run-in AE within a SOC will be 
counted only once in that SOC. A subject with multiple occurrences of 
run-in AE within a PT will be counted only once in that PT. 
 


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7.11.2 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Hematology 
 
RBC 
Platelets 
WBC 
 
WBC Differentials (Neutrophils, Eosinophils, Basophils, Lymphocytes, 
Monocytes)  
 
Serum Chemistry 
 
ALT 
AST 
Lactate dehydrogenase 
(LDH)  
 
Gamma glutamyl 
transferase (GGT) 
Albumin 
Alkaline phosphatase 
(ALP) 
 
Bilirubin (Total 
bilirubin) 
Protein (Total 
protein) 
Cholesterol (Total 
cholesterol) 
 
High density 
lipoprotein (HDL) 
cholesterol 
Low density 
lipoprotein (LDL) 
cholesterol 
Triglycerides 
 
Glucose 
HGB A1C 
Creatinine 
 
Blood urea nitrogen 
(BUN) 
Creatine kinase 
Urate 
 
Sodium 
Potassium 
Chloride 
 
Calcium 
Phosphate 
Magnesium 
 
Bile acid (total bile 
acid [TBA]) 
Glutamate 
dehydrogenase 
(GLDH) 
 
Visit: 
Baseline, Week 2*, 4, 8, 12, 16, 20, 24 and Follow-up 
*: only TBA and GLDH 
Analytical 
Method(s) : 
 
For each variable, summaries (1) to (3) will be provided  by treatment 
group. 
For applicable variables, summaries (4) and (5) will be provided  by 
treatment group. 


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(1) Summary of Laboratory Test Results and Change from Baseline by 
Visit 
Descriptive statistics for observed values for each visit and changes 
from baseline will be provided. 
 
(2) Case Plots 
Plots over time for each subject will be presented. 
 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
For each laboratory test, the laboratory values will be classified as 
"Low", "Normal" or "High" relative to the normal reference range 
provided by the central laboratory. The shift tables will be based on 
these classifications. 
 
(4) Number and Percentage of Subjects with Markedly Abnormal 
Values of Laboratory Parameters 
Overall frequency distributions of MAV during treatment period 
will be provided. If a laboratory parameter has both lower and upper 
MAV criteria, analysis will be performed for each. Further details 
are given in Appendix. 
 
(5) Number and Percentage of Subjects with Elevated Liver Enzyme 
Laboratory Parameters 
Overall frequency distributions of elevated hepatic parameters 
during treatment period will be provided. Further details are given in 
Appendix. 
 
7.11.2.2 Urinalysis 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Protein 
 
[-,  +-,  1+,  2+,  3+,  4+] 
 
Glucose 
[-,  1+,  2+,  3+,  4+,  5+] 
 
Occult blood 
[-,  +-,  1+,  2+,  3+] 
 
Bilirubin 
[-,  +-,  1+,  2+,  3+] 
 
Urobilinogen 
[+-,  1+,  2+,  3+] 


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Visit: 
Baseline , Week 4, 8, 12, 16, 20, 24 and Follow-up 
Analytical 
Method(s) : 
 
For each variable, summaries (1) and (2) will be provided by treatment 
group.  
 
(1) 
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. 
 
(2) 
Summary of Shifts 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. 
For each urine laboratory test, the laboratory values will be 
classified as "Normal" or " Abnormal " relative to the normal 
reference range provided by the central laboratory. The shift tables 
will be based on these classifications. 
 
7.11.3 Vital Signs 
7.11.3.1 Vital Signs and Weight 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Systolic Blood Pressure 
 
 
Diastolic Blood Pressure 
 
 
Pulse Rate 
 
 
Body temperature 
 
 
Weight 
 
Visit: 
Baseline , Week 4, 8, 12, 16, 20, 24 and Follow-up  
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 Parameters and Weight and Change from 


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Baseline by Visit 
Descriptive statistics for observed values for each visit and changes 
from baseline will be provided. 
 
(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 during treatment period 
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. 
 
7.11.4 12-Lead ECGs 
7.11.4.1 12-lead ECG 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
12-lead ECG Interpretation 
 
[Within Normal Limits, Abnormal but not 
Clinically Significant, Abnormal and 
Clinically Significant] 
Visit: 
Baseline , Week24 and Follow-up   
Analytical 
Method(s) : 
 
For 12-lead ECG interpretation, summary (1) will be provided by 
treatment group. 
 
(1) Summary of Shift of 12-lead ECG Interpretation 
Shift table showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 
7.11.5 Other Observations Related to Safety 
7.11.5.1 Bone Mineral Density and Biochemical Bone Metabolism Markers 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
T score 
 
[Min <= -<=-2.500,                


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-2.499<= - <=-1.000,             
-0.999<= - <= MAX] 
 
Bone Mineral Density (g/cm2 ) 
 
 
Percent Change from baseline on Bone 
Mineral Density (%) 
[Min<= - <-7, -7<= - <=Max] 
 
 
NTELOP (nmol BCE/L) 
 
 
Bone Type Alkaline Phosphatase (µg/L) 
 
Visit: 
Baseline , Week 12, 24 
Analytical 
Method(s) : 
 
For each variable except T score, summaries (1), (3), and (4) will be 
provided by treatment group. 
For T score, summary (2), (3), (4), and (5) will be provided by treatment 
group. 
 
(1) Summary of Parameters and percent Change from Baseline by Visit 
Descriptive statistics for observed values for each visit and percent 
changes from baseline will be provided. 
For categorical variables, frequency will be summarized by 
treatment group for each visit. 
 
(2) Summary of Parameters and Change from Baseline by Visit 
Descriptive statistics for observed values for each visit and changes 
from baseline will be provided. 
 
(3) Case Plots 
Plots over time for each subject will be presented. 
 
(4) Mean Plot with Standard Deviations  
For T score, mean of observed values and changes from baseline 
will be plotted by visit. 
For other variables, mean of observed values and percent changes 
from baseline will be plotted by visit. 
 
(5) Summary of Shift of T score  
Shift table showing the number of subjects in each category at 
baseline and each post-baseline visit will be provided. 


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7.11.5.2 Return of Menstrual Cycles 
Analysis Set: Safety Analysis Set 
Analysis 
Variable(s) : 
 
Duration of Menstruation Recovery (Days) 
 
Analytical 
Method(s) : 
 
Summary (1) will be provided by treatment group. 
 
(1) Summary of Duration of Menstruation Recovery  
Descriptive statistics for observed values will be provided. 
 
7.12 
Interim Analysis 
Not applicable 
7.13 
Changes in the Statistical Analysis Plan  
Change from previous version are described in following table. 
 
Page Previous version 
Current version 
Reason 
14 
7.1.1 Study Definitions 
 
7.1.1 Study Definitions 
Oral iron preparation  
The drug with the following 
drug code of WHODD: 
00023503001, 
00023505001, 
00023520001, 
00023550009, 
00023550074, 90059601001 
Specify the 
definition of Oral 
iron preparation 
based on  blind 
review 
17 
7.1.4 Methods for Handling 
Missing Data 
 
7.1.4 Methods for Handling 
Missing Data 
•For LH, FSH, E2, P and 
clinical laboratory tests, 
values less than the lower 
limit of quantification will 
be treated as zero when 
calculating the descriptive 
statistics. 
Specify how to deal 
with value with 
lower limit of 
quantification for 
LH, FSH, E2, P 
and clinical 
laboratory 
 


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23 
7.4Demographic and Other 
Baseline Characteristics 
Other Medicines for 
UterineFibroids 
7.4Demographic and Other 
Baseline Characteristics 
Other Medicines for Uterine 
Fibroids 
Typo 
26 
7.8.1.1Primary Analysis 
If the lower bound of the 
95%CI is greater or equal to 
the non-inferiority margin of 
15%,, then non-inferiority of 
TAK-385 40mg to leuprorelin 
will be concluded. 
7.8.1.1Primary Analysis 
If the lower bound of the 
95%CI is greater or equal to 
the non-inferiority margin 
of -15%, then non-
inferiority of TAK-385 
40mg to leuprorelin will be 
concluded. 
Typo 
27 
7.8.1.4Examination of 
Subgroups 
Cervical Fibroid[Yes, No] 
7.8.1.4Examination of 
Subgroups 
removed 
Removed based on  
blind review 
28 
7.8.2.1PBAC Score 
For each variable, frequency 
will be summarized by 
treatment group. The point 
estimate and 2-sided 95% 
confidence interval of the 
difference in the percentage 
will be calculated between 
TAK-385 40 mg group and 
leuprorelin group, using FM 
method. 
7.8.2.1PBAC Score 
For each variable, frequency 
will be summarized by 
treatment group. The point 
estimate and 2-sided 95% 
confidence interval of the 
difference in the percentage 
will be calculated between 
TAK-385 40 mg group and 
leuprorelin group, using FM 
method with the non-
inferiority margin of -15%. 
The confidence interval will 
be presented in a descriptive 
manner and not for the 
purpose of statistical 
inference. 
Specify the detail 
description how to 
calculate CI using 
FM method, based 
on the comment. 
29 
7.8.2.3Hemoglobin 
 
7.8.2.3Hemoglobin 
HGB at Baseline 
(g/dL)[Min<= - <12, 12<= - 
<=Max] 
Added based on  
blind review 
32 
 
Section 7.8.3.4 was newly 
added. 
Added based on the 
comment. 


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42 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
For each variable, summaries 
(1) and (2) will be provided 
by treatment group. 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
For each variable except T 
score, summaries (1), (3), 
and (4) will be provided by 
treatment group. 
Modified based on  
blind review 
42 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
For T score, summary (3) will 
be provided by treatment 
group. 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
For T score, summary (2), 
(3), (4), and (5) will be 
provided by treatment 
group. 
Modified based on  
blind review 
42 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
Descriptive statistics for 
observed values for each visit 
and changes from baseline 
will be provided. 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
Descriptive statistics for 
observed values for each 
visit and percent changes 
from baseline will be 
provided. 
Modified based on  
blind review 
42 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
(2)Summary of Parameters 
and Change from Baseline 
by Visit 
Descriptive statistics for 
observed values for each 
visit and changes from 
baseline will be provided. 
Modified based on  
blind review 
43 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
 
7.11.5.1Bone Mineral 
Density and Biochemical 
Bone Metabolism Markers 
(4)Mean Plot with Standard 
Deviations  
Modified based on  
blind review 


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For T score, mean of 
observed values and 
changes from baseline will 
be plotted by visit. 
For other variables, mean of 
observed values and percent 
changes from baseline will 
be plotted by visit. 
45 
Appendix 1. Criteria for 
Markedly Abnormal Values 
For each parameter, all 
evaluable data (i.e., non-
missing and acceptable 
according to the Handling 
Rules for Analysis Data) 
obtained up to Follow-up Day 
14 will be classified as a 
MAV or not. 
Appendix 1. Criteria for 
Markedly Abnormal Values 
For each parameter, all 
evaluable data (i.e., non-
missing and acceptable 
according to the Handling 
Rules for Analysis Data) 
obtained up to Follow-up 
Day 42 will be classified as 
a MAV or not. 
Modified to be 
accordance with 
CCT-001 study. 
46 
Appendix 1. Criteria for 
Markedly Abnormal Values 
Pulse (bpm) 
Appendix 1. Criteria for 
Markedly Abnormal Values 
Pulse Rate (bpm) 
Typo 
46 
Appendix 1. Criteria for 
Markedly Abnormal Values 
Body Temperature (°C) 
Appendix 1. Criteria for 
Markedly Abnormal Values 
Body temperature (°C) 
Typo 
48 
Appendix 2. Criteria for 
Elevated Liver Enzyme 
All evaluable data (ie, non-
missing and acceptable 
according to the Handling 
Rules for Analysis Data) 
obtained up to Follow-up Day 
14 will be used to determine 
whether each criteria for 
elevated liver enzyme in the 
table below is met or not. 
Appendix 2. Criteria for 
Elevated Liver Enzyme 
All evaluable data (ie, non-
missing and acceptable 
according to the Handling 
Rules for Analysis Data) 
obtained up to Follow-up 
Day 42 will be used to 
determine whether each 
criteria for elevated liver 
enzyme in the table below is 
met or not. 
Modified to be 
accordance with 
CCT-001 study. 
52 
Appendix 3. UFS-QoL 
Scoring Manual 
Appendix 3. UFS-QoL 
Scoring Manual 
Modified based on  
blind review 


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Transformed Score =((Actual 
raw score – lowest possible 
raw score)/(Possible raw 
score range))*100 
Transformed Score 
=((Actual raw score – 
lowest possible raw 
score)/(Possible raw score 
range))*100 (rounded to the 
nearest integer) 
53 
Appendix 3. UFS-QoL 
Scoring Manual 
Transformed Score 
=((Highest possible score – 
Actual raw score)/(Possible 
raw score range))*100 
Appendix 3. UFS-QoL 
Scoring Manual 
Transformed Score 
=((Highest possible score – 
Actual raw score)/(Possible 
raw score range))*100 
(rounded to the nearest 
integer) 
Modified based on  
blind review 
54 
Appendix 4. WPAI Scoring 
Manual 
Multiply scores by 100 to 
express in percentages. 
Appendix 4. WPAI Scoring 
Manual 
Multiply scores by 100 to 
express in percentages 
(rounded to the nearest 
integer). 
Modified based on  
blind review 
 


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8.0 
REFERENCES 
Farrington C P, Manning G: Test statistics and sample size formulae for comparative binomial 
trials with null hypothesis of non-zero risk difference or non-unity relative risk. Statistics in 
Medicine 1990; 9: 1447-1454.