Clinical trial NCT03085095
Conditions: Prostate Cancer
Sponsor: Myovant Sciences GmbH
Start date: 2017-04-18; Completion date: 2021-11-26
Enrollment: 1134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the efficacy and safety of relugolix 120 milligrams (mg) orally once daily for 48 weeks on maintaining serum testosterone suppression to castrate levels (\< 50 nanograms/deciliter \[ng/dL\]) in participants with androgen-sensitive advanced prostate cancer.

Detailed description:
This is a phase 3, multinational, randomized, open-label, parallel group study to evaluate the efficacy and safety of oral daily relugolix 120 mg in participants with androgen-sensitive advanced prostate cancer who require at least 1 year of continuous androgen-deprivation therapy. Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan based on local labels), every 3 months by subcutaneous injection will be administered to participants.

There are 2 analyses for this study, a primary analysis and a final analysis.

Primary Analysis:

The primary analysis of efficacy and safety has been completed (N=934). Participants were randomized 2:1 to receive relugolix or leuprolide for 48 weeks, followed by a 30-day safety follow-up visit or early termination 30-day safety follow-up.

Final Analysis:

The final analysis will occur after additional participants with metastatic disease (approximately 130) have been enrolled and randomized from any sites to the study, and have completed the 48-week treatment period. A cohort of participants enrolled in China and Taiwan will be analyzed separately once they have completed treatment to support registration in China.

Eligible participants were randomized 2:1 to relugolix or leuprolide arm and will attend visits monthly (every 4 weeks) where serum testosterone and prostate-specific antigen will be assessed. Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, and 12-lead electrocardiograms.

Castration resistance-free survival will be assessed up to Week 49, Day 1 of the study and reported as part of the final analysis.

The study enrolled 1134 participants, including 139 participants with metastatic advanced prostate cancer to support the analysis of the secondary endpoint of castration resistance-free survival and 93 Chinese participants (enrolled in China and Taiwan) to support registration in China.

Arms: arm 1: Relugolix for 48 weeks arm 2: Leuprolide acetate for 48 weeks
Interventions: intervention 1: Relugolix intervention 2: Leuprolide Acetate
Intervention descriptions: intervention 1: Relugolix 120-mg tablet administered orally once daily following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1 intervention 2: Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3 months by subcutaneous injection

Protocol documents:
Prot_001.pdf: 
Study Title:   
HERO: A Multinational Phase 3 Randomized, Open-Label, Parallel Group 
Study to Evaluate the Safety and Efficacy of Relugolix in Men with 
Advanced Prostate Cancer 
 
NCT Number:   
03085095 
 
Document Date:   
Protocol Version 1 /13 January 2017 
 
 
 
Amendment 1 / 02 January 2018 
 
 
 
Amendment 2  / 18 January 2018 
 
 
 
Amendment 3/ 23 October 2018 


 
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16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
Original Protocol (13-Jan-2017) 
Amendment 1 (02-Jan-2018) 
Amendment 2 (18-Jan-2018) 
Amendment 3 (23-Oct-2018) 
 
 


Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
HERO:  A Multinational Phase 3 Randomized, Open-label, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
Relugolix in Men with Advanced Prostate Cancer 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3201 
Indication: 
Advanced Prostate Cancer 
Sponsor: 
Myovant Sciences GmbH 
c/o Vischer AG 
Aeschenvorstadt 4 
CH-4010 Basel 
Switzerland 
IND Number: 
118736 
EudraCT Number: 
2017-000160-15 
Version / Effective Date: 
Version 1 /13 Jan 2017 
Study Medical Monitor: 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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Clinical Study Protocol: HERO (MVT-601-3201) 
Version 1.0, 13 Jan 2017 
SPONSOR SIGNATURE PAGE 
HERO: A Multinational Phase 3 Randomized, Open-label, Parallel Group Study to Evaluate the 
Safety and Efficacy ofRelugolix in Men with Advanced Prostate Cancer 
Protocol Number: MVT-601-3201 
This protocol has been approved by Myovant Sciences GmbH. The following signatures 
document this approval. 
Date 
l3 
2o t 7 
Date 
Date 
Myovant Sciences GmbH 
2 
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INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
Principal Investigator Name (Printed)  
Signature 
 
 
 
 
 
Date 
 
Site 
 
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TABLE OF CONTENTS 
Sponsor Signature Page .............................................................................................................................. 2 
Investigator Statement ................................................................................................................................ 3 
List of Tables ............................................................................................................................................... 8 
List of Figures .............................................................................................................................................. 8 
List of Abbreviations .................................................................................................................................. 9 
1. 
Protocol Synopsis ......................................................................................................................... 11 
1.1. 
Schedule of Activities ................................................................................................................ 22 
2. 
Introduction .................................................................................................................................. 26 
2.1. 
Prostate Cancer .......................................................................................................................... 26 
2.2. 
Relugolix ................................................................................................................................... 27 
2.2.1. 
Indication .......................................................................................................................... 27 
2.2.2. 
Pharmacology ................................................................................................................... 27 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 28 
2.2.4. 
Previous Human Experience ............................................................................................. 28 
3. 
Study Objectives and Endpoints ................................................................................................. 35 
4. 
Investigational Plan ..................................................................................................................... 38 
4.1. 
Overall Study Design................................................................................................................. 38 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 40 
4.3. 
Selection of Study Population ................................................................................................... 41 
4.3.1. 
Inclusion Criteria .............................................................................................................. 41 
4.3.2. 
Exclusion Criteria ............................................................................................................. 43 
4.4. 
Other Eligibility Criteria Considerations ................................................................................... 45 
4.5. 
Screening ................................................................................................................................... 45 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification Number ............ 45 
4.7. 
Removal of Patients from Therapy ............................................................................................ 46 
4.8. 
Contraception/Pregnancy Avoidance ........................................................................................ 48 
5. 
Treatments .................................................................................................................................... 48 
5.1. 
Treatments Administered .......................................................................................................... 48 
5.2. 
Identity of Investigational Product ............................................................................................ 49 
5.2.1. 
Product Characteristics ..................................................................................................... 49 
5.3. 
Randomization and Stratification .............................................................................................. 49 
5.4. 
Directions for Administration .................................................................................................... 50 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 51 
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5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption ......................................................... 51 
5.7. 
Storage, Packaging, and Labeling ............................................................................................. 51 
5.8. 
Blinding ..................................................................................................................................... 52 
5.9. 
Study Drug Accountability and Treatment Compliance ........................................................... 52 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 52 
5.10.1. 
Prohibited Medications ..................................................................................................... 52 
5.10.2. 
Permitted Medications ...................................................................................................... 54 
6. 
Study Assessments and Procedures ............................................................................................ 54 
6.1. 
Schedule of Observations and Procedures ................................................................................. 54 
6.2. 
Screening Period (Day -28 to Day -1) ....................................................................................... 54 
6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) ........................................................... 55 
6.4. 
Follow-up Period ....................................................................................................................... 57 
6.5. 
Unscheduled Visits .................................................................................................................... 58 
6.6. 
Study Procedures ....................................................................................................................... 58 
6.6.1. 
Efficacy-Related Procedures ............................................................................................. 58 
6.6.2. 
Safety-Related Procedures ................................................................................................ 61 
6.7. 
Biological Sample Retention and Destruction ........................................................................... 64 
7. 
Safety Considerations .................................................................................................................. 64 
7.1. 
Adverse Event Definitions......................................................................................................... 64 
7.1.1. 
Adverse Event ................................................................................................................... 64 
7.1.2. 
Serious Adverse Event ...................................................................................................... 65 
7.2. 
Adverse Event Reporting........................................................................................................... 66 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 67 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 67 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 68 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 68 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 69 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 69 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 70 
7.7. 
Study Drug Overdose Management .......................................................................................... 71 
7.8. 
Pregnancy Reporting ................................................................................................................. 71 
7.9. 
Benefit/Risk Assessment ........................................................................................................... 71 
8. 
Data Quality Assurance ............................................................................................................... 73 
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8.1. 
Clinical Procedures .................................................................................................................... 73 
8.2. 
Monitoring ................................................................................................................................. 73 
8.3. 
Independent Data and Safety Monitoring Board ....................................................................... 74 
8.4. 
Steering Committee ................................................................................................................... 74 
9. 
Statistical Considerations and Data Analyses ........................................................................... 74 
9.1. 
Randomization Methods ............................................................................................................ 74 
9.2. 
Analysis Populations ................................................................................................................. 75 
9.3. 
Efficacy Analyses ...................................................................................................................... 75 
9.3.1. 
Primary Endpoint Analyses .............................................................................................. 75 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 76 
9.4. 
Safety Analyses ......................................................................................................................... 77 
9.5. 
Pharmacokinetic Analyses ......................................................................................................... 77 
9.6. 
Endocrine Marker Analyses ...................................................................................................... 78 
9.7. 
Exploratory Analyses ................................................................................................................ 78 
9.8. 
Interim Analyses ........................................................................................................................ 78 
9.9. 
Sample Size ............................................................................................................................... 78 
10. 
Responsibilities ............................................................................................................................. 79 
10.1. 
Investigator Responsibilities...................................................................................................... 79 
10.1.1. 
Good Clinical Practice ...................................................................................................... 79 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 80 
10.1.3. 
Informed Consent ............................................................................................................. 80 
10.1.4. 
Confidentiality .................................................................................................................. 80 
10.1.5. 
Electronic Case Report Forms .......................................................................................... 82 
10.1.6. 
Investigational Product Accountability ............................................................................. 82 
10.1.7. 
Inspections ........................................................................................................................ 83 
10.1.8. 
Protocol Compliance ......................................................................................................... 83 
10.2. 
Sponsor Responsibilities............................................................................................................ 84 
10.2.1. 
Protocol Modifications ..................................................................................................... 84 
10.2.2. 
Study Report ..................................................................................................................... 84 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ............................ 84 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 84 
10.3.1. 
Access to Information Monitoring .................................................................................... 84 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 85 
10.3.3. 
Study Discontinuation ....................................................................................................... 85 
10.3.4. 
Publications ....................................................................................................................... 85 
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References .................................................................................................................................................. 86 
Appendices ................................................................................................................................................. 90 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status .......................................... 90 
Appendix 2. 
EuroQol EQ-5D-5L Questionnaire ............................................................................... 91 
Appendix 3. 
Quality of Life Questionnaire:  EORTC QLQ-C30 ..................................................... 93 
Appendix 4. 
Quality of Life Questionnaire:  EORTC QLQ-PR25 ................................................... 95 
Appendix 5. 
Adverse Event Severity Grading .................................................................................. 97 
Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes ............................................................ 98 
 
 
 
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LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-3201............................................................. 22 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks ...................... 30 
Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) ........................................... 32 
Table 4-1 
Removal of Patients from Treatment ................................................................................ 46 
Table 5-1 
Description of MVT-601-3201 Study Drugs .................................................................... 49 
Table 5-2 
Prohibited Medications and Washout Periods .................................................................. 53 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 62 
Table 7-1 
Causal Relationship to Study Drug ................................................................................... 67 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 68 
Table 7-3 
Relugolix Potential Risks and Mitigation ......................................................................... 72 
 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury ........................ 98 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests .............................. 99 
 
LIST OF FIGURES 
Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of Relugolix 
and Degarelix at Week 25 ................................................................................................. 31 
Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent Reduction 
by Dose of Relugolix at Week 25 Day 1 .......................................................................... 33 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent Reduction 
by Leuprolide Acetate at Week 25 Day 1 ......................................................................... 33 
Figure 4-1 
Schematic of Study Design ............................................................................................... 40 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
3-M 
3-month 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-τ 
area under the concentration-time curve from time 0 to the end of the dosing 
interval 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHT 
dihydrotestosterone 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organisation of Research and Treatment of Cancer 
EOT 
end of treatment 
EuroQol EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level Questionnaire 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonization 
ID 
identification 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat (population) 
IWRS 
interactive voice/web recognition system 
LH 
luteinizing hormone 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NOAEL 
no-observed-adverse-effect-level 
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Term 
Explanation 
Obs 
observed 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
PSA 
prostate-specific antigen 
Q12W 
once every 12 weeks 
Q4W 
once every 4 weeks 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
SHBG 
sex hormone binding globulin 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
HERO:  A Multinational Phase 3, Randomized, Open-label, Parallel-
group Study to Evaluate the Safety and Efficacy of Relugolix in Men 
With Advanced Prostate Cancer 
Protocol Number 
MVT-601-3201 
Location 
Multinational, including North and South America, Europe, and Asia-
Pacific 
Study Centers 
Approximately 200 sites 
Study phase 
Phase 3 
Target Population 
Men aged 18 or older diagnosed with androgen-sensitive advanced 
prostate cancer who are candidates for at least 1 year of continuous 
androgen deprivation therapy for the management of androgen-sensitive 
advanced prostate cancer and who are not be candidates for surgical 
therapy.  Patients previously treated with taxanes or expected to receive 
taxanes after initiation of androgen deprivation therapy are excluded, as 
are patients receiving androgen deprivation therapy adjuvant or 
neoadjuvant to radiotherapy as primary definitive therapy. 
Number of 
Patients Planned 
1125 total patients 
Study Objectives 
Primary: 
• 
To evaluate the ability of relugolix to achieve and maintain serum 
testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) 
in men with androgen-sensitive advanced prostate cancer. 
 
Secondary: 
• 
To evaluate the time course and change in serum testosterone during 
treatment with relugolix; 
• 
To evaluate the time course and magnitude of prostate-specific 
antigen (PSA) reduction during treatment with relugolix; 
• 
To evaluate testosterone recovery following discontinuation of 
relugolix; 
• 
To evaluate quality of life using validated patient-reported outcome 
instruments; 
• 
To evaluate the safety of relugolix 120 mg once daily in men with 
androgen-sensitive advanced prostate cancer; 
• 
To evaluate the effect of relugolix and leuprolide acetate on 
endocrine pharmacodynamic parameters; 
• 
To collect relugolix plasma concentration data to further evaluate 
relugolix population pharmacokinetics (PK) and the relationship 
between relugolix exposure and serum testosterone; and 
• 
To characterize the relugolix plasma PK parameters in a subset of 
patients from China and Japan. 
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Exploratory: 
• 
To explore the overall survival of patients treated with relugolix; and 
• 
To explore the contribution of genetic variance on drug response. 
Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 
22.5 mg (or 11.25 mg in some Asian countries), every 3-months (3-M) by subcutaneous or 
intramuscular injection will be administered to patients with prostate cancer who require 
androgen deprivation therapy.  This study will evaluate the ability of relugolix to achieve and 
maintain serum testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 
48 weeks in patients with androgen-sensitive advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local 
primary intervention with curative intent, newly diagnosed metastatic disease (excluding 
metastases to the brain), and/or advanced localized disease.  Patients may receive radiotherapy, 
cryotherapy or high frequency ultrasound no sooner than 2 months after initiation of androgen 
deprivation therapy.  Patients may be included if they have not previously received androgen 
deprivation therapy for more than 12 months, and if the androgen deprivation therapy was 
completed at least 12 months prior to baseline.  Patients previously treated with taxanes or 
expected to receive taxanes after initiation of androgen deprivation therapy are excluded, as are 
patients receiving androgen deprivation therapy adjuvant or neoadjuvant to radiotherapy as 
primary definitive therapy.  Baseline serum testosterone must be ≥ 150 ng/dL (5.2 nmol/L) to be 
enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once 
daily following a loading dose of 360 mg on Day 1 or leuprolide acetate 22.5 mg (or 11.25 mg 
in some Asian countries) 3-M depot subcutaneous or intramuscular injection, respectively, plus 
an antiandrogen for the first 4 weeks or longer if indicated in the opinion of the investigator.  
Randomization will be stratified by geographic region, presence of metastatic disease, and age. 
Approximately 1125 patients will be enrolled in this study from approximately 200 study 
centers in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-
reported outcomes (European Organisation of Research and Treatment of Cancer [EORTC] 
QLQ-C30, European Quality of Life 5-Dimesion 5-Level questionnaire [EuroQol EQ-5D-5L]) 
will be assessed approximately every 3 months during the Treatment Period and more 
frequently during the Follow-up Period.  Additional serum endocrine evaluations will include:  
LH, FSH, dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will 
be collected throughout the study.  Full PK profiles will be determined in a subset of patients in 
China and Japan.  Safety assessments will include treatment-emergent adverse events, vital 
signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECG), and 
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visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive additional oral therapy, systemic antineoplastic, and/or radiotherapy as 
prescribed by the investigator. 
 
 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
All of the following inclusion criteria must have been met prior to randomization unless 
otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent 
form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer 
with one of the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention 
with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency 
ultrasound and not a candidate for salvage treatment by surgery (radiotherapy, 
cryotherapy, or high frequency ultrasound are allowed after 2 months of androgen 
deprivation therapy); or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease not suitable for local primary surgical intervention with 
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curative intent (radiotherapy, cryotherapy, or high frequency ultrasound are allowed 
after 2 months of androgen deprivation therapy); 
5. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (5.2 nmol/L); 
6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 µg/L), or, when 
applicable, post radical prostatectomy of > 0.2 ng/mL (0.2 µg/L) or post radiotherapy, 
cryotherapy, or high frequency ultrasound > 2.0 ng/mL (2.0 µg/L) above the post 
interventional nadir; 
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial 
screening and at baseline (refer to Appendix 1); 
8. Is a male patient who, even if surgically sterilized (ie, status post vasectomy): 
a. Agrees to use a male condom if having sex with a woman of childbearing age or a 
pregnant woman, during the entire study Treatment Period and through 4 months after 
the last dose of study drug; or 
b. Agrees to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner) and withdrawal are not acceptable 
methods of contraception; 
9. Must agree not to donate sperm from first dose of study drug through 4 months after the last 
dose of study drug; 
10. A randomization authorization form has been signed by a study medical monitor approving 
the patient for randomization into the trial. 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. In the investigator’s opinion, is likely to require chemotherapy or surgical therapy for 
symptomatic disease management within 2 months of initiating androgen deprivation 
therapy; 
2. Previously received GnRH analog or other form of androgen deprivation therapy (estrogen 
or antiandrogen) for > 12 months total duration.  If androgen deprivation therapy was 
received for ≤ 12 months total duration, then that therapy must have been completed at least 
12 months prior to baseline; 
3. Previous treatment for prostate cancer with a taxane-based regimen; 
4. Metastases to brain per prior clinical evaluation; 
5. Features of the patient’s medical condition that make life expectancy due to other medical 
conditions of less than 5 years; 
6. Scheduled for major surgery after baseline; 
7. History of surgical castration; 
8. Diagnosis of or treatment for another malignancy within the 2 years before baseline, or 
presence of another malignancy with evidence of residual disease.  Patients with non-
melanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.  Patients with Stage 0 or Stage 1 melanoma or superficial 
Stage 0 or Stage 1 bladder cancer, if curatively managed prior to screening, are not 
excluded.  The medical monitor should be contacted for any questions regarding this 
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exclusion criterion; 
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable 
underlying disease, or the following laboratory values: 
a. Serum gamma-glutamyl transferase > 2.0 x upper limit of normal (ULN); 
b. Serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
> 1.0 x ULN; 
c. Total bilirubin > 1.0 x ULN (unless secondary to Gilbert’s syndrome or the pattern is 
consistent with a diagnosis of Gilbert’s syndrome) or; 
d. Serum creatinine > 2.0 mg/dL; 
10. Uncontrolled diabetes with hemoglobin A1c (HbA1c) > 10% or previously undiagnosed 
diabetes mellitus with screening HbA1c > 8% (such excluded patients may be rescreened 
after referral and evidence of improved control of their condition); 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(hepatitis A virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus surface 
antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, 
confirmed by HCV ribonucleic acid); 
12. Known human immunodeficiency virus infection; 
13. Within 6 months before baseline, a history of myocardial infarction, angina, unstable 
symptomatic ischemic heart disease, or congestive heart failure, or any history of clinically 
significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, 
or torsades de pointes, or history of Mobitz II second degree or third degree heart block 
without permanent pacemaker in place or untreated supraventricular tachycardia (heart rate 
≥ 120 beats per minute); thromboembolic events (eg, deep vein thrombosis, pulmonary 
embolism, or symptomatic cerebrovascular events); or any other significant cardiac 
condition (eg, pericardial effusion, restrictive cardiomyopathy).  Patients with chronic stable 
atrial fibrillation on stable anticoagulant therapy or patients with stable cardiac rhythm 
controlled by a pacemaker are allowed; 
14. The following ECG abnormalities are excluded: 
a. Q-wave infarction, unless identified 6 or more months before the Screening visit; 
b. QT interval corrected for heart rate (QTc) > 470 msec.  If the QTc is prolonged in a 
patient with a pacemaker, the patient may be enrolled in the study upon discussion with 
the medical monitor; or 
c. Congenital long QT syndrome; 
15. Uncontrolled hypertension despite appropriate medical therapy (sitting blood pressure of 
greater than 160 mmHg systolic and/or 100 mmHg diastolic at 2 separate measurements no 
more than 45 minutes apart during the Screening visit).  Patients may be re-screened after 
referral and further management of hypertension; 
16. Hypotension, as indicated by systolic blood pressure < 84 mmHg on 2 repeat measures at 
least 15 minutes apart, or treated ongoing symptomatic orthostatic hypotension with 
> 20 mmHg decrease in systolic blood pressure one minute or more after assuming upright 
position; 
17. Bradycardia as indicated by a heart rate of < 45 beats per minute on the ECG at the 
Screening or Baseline Day 1 visit; 
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18. Treatment for prostate cancer with any investigational products within 12 months before the 
first dose of study drug (approved products under investigation for an alternative condition, 
not directly related to therapy for prostate cancer, may be allowed); 
19. Treatment with an investigational product for indications other than prostate cancer within 
3 months; 
20. Previous treatment with relugolix in a clinical study; 
21. Patient is a study site employee or is a primary family member (spouse, parent, child, or 
sibling) of a site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets; 
23. Use of any medication listed in the prohibited medications table (see Section 5.10.1) 
without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form [eCRF]); 
26. Any serious medical condition that limits life expectancy to less than 5 years, or any other 
medical or psychiatric condition that, in opinion of investigator, would interfere with 
completion of treatment according to this protocol. 
Dose and Route of 
Administration 
Test Product 
Relugolix 120 mg tablet strength will be available as immediate-release 
film-coated tablets, and 1 tablet (120 mg) will be administered once daily 
following an oral loading dose of 360 mg (three 120-mg tablets) on 
Day 1.  These tablets will be presented in 45-tablet bottles and dispensed 
to patients every 4 weeks at scheduled study visits. 
All protocol-specific inclusion criteria and none of the exclusion criteria 
must be met and documented prior to study drug administration.  Study 
drug will be dispensed only to eligible patients who are under the 
supervision of the investigator or identified subinvestigator(s). 
Reference Product 
Leuprolide acetate, 22.5 mg (or 11.25 mg in some Asian countries), 
3-M depot subcutaneous or intramuscular injection will be administered 
per the approved dose and method of dosing in the region where the 
patient is enrolled.  Leuprolide acetate 3-M depot injection will be 
administered on Day 1 (with an antiandrogen of choice, if indicated 
according to the investigator, for the first 4 weeks or longer), then at 12-
week intervals thereafter for 48 weeks.  Preparation of the depot injection 
should follow the instructions provided by the manufacturer. 
Duration of 
Treatment 
The duration of treatment will be 48 weeks.  The last dose of leuprolide 
acetate 3-M depot will be administered at the Week 37 visit. 
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Criteria for 
Evaluation 
The following treatment arms will be evaluated after 48 weeks of study 
treatment: 
• 
Arm A:  Oral relugolix 120 mg once daily following a loading dose 
of 360 mg (three 120-mg tablets) on Day 1. 
• 
Arm B:  Leuprolide acetate 3-M depot injection, 22.5 mg (or 
11.25 mg in some Asian countries). 
 
Primary Endpoint 
• 
Sustained castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study 
treatment from Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
 
Secondary Endpoints 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) prior to 
dosing on Week 1 Day 4, prior to dosing on Week 2, and prior to 
dosing on Week 3; 
o Profound castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 20 ng/dL (0.7 nmol/L) while on 
study treatment from Week 25 Day 1 through Week 49 Day 1; 
o Time to testosterone recovery in the first 100 patients randomized 
to relugolix and the first 50 patients randomized to leuprolide 
acetate who complete 48 weeks of treatment and who do not plan 
to start alternative androgen deprivation therapy within the 
following 12 weeks (or within 24 weeks following the last 
injection of leuprolide acetate 3-M depot); 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed PSA response by Prostate 
Cancer Clinical Trials Working Group 3 guidelines at the Week 2 
and 5 visits [Scher, 2016]; 
o Proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit; 
• 
Absolute values and changes from baseline in the scores of the 
EORTC-QLQ-C30 global health domain, and the EORTC-QLQ-
PR25 sexual activity and hormonal-treatment-related symptom 
subdomains, at regular intervals during treatment, and as applicable 
during the Follow-up and/or at End of Treatment visits; 
• 
Absolute values and changes from baseline of the remaining domains 
in the EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular intervals during 
treatment, and as applicable during the Follow-up visits; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical laboratory data; 
• 
Endocrine marker effects of relugolix and leuprolide acetate as 
measured as absolute value and change from baseline for: 
o LH at the Week 2, Week 3, and Week 5 visits, and then every 
4 weeks until the last follow-up visit; 
o FSH at the Week 5, Week 13, Week 25, Week 37, and Week 49 
visits; 
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o Dihydrotestosterone at the Week 5, Week 13, Week 25, Week 37, 
and Week 49 visits; and 
o Sex hormone binding globulin at the Week 13, Week 25, and 
Week 49 visits; 
• 
Predose relugolix plasma concentrations; 
• 
Single and repeat-dose plasma relugolix PK parameters such as 
maximum plasma concentration (Cmax), area under the concentration-
time curve from time 0 to the end of the dosing interval (AUC0-τ), and 
time to maximum plasma concentration (tmax) in a subset of patients 
from China and Japan during the Day 1 visit. 
 
Exploratory Endpoints 
• 
Overall survival defined as time from randomization to date of death 
prior to data cutoff date; and 
• 
The presence of polymorphisms in germline genes related to the 
hypothalamic-pituitary-androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix. 
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Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) population defined as all 
randomized patients who have taken at least one dose of study treatment.  Randomization will 
be stratified by geographic region (North and South America versus Europe versus Asia and 
Rest of World), presence of metastatic disease on baseline imaging (yes versus no), and age 
(≤ 75 years old versus > 75 years old).  The 2-sided type I error rate for this study is 0.05. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the sustained castration rate defined as the cumulative 
probability of achieving testosterone suppression to castrate levels of ≤ 50 ng/dL (1.7 nmol/L) 
while on study treatment from Week 5 Day 1 (Study Day 29) through Week 49 Day 1 (Study 
Day 337).  This probability will be estimated for each treatment group using the Kaplan-Meier 
method with the confidence interval calculated using the exponential Greenwood formula via 
log-log transformation of the survival function.  Patients who discontinue treatment prior to 
observing a testosterone level > 50 ng/dL (1.7 nmol/L) will be censored at the last testosterone 
assessment prior to discontinuation.  Detailed censoring rules will be prespecified in the 
statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• 
Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix 
is greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression to castrate levels in the 
relugolix treatment group will be calculated and must be greater than or equal to 90% to 
meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression to castrate levels.  The lower bound of the 95% confidence 
interval for the difference in the cumulative probability of sustained testosterone 
suppression to castrate levels between the 2 treatment groups will be calculated and 
must be greater than or equal to the non-inferiority margin of -10% to meet this 
criterion. 
The 2-sided type I error rate will be 0.05 for each individual evaluation criterion. 
Secondary Efficacy Endpoints: 
1. Castration rate:  the cumulative probability of testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) prior to dosing on Week 1 Day 4, prior to dosing on Week 2, and prior to 
dosing on Week 3; 
2. Profound castration rate:  the cumulative probability of testosterone suppression to 
≤ 20 ng/dL (0.7 nmol/L) from Week 25 through Week 49; 
3. PSA response rate:  proportion of patients with a ≥ 50% decrease in PSA from baseline at 
Week 2 and confirmed at Week 5; 
4. Undetectable PSA rate:  proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit; 
5. Time to testosterone recovery in the first 100 relugolix-treated and first 50 leuprolide 
acetate-treated patients who complete 48 weeks of treatment and do not start alternative 
androgen deprivation therapy within 12 weeks after the last dose of relugolix or within 
24 weeks following the last received injection of leuprolide acetate.  Kaplan-Meier methods 
will be used to describe survival distributions; 
6. Quality of Life:  absolute values and changes from baseline in the scores of the EORTC-
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QLQ-C30 global health domain, and the EORTC-QLQ-PR25 sexual activity and hormonal-
treatment-related symptom subdomains, at regular intervals during treatment, and as 
applicable at the Follow-up and/or End-of-Study visits will be presented.  Additionally, 
absolute values and changes from baseline of the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as EQ-5D-5L, at regular intervals during treatment, 
and as applicable during the Follow-up visits will be presented.  Change from baseline will 
be analyzed using mixed-model repeated measures methodology. 
Exploratory Endpoints: 
1. Overall survival:  Overall survival defined as time from randomization to date of death prior 
to data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions; 
2. The effect of polymorphisms in germline genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or drug metabolizing enzymes and transporter 
proteins on the efficacy and safety of relugolix will be described in a separate statistical 
analysis plan. 
The methods and procedures needed to maintain a study-wide 2-sided type I error rate of 0.05 
across primary and secondary endpoint testing will be described in the statistical analysis plan. 
 
Pharmacokinetics 
Relugolix plasma concentrations will be summarized and described using population PK 
methods.  Plasma PK parameters in a subset of patients from China and Japan will be 
determined using noncompartmental methods. 
 
Safety 
Safety assessments, including adverse events, vital signs, clinical laboratory tests, and ECGs, 
will be summarized for the treatment-emergent period.  The treatment-emergent period is 
defined as the time from first dose of study drug through 30 days after the last dose of relugolix 
or 12 weeks plus 30 days after the last dose of leuprolide acetate.  Safety analyses will be based 
on all randomized patients who receive any amount of study drug (Safety population).  Drug 
exposure will be summarized by descriptive statistics.  Severity of all treatment-emergent 
adverse events will be evaluated by the investigator based on the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred 
term, higher-level term, and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of patients with adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to study drug, and 
severity.  Descriptive rather than inferential statistics will be used.  Laboratory values also will 
be classified by toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory 
shift tables of baseline versus post baseline results will be produced. 
An independent Data and Safety Monitoring Board will monitor all available safety data on a 
periodic basis.  The roles and responsibilities of the Data and Safety Monitoring Board will be 
described in detail in a separate charter. 
 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• 
True probabilities of sustained castration rates are 94% and 96% for relugolix and 
leuprolide acetate, respectively; 
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• 
2:1 randomization ratio (relugolix:leuprolide acetate); 
• 
Dropout rate of 15%. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of ≤ 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and a 2-sided type I error 
rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) will 
yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate. 
The primary analysis of the primary efficacy endpoint will be performed after at least 
915 patients have had the opportunity to complete 48 weeks of study drug treatment.  The 
evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans. 
Up to approximately 1125 men will be randomized in order to fulfill the regulatory 
requirements of all participating countries.  This includes approximately 90 patients from Japan, 
approximately 111 patients in South Korea, and approximately 200 patients from China PR. 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3201 
Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,b,c 
Safety 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
9d 
Wk 
13d 
Wk 17 
and 21d 
Wk 
25d 
Wk 29 
and 33d 
Wk 
37d 
Wk 41 
and 45d 
Wk 
49d,e 
30-Day 60-Day 90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
22 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 
and 
309 
337 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not applicable 
±1 day 
± 7 days 
± 7 days 
Informed 
Consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dispensation: 
Relugolix 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Drug 
Administration: 
Relugolix Once 
Daily 
 
X 
X 
Patients will receive a single loading dose of oral relugolix 360 mg on Day 1 in the clinic; 
Starting on Day 2, patients will receive oral relugolix 120 mg once daily 
 
 
 
Study Drug 
Administration: 
Leuprolide 
Acetate 3-M 
Depot 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including 
detailed prostate 
cancer history) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, BMI 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGg 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,b,c 
Safety 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
9d 
Wk 
13d 
Wk 17 
and 21d 
Wk 
25d 
Wk 29 
and 33d 
Wk 
37d 
Wk 41 
and 45d 
Wk 
49d,e 
30-Day 60-Day 90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
22 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 
and 
309 
337 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not applicable 
±1 day 
± 7 days 
± 7 days 
ECOG 
Performance 
Assessment 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
Complete 
Physical Exam 
and Visual 
Acuityh 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Symptom Based 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Abdominopelvic 
CT or MRI and 
Bone Scani 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EuroQol EQ-
5D-5L Health 
Questionnaire 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
EORTC-QLQ-
PR25 and 
EORTC-QLQ-
C30 Quality of 
Life 
Questionnaires 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Xi 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Chemistry 
X 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Lipid & HbA1ck 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
Testosterone/LH 
X 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
X 
X 
X 
SHBG 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
FSH/DHT 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,b,c 
Safety 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
9d 
Wk 
13d 
Wk 17 
and 21d 
Wk 
25d 
Wk 29 
and 33d 
Wk 
37d 
Wk 41 
and 45d 
Wk 
49d,e 
30-Day 60-Day 90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
22 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 
and 
309 
337 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not applicable 
±1 day 
± 7 days 
± 7 days 
Blood Sample 
for Relugolix 
PKm,n 
 
Xm,n 
Xm,n Xm,n 
 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
 
 
 
Blood Sample 
for DNAo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Status 
Surveyp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Abbreviations:  3-M, 3-month; BMI, body mass index; CT, computed tomography; DHT, dihydrotestosterone; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of 
treatment; EuroQol EQ-5D-5L, European Quality of Life 5-Dimension 5-Level; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; LH, luteinizing 
hormone; MRI, magnetic resonance imaging; PK, pharmacokinetics; PSA, prostate-specific antigen; SHBG, sex hormone binding globulin 
a. 
The study day in which the Follow-up visit occurs is not specified in the table because these visits occur relative to when the patient takes his last dose 
of study drug.  The End of Treatment (EOT) is defined as the last dose of relugolix or 12 weeks after the last leuprolide acetate injection. 
b. May occur earlier for patients who are starting alternative androgen deprivation therapy, or do not complete 12 weeks of study treatment.  Adverse 
events, serious adverse events, and concomitant medications should continue to be collected and recorded through 30 days after the End of Treatment.  
All other study procedures should be completed before the start of alternative androgen deprivation therapy. 
c. 
Patients who have started alternative androgen deprivation therapy will not participate in the 60- and 90-day Follow-up visits.  For the first 100 patients 
receiving relugolix and 50 patients receiving leuprolide acetate who complete 48 weeks of study drug treatment and, in the opinion of the investigator, 
can remain off androgen deprivation therapy for 90 days will be included in the testosterone recovery 60- and 90-day Follow-up visits. 
d. For patients assigned to the relugolix treatment arm, the patient should be called 7 days before their next visit to check on compliance with their study 
medication. 
e. 
If patient terminates early from study treatment, the patient should be asked to come in as soon as possible and complete this visit. 
f. 
The informed consent form must be signed before any study-mandated procedures are performed. 
g. 12-lead ECGs should be read locally by a qualified physician. 
h. A complete physical examination should be performed.  Visual acuity will be evaluated by a standard visual eye chart.  The patient should wear any 
prescribed glasses or contacts during the visual acuity assessment. 
i. 
An abdominopelvic CT or MRI and a bone scan should be performed and read locally to determine the presence of metastatic disease within 60 days 
prior to randomization. 
j. 
Serious adverse events should be collected from the time the patient signs the informed consent form through 30 days after the last dose of relugolix 
treatment or 12 weeks and 30 days after the last injection of leuprolide acetate.  Treatment-emergent adverse events are collected from the time of the 
first dose of study drug through 30 days after the last dose of relugolix treatment or 12 weeks and 30 days after the last injection of leuprolide acetate. 
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k. Blood samples must be obtained fasting; nothing to eat or drink (other than water) overnight and prior to obtaining the sample. 
l. 
All testosterone samples obtained from Week 5 and beyond are to be collected during a ± 7-day window. 
m. Blood samples for PK analysis will be collected for all patients assigned to the relugolix treatment arm.  Samples will be collected predose; patients will 
be required to arrive at the clinic on an empty stomach (after an overnight fast or at least 2 hours after food; food should be withheld for 1 hour after 
dosing).  Patients will be dosed in the clinic at these visits. 
n. A subset of patients from China and Japan will have additional samples collected predose, and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and 
Week 2 visits.  A predose sample also will be collected at the Day 4 visit.  Patients will be required to arrive at the clinic on an empty stomach (after an 
overnight fast or at least 2 hours after food; food should be withheld for 1 hour after dosing).  Patients will be dosed in the clinic at these visits. 
o. The blood sample for DNA should be collected at the Baseline Day 1 visit, but may be collected at any visit if it is missed at that visit. 
p. During the final weeks prior to database lock, sites will be asked to contact all study participants or their immediate family regarding the current health 
status of previously enrolled/completed study patients. 
 
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2. 
INTRODUCTION 
2.1. 
Prostate Cancer 
Prostate cancer is the most prevalent form of cancer in men and the second leading cause of 
death due to cancer in men in the US [Greenlee, 2001] and Europe [Ferlay, 2007].  The median 
age of diagnosis is 70 years, and diagnosis before the age of 40 years is rare [Cersosimo, 1996].  
In Japanese men, prostate cancer was the fourth leading cancer diagnosis in 2007 [Foundation 
for Promotion of Cancer Research, 2012].  The incidence of invasive prostate cancer increases 
with age; a clear increase is seen among men aged 60 years or older [Siegel, 2014]. 
If prostate cancer is diagnosed at a stage where it is confined to the prostate gland and immediate 
surroundings, it is generally treated by surgical removal of the prostate gland, or prostatectomy, 
or with radiation.  Often, these procedures are successful in curing men of their disease.  Men 
whose disease progresses after prostatectomy or radiation are said to have advanced prostate 
cancer.  Advanced prostate cancer is defined as either:  PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; newly diagnosed metastatic prostate 
cancer; or advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  The cure rate following surgery, depending on the stage of the cancer, is about 70% 
overall and, following radiation, about 50% to 60%. 
Approximately 25% to 30% of men will, therefore, progress to advanced disease, excluding 
those with metastatic disease at the time of diagnosis.  Androgens, such as testosterone and its 
more potent metabolite dihydrotestosterone, are strong tumor promoters for prostate cancer 
[Bosland, 2014].  Through the androgen receptor, they synergistically augment the effect of other 
tumor promoters or carcinogens.  Although prostate cancer is driven by presumed mutations in 
other tumor promoting pathways and/or by translocations leading to aberrant activation of the 
androgen receptor pathway, most early-stage prostate cancer cells remain either sensitive to or 
dependent upon circulating androgens.  Thus, for more than 60 years, androgen deprivation 
therapy with surgical or medical castration has been the foundational therapy for either advanced 
inoperable or metastatic cancer.  Increasingly, androgen deprivation therapy is used earlier as a 
neoadjuvant/adjuvant treatment to radiation therapy or for biochemical or clinical relapse after 
local therapies of curative or palliative intent.  More than 80% of men with progressive or 
advanced disease initially respond to androgen deprivation therapy with varying degrees of 
tumor regression or stabilization [Kreis, 1995].  The duration and depth of response to androgen 
deprivation therapy is presumably dependent on the underlying tumor biology and burden.  Thus, 
patients with metastases respond for an average of 2 years before any biochemical evidence of 
castration resistance occurs.  By contrast, patients with biochemical-only evidence of progressive 
disease may respond to androgen deprivation therapy for 5 years or more [Klotz, 2015]. 
Currently, most patients in developed countries receive medical rather than surgical castration.  
GnRH (or LH-releasing hormone) agonists (ie, long-acting leuprolide acetate depot injections) 
are the current mainstay of medical castration, causing long-term desensitization and down 
regulation of the hypothalamic-pituitary gonadal axis.  One disadvantage of the agonist form of 
GnRH is the initial stimulation of the axis lasting 1 to 3 weeks that occurs prior to 
desensitization.  This results in a rise in LH and testosterone levels and an increase in clinical 
symptoms.  In addition, at the time of repeat injection of GnRH agonist depot, microsurges of 
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LH and testosterone may occur, although the apparent incidence is low [Klotz, 2008].  The initial 
flare response may be managed with simultaneous antiandrogen administration, such as with 
bicalutamide. 
Recently, GnRH antagonists, in particular degarelix, [Firmagon, 2016], have become available as 
an alternative form of medical castration.  Degarelix, an injectable peptide, has been approved in 
some countries for the treatment of patients with advanced prostate cancer.  As a GnRH 
antagonist, degarelix achieves medical castration and PSA response with no initial agonist 
activity within the first 1 to 2 weeks of administration, and effectively can obviate the need for 
concomitant antiandrogen treatment.  Post-hoc analyses of degarelix trials [Tombal, 2010] 
suggest that it may have additional advantages regarding disease response or secondary relapse; 
however, such differences require confirmation in prospective studies.  Because of the need for 
monthly depot injections, with large volumes and accompanying local reactions, the use of 
degarelix in clinical practice has remained low. 
Relugolix, previously known as TAK-385, is a potent and highly selective oral small molecule 
antagonist for the human GnRH receptor.  For patients, relugolix may offer the advantages 
conferred by a direct receptor antagonist, including a more rapid onset of action and the absence 
of clinical flare or worsening of symptoms from the initial rise in androgens caused by GnRH 
agonists, as well as having the added convenience and relative comfort of oral dosing. 
2.2. 
Relugolix 
2.2.1. 
Indication 
Relugolix is being developed as a once daily oral medication for the treatment of advanced 
prostate cancer.  The proposed dose of relugolix is 120 mg administered orally once daily 
following a loading dose of 360 mg (three 120-mg tablets) on Day 1. 
2.2.2. 
Pharmacology 
Relugolix is an orally-active, potent, highly-selective, high-affinity small molecule GnRH 
receptor antagonist with a novel structure.  Relugolix was discovered and initially studied by 
Takeda Pharmaceutical Company, Limited, before development rights outside of Japan and 
certain East Asian countries were licensed to Myovant Sciences GmbH. 
Relugolix antagonizes the human GnRH receptors present on the gonadotrophin-secreting cells 
of the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
LH and FSH fall rapidly, followed by a decline over a few days in testosterone in men and 
estradiol and progesterone levels in women.  Relugolix acts as a potent and highly selective 
antagonist for the human GnRH receptor.  The affinity of relugolix for the human GnRH 
receptor in vitro was approximately 50-fold higher than that of GnRH in the presence of protein 
(40% fetal bovine serum).  Transgenic knock-in mice expressing the human GnRH receptor 
treated with relugolix had substantial reductions in reproductive organ weights of both female 
and male mice, suggesting that relugolix may suppress blood estrogen and testosterone levels, 
respectively.  Orally administered relugolix suppressed the hypothalamic-pituitary axis in 
castrated cynomolgus monkeys at doses of 1 mg/kg and higher. 
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2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level for liver findings in the 39-week monkey 
toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (area under the 
concentration-time curve [AUC]) in men receiving 120 mg once daily (0.469 μg⋅hr/mL), the 
dose of relugolix to be administered in this study.  Both the liver and PLD findings demonstrated 
evidence of reversibility following a 13-week recovery period in monkeys.  No evidence of PLD 
has been observed in clinical studies.  The relugolix toxicology program supports the conduct of 
clinical studies up to the NOAEL (15 mg/kg/day) exposure (5.2 μg·hr/mL) for liver toxicity in 
monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human Thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies have been completed.  In 
addition, 6 clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 
2 studies in men with prostate cancer (US and Europe), and 2 phase 3 studies in women with 
uterine fibroids in Japan.  More than 1380 patients and healthy volunteers have received at least 
one dose of relugolix, including 158 women receiving relugolix 40 mg once daily for at least 
28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg once daily for at 
least 24 weeks and for as long as 48 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of testosterone in male subjects and estradiol in female subjects.  After oral 
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administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The PK and pharmacodynamics of relugolix have been evaluated, and 
appear to be similar in Western and Asian volunteers, despite the lower mean body mass index 
observed in Asian volunteers. 
A relative bioavailability and food effect study was conducted using the global phase 3 prostate 
cancer formulation of 120 mg relugolix.  After administration with a high-fat, high-calorie 
breakfast, the Cmax and AUC of relugolix were reduced, on average, by 21.4% and 18.8%, 
respectively. 
In the phase 1 study C27001, serum LH, FSH, dihydrotestosterone, and testosterone 
concentrations were determined in healthy men following single and multiple oral doses of 
relugolix or placebo for up to 28 days.  Loading doses of ≥ 160 mg on Day 1 were used to 
shorten the time to testosterone suppression.  Relugolix caused an immediate and effective 
suppression of LH, FSH, and testosterone.  After 14 days of once daily dosing, mean LH and 
serum testosterone concentration profiles were similar for the 40, 80, and 180 mg relugolix dose 
cohorts.  LH, FSH, and testosterone concentrations began decreasing 2 to 6 hours postdose on 
Day 1 and remained suppressed through Day 14.  However, the relugolix once daily maintenance 
dose was a major determinant of sustained testosterone suppression.  Profound castration 
(defined as average testosterone levels < 20 ng/dL or 0.7 nmol/L) was achieved with 40, 80, or 
180 mg once daily for 14 days; however, 20 mg once daily was insufficient in maintaining 
adequate suppression of serum LH and testosterone concentration levels during the second week. 
In healthy, older men receiving 14 or 28 days of dosing, effective castration was consistently 
achieved over 14 and 28 days dosing at daily doses of 40 to 180 mg (14 days) and 80 to 160 mg 
(28 days).  Use of a loading dose for up to 3 days (or once daily doses of ≥ 160 mg) resulted in 
castration levels of testosterone (< 50 ng/dL or 1.7 nmol/L) within 24 to 48 hours.  Results 
obtained after 28 days of dosing suggested that the likely minimal, fully effective maintenance 
dose for sustained castration would be relugolix ≥ 80 mg once daily.  Doses of 80 mg and 
120 mg were moved forward into phase 2 development. 
Relugolix is to be administered in the fasted state (at least 1 hour before or 2 hours after a meal), 
as food decreases the extent of relugolix absorption by approximately 20%.  The exposure of 
relugolix is increased by inhibitors of P-glycoprotein up to 6-fold, but relugolix does not 
significantly impact the exposure of cytochrome P450 (CYP) 1A2, 2C9, 2D6, or 3A4 substrates.  
In a dedicated study, relugolix did not prolong QTc at single doses of 60 or 360 mg. 
2.2.4.2. 
Clinical Studies in Men with Prostate Cancer 
One phase 1 study and 2 phase 2 studies have been conducted evaluating relugolix in men with 
prostate cancer. 
Study TB-AK160108 is an ongoing multicenter phase 1, open-label, dose range-finding study 
conducted in hormone treatment-naïve Asian patients with non-metastatic prostate cancer.  The 
study consists of a dose-rising phase (Part A) and an expansion phase (Part B).  In Part A, a 
loading dose of relugolix (320 or 360 mg) was administered on Day 1 followed by once daily 
dosing on Days 2 through 28, with the dosage dependent on the individual cohort of 3 to 4 
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patients each.  In Part B, 30 patients receive a maximum of 96 weeks treatment at doses of 
80 and 120 mg once daily (N = 15 each arm, loading dose of 320 mg on Day 1).  Testosterone 
reduction by both doses of relugolix was rapid and sustained through 48 weeks.  Both the 80-
 and 120-mg once daily doses were evaluated in phase 2 clinical studies. 
Study C27003 is a phase 2 study that enrolled men in North America or the United Kingdom 
requiring 6 months of androgen deprivation therapy as neoadjuvant and adjuvant therapy to 
external beam radiation therapy.  Patients were randomized to relugolix 120 mg once daily 
following a single oral loading dose of 320 mg (N = 65) or to degarelix 80 mg subcutaneously 
every 4 weeks following a single loading dose of 240 mg (N = 38) for 24 weeks.  External beam 
radiation therapy was initiated for most patients between Week 13 and Week 15. 
Relugolix 120 mg administered orally once daily rapidly suppressed testosterone levels below 
the castration threshold (50 ng/dL [1.7 nmol/L]) within the first week of therapy and maintained 
those levels from the end of Week 4 through at least 24 weeks.  The levels of testosterone 
suppression achieved by relugolix were similar to those achieved by monthly injections of 
degarelix.  Profound castration rates below the lower testosterone threshold of < 20 ng/dL 
(0.7 nmol/L) were also similar in the relugolix and degarelix groups (Table 2-1). 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks 
 
Relugolix 
120 mg QDa 
N = 65 
Degarelix 
80 mg Q4Wb 
N = 38 
Castration rate over 24 weeks, % 
(95% CI) 
95% 
(87.1, 99.0) 
89% 
(75.2, 97.1) 
Note:  Castration rate is defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5, Day 1 to specific time point (Week 25, Day 1). 
Abbreviations:  CI, confidence interval; Q4W, once every 4 weeks; QD, once daily 
a. 
Loading dose of 320 mg on Day 1 
b. Loading dose of 240 mg on Day 1, then dosed every month 
 
The percentage PSA reductions and absolute PSA values over time were consistent with the 
rapid testosterone reductions observed with both therapies and were similar between the 
relugolix and degarelix treatment arms.  Prostate gland size was measured during screening and 
following 8 to12 weeks of study drug treatment.  In both treatment groups, the average reduction 
in estimated prostate volumes was similar, approximately 30%.  Following discontinuation of 
therapy at the end of 24 weeks, patients were followed for an additional 12 weeks to evaluate 
testosterone recovery and associated changes in PSA and quality of life.  At the end of the 
follow-up period, approximately half of the patients receiving relugolix had recovered either to 
the baseline testosterone value or to > 280 ng/dL, whichever was less, compared to only 6% of 
patients receiving degarelix (Figure 2-1). 
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Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of 
Relugolix and Degarelix at Week 25 
 
Note:  Y-axis shows testosterone value (ng/dL); x-axis shows study week. 
 
Study C27002 is a phase 2 study of relugolix and leuprolide acetate in patients with prostate 
cancer who require first-line androgen deprivation therapy, which is ongoing in North America.  
This study was designed to help plan the population, dosing, and assessment schedules for 
phase 3 studies in patients with advanced prostate cancer.  Eligible patients in C27002 have 
evidence of advanced prostate cancer including either:  1) PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; 2) newly diagnosed metastatic prostate 
cancer; or 3) advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  In this open-label, parallel group study, patients were randomized to receive 1 of 
2 dose levels of oral relugolix (80 or 120 mg [patients randomized to relugolix received a loading 
dose of 320 mg on Day 1], N = 50 per group) or to an observation cohort to receive standard 
GnRH therapy with leuprolide acetate 22.5 mg administered by intramuscular injection every 
12 weeks (N = 25).  Relugolix or leuprolide acetate was administered for up to 48 weeks with 
patients randomized to leuprolide acetate receiving their last on-study 12-week depot injection at 
Week 37. 
The primary objective of this phase 2 study was to evaluate the ability of relugolix to achieve 
and maintain testosterone suppression (< 50 ng/dL [1.7 nmol/L]) through Week 25.  Results 
from the completed study C27002 demonstrate that both doses of relugolix, 80 mg and 120 mg 
once daily, rapidly reduced testosterone levels below the castration threshold within the first 
week of therapy and maintained those levels in 91% of patients through 24 weeks of treatment 
(Table 2-2). 
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Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) 
 
Relugolix 
Leuprolide 
Acetate 
22.5 mg Q12W 
N = 24 
 
80 mg QD 
N = 56 
120 mg QD 
N = 54 
Total 
N = 110 
Patients with at least 1 dose of 
treatment, n 
56 
54 
110 
24 
Castration ratea over 24 weeks 
 
 
 
 
n (%) 
51 (91) 
49 (91) 
100 (91) 
23 (96) 
95% CIb 
80.4-97.0 
79.7-96.9 
83.9-95.6 
78.9-99.9 
Profound castration ratec over 24 weeks 
 
 
 
 
n (%) 
39 (70) 
41 (76) 
80 (73) 
18 (75) 
95% CIb 
55.9-81.2 
62.4-86.5 
63.4-80.8 
53.3-90.2 
Abbreviations:  CI, confidence interval; Q12W, once every 12 weeks; QD, daily 
a. 
Castration rate was defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5 Day 1 to specific time point. 
b. The 2-sided 95% CI was calculated using the normal approximation method, if the number of non-castration 
patients was = 5 in any treatment arm, the exact CI was presented. 
c. 
Profound castration rate was defined as the estimated proportion of patients who had testosterone concentrations 
< 20 ng/dL at all scheduled visits Week 13 Day 1 through specific time point. 
 
Castration to below the lower testosterone threshold of < 20 ng/dL was also similar in the 
2 relugolix arms and to that observed in the leuprolide acetate arm.  On average, in patients 
receiving relugolix, testosterone decreased to below the castration threshold of 50 ng/dL 
(1.7 nmol/L) by the Day 4 visit, and to below the profound castration threshold of 20 ng/dL 
(0.7 nmol/L) by the Week 5 visit.  In contrast, in patients receiving leuprolide acetate, 
testosterone levels rose during the first 1 to 2 weeks of therapy and then declined to castrate 
levels by Week 5.  PSA responses between the 2 relugolix arms and leuprolide acetate were 
similar as demonstrated by PSA waterfall plots showing the reduction in PSA from baseline for 
individual patients (Figure 2-2 [relugolix] and Figure 2-3 [leuprolide acetate]). 
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Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent 
Reduction by Dose of Relugolix at Week 25 Day 1 
 
 
Note:  Last observation carried forward method was used to impute percent prostate-specific antigen reductions for 
patients without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen; QD, once 
daily; TAK-385, relugolix 
 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent 
Reduction by Leuprolide Acetate at Week 25 Day 1 
 
Notes: 
The leuprolide acetate dose was 22.5 mg every 12 weeks. 
Last observation carried forward method was used to impute percent prostate-specific antigen reductions for patients 
without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen 
 
A more detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Visit
Obs on Week 25 Day 1
LOCF by Week 25 Day 1
PSA Percent Reduction
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Investigator Brochure, Version 9.0, dated 09 November 2016, along with a full discussion of the 
safety profile of relugolix. 
2.2.4.3. 
Clinical Safety of Relugolix in Men with Prostate Cancer 
A full description of the safety data for relugolix from clinical trials is available in the 
Investigator Brochure.  Overall, approximately 632 healthy volunteers (330 women, 302 men), 
535 female patients with uterine fibroids (N = 229) or endometriosis (N = 306), and 218 male 
patients with prostate cancer received at least 1 dose of relugolix.  Data from the 175 patients 
with prostate cancer who received relugolix in randomized, open-label, parallel-group phase 2 
studies, C27002 and C27003, provide the basis for the frequency of expected adverse events 
associated with relugolix in the prostate cancer indication.  The adverse drug reactions in the 
prostate cancer indication observed in the phase 2 studies include hot flush (59%), fatigue (26%), 
arthralgia (10%), nausea (5%), and gynecomastia (3%).  No clinical evidence of PLD has 
observed in any relugolix clinical study. 
Leuprolide Acetate Depot 3-M 
Leuprolide acetate depot is indicated for the palliative treatment of advanced prostatic cancer. 
Leuprolide acetate acts as an agonist at pituitary GnRH (gonadotropin-releasing hormone) 
receptors.  Leuprolide acetate has greater receptor affinity, reduced susceptibility to enzymatic 
degradation, and is approximately 100-fold more potent than the natural GnRH molecule.  GnRH 
agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial 
release of both LH and FSH, which causes a subsequent increase in testosterone production from 
testicular Leydig cells.  Initially, leuprolide acetate stimulates LH production, which in turn 
causes a surge of testosterone and dihydrotestosterone for 5 to 12 days before the ultimate 
inhibition of LH.  This androgen surge of male hormones can cause a flare reaction (“clinical 
flare”), which may lead to an increase in bone pain, bladder obstruction, or other symptoms due 
to prostate cancer [Tolis, 1982; Schally, 1980; Waxman, 1985; Conn, 1991; Limonata, 2001]. 
Chronic stimulation by the GnRH agonist ultimately desensitizes the GnRH receptors, 
downregulating the secretion of gonadotropins, LH, and FSH, leading to hypogonadism and thus 
a dramatic reduction in testosterone and dihydrotestosterone, on which continued growth of 
prostate cancer cells depends.  The fall in serum LH leads to a decrease in serum testosterone to 
castrate levels within 3 to 4 weeks after the start of treatment.  Continued treatment maintains 
serum testosterone at castrate levels. 
The decrease in testosterone production is generally reversible over time upon cessation of 
GnRH agonist therapy.  However, testosterone production does not always return to baseline 
levels and may be related to the duration of GnRH agonist therapy, patient age, and other factors. 
The flare phenomenon can be effectively prevented with antiandrogen therapy, which blocks the 
effect of the increased serum testosterone [Loblaw, 2004].  First generation antiandrogens such 
as flutamide, bicalutamide, and nilutamide bind to androgen receptors and competitively inhibit 
their interaction with testosterone and dihydrotestosterone.  They are often used in an attempt to 
limit the clinical sequelae produced by the hormonal surge resulting from GnRH agonist 
treatment. 
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The most common adverse reactions (> 10%) reported for marketed formulations of leuprolide 
acetate depot in common use include the following examples: 
• Leuprolide (leuprorelin) acetate 11.25 mg:  weight fluctuation, hot flash, hyperhidrosis, 
muscle weakness, bone pain, decreased libido, erectile dysfunction, testicular atrophy, 
fatigue, injection site reaction [Prostap 3 DCS, 2016] 
• Leuprolide acetate 22.5 mg:  general pain, injection site reaction, hot flashes/sweats, 
gastrointestinal disorders, joint disorders, testicular atrophy, urinary disorders [Lupron 
Depot, 2016] 
In post marketing experience, mood swings, depression, rare reports of suicidal ideation and 
attempt, rare reports of pituitary apoplexy, and rare reports of serious drug induced liver injury 
have been reported.  A risk of developing or worsening diabetes has been reported in men 
receiving this class of drug. 
The package insert (approved labeling) for the leuprolide acetate study drug provided for this 
study should be referenced for warnings, precautions, and safety information. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
This phase 3 trial has 2 separate evaluation criteria for the primary efficacy endpoint to support 
different regulatory requirements for assessing benefit as listed briefly below and described in 
detail in the statistical analysis plan.  Patients enrolled into this phase 3 trial will be randomized 
2:1 to either relugolix 120 mg once daily following an oral loading dose of 320 mg on Day 1, or 
to leuprolide acetate 22.5 mg (or 11.25 mg in some Asian countries) 3-M depot injection.  
Patients randomized to leuprolide acetate will also receive an antiandrogen if indicated at the 
discretion of the investigator. 
The first criterion for the primary efficacy endpoint will evaluate only patients randomized to 
relugolix.  The second criterion for the primary efficacy endpoint will evaluate the non-
inferiority of patients randomized to relugolix to those randomized to leuprolide acetate as 
described below. 
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Objectives 
Endpoints 
Primary 
• 
To evaluate the ability of relugolix to achieve 
and maintain serum testosterone suppressed to 
castrate levels of ≤ 50 ng/dL (1.7 nmol/L) in 
patients with androgen-sensitive advanced 
prostate cancer. 
The primary endpoint is the sustained castration 
rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
• 
Evaluation Criterion 1:  to determine whether 
the sustained castration rate (defined as the 
cumulative probability of testosterone 
suppression to ≤ 50 ng/dL [1.7 nmol/L] while 
on study treatment from Week 5 Day 1 
through Week 49 Day 7) for relugolix is 
greater than or equal to 90%.  The lower 
bound of the 95% confidence interval for the 
cumulative probability of sustained 
testosterone suppression in the relugolix 
treatment group will be calculated and must be 
at least 90% to meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-
inferiority of relugolix compared to leuprolide 
acetate 3-M depot injection as assessed by the 
cumulative probability of sustained 
testosterone suppression.  The lower bound of 
the 95% confidence interval for the difference 
in the cumulative probability of sustained 
testosterone suppression between the 
2 treatment groups will be calculated and must 
be greater than or equal to the non-inferiority 
margin of -10% to meet this criterion. 
Secondary 
• 
To evaluate the time course and change in 
serum testosterone during treatment with 
relugolix; 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative 
probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing 
on Week 1 Day 4, prior to dosing on 
Week 2, and prior to dosing on Week 3; 
o Profound castration rate defined as the 
cumulative probability of testosterone 
suppression to ≤ 20 ng/dL (0.7 nmol/L) 
while on treatment from Week 25 Day 1 
through Week 49 Day 1); 
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Objectives 
Endpoints 
• 
To evaluate the time course and magnitude of 
PSA reduction during treatment with 
relugolix; 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed 
PSA response (by Prostate Cancer 
Clinical Trials Working Group 3 
[Scher, 2016]) at the Week 2 and 5 visits; 
o Proportion of patients with PSA 
concentration < 0.2 ng/mL [0.2 µg/L] at 
the Week 25 visit; 
• 
To evaluate testosterone recovery following 
discontinuation of relugolix; 
• 
Time to testosterone recovery in the first 
100 patients randomized to relugolix and the 
first 50 patients randomized to leuprolide 
acetate who complete  48 weeks of treatment 
and who do not plan to start alternative 
androgen deprivation therapy within the 
following 12 weeks (or within 24 weeks 
following the last injection of leuprolide 
acetate 3-M depot); 
• 
To evaluate quality of life using validated 
patient-reported outcome instruments; 
• 
Absolute values and changes from baseline in 
the scores of the EORTC-QLQ-C30 global 
health domain, and the EORTC-QLQ-PR25 
sexual activity and hormonal-treatment-related 
symptom subdomains, at regular intervals 
during treatment, and as applicable during the 
Follow-up and/or End of Treatment visits; 
• 
Absolute values and changes from baseline of 
the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular 
intervals during treatment, and as applicable 
during the Follow-up visits; 
• 
To evaluate the safety of relugolix 120 mg 
once daily in men with androgen-sensitive 
advanced prostate cancer; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical 
laboratory data; 
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Objectives 
Endpoints 
• 
To evaluate the effect of relugolix and 
leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
Endocrine marker effects of relugolix and 
leuprolide acetate as measured as absolute 
value and change from baseline for: 
o LH at the Week 2, Week 3, and Week 5 
visits, and then every 4 weeks until the 
last follow-up visit; 
o FSH at the Week 5, Week 13, Week 25, 
Week 37, and Week 49 visits; 
o Dihydrotestosterone at the Week 5, 
Week 13, Week 25, Week 37, and 
Week 49 visits; 
o Sex hormone binding globulin at the 
Week 13, Week 25, and Week 49 visits; 
• 
To collect relugolix plasma concentration data 
to further evaluate relugolix population PK 
and the relationship between relugolix 
exposure and serum testosterone; and 
• 
Predose relugolix plasma concentrations; 
• 
To characterize the relugolix plasma PK 
parameters in a subset of patients from China 
and Japan. 
• 
Single and repeat-dose plasma relugolix PK 
parameters such as Cmax, AUC0-τ, and tmax in a 
subset of patients from China and Japan. 
Exploratory 
• 
To explore the overall survival of patients 
treated with relugolix; and 
• 
Overall survival defined as time from 
randomization to date of death prior to data 
cutoff date; 
• 
To explore the contribution of genetic 
variance on drug response. 
• 
The presence of polymorphisms in germline 
genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter 
proteins that might be implicated in the drug 
disposition, safety, or efficacy of relugolix. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension 
22.5 mg (or 11.25 mg in some Asian countries) every 3-months (3-M) by subcutaneous or 
intramuscular injection will be administered to patients with prostate cancer who require 
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androgen deprivation therapy.  This study will evaluate the ability of relugolix to achieve and 
maintain serum testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 
48 weeks in patients with androgen-sensitive advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local primary 
intervention with curative intent, newly diagnosed metastatic disease (excluding metastases to 
the brain), and/or advanced localized disease.  Patients may receive radiotherapy, cryotherapy or 
high frequency ultrasound no sooner than 2 months after initiation of androgen deprivation 
therapy.  Patients may be included if they have not previously received androgen deprivation 
therapy for more than 12 months, and if the androgen deprivation therapy was completed at least 
12 months prior to baseline.  Patients previously treated with taxanes or expected to receive 
taxanes after initiation of androgen deprivation therapy are excluded, as are patients receiving 
androgen deprivation therapy adjuvant or neoadjuvant to radiotherapy as primary definitive 
therapy.  Baseline serum testosterone must be ≥ 150 ng/dL (5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once daily 
following a loading dose of 360 mg on Day 1 or leuprolide acetate 22.5 mg (or 11.25 mg in some 
Asian countries) 3-M depot subcutaneous or intramuscular injection, respectively, plus an 
antiandrogen for the first 4 weeks or longer if indicated in the opinion of the investigator.  
Randomization will be stratified by geographic region, presence of metastatic disease, and age. 
Approximately 1125 patients will be enrolled in this study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-reported 
outcomes (EORTC-QLQ-C30, EORTC-QLQ-PR25, EuroQol EQ-5D-5L) will be assessed 
approximately every 3 months during the Treatment Period and more frequently during the 
Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China and 
Japan.  Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, 12-lead ECG, and visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive additional oral therapy, systemic antineoplastic, and/or radiotherapy as 
prescribed by the investigator. 
A schematic of the overall study design is provided in Figure 4-1. 
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Figure 4-1 Schematic of Study Design 
 
 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is designed to establish the safety and efficacy of relugolix 120 mg orally 
once daily in men with advanced prostate cancer who require at least 1 year of continuous 
androgen deprivation therapy for androgen-sensitive disease.  This study will focus on the 
primary objective of evaluating the ability of relugolix to achieve and maintain suppression of 
serum testosterone to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) in patients with advanced prostate 
cancer.  During the Treatment Period of the study (Day 1 to Week 49 [Study Day 337]), patients 
will be randomized to one of the study treatment arms:  oral loading dose of relugolix (360 mg) 
followed by 120 mg once daily of relugolix or leuprolide acetate 3-M depot injection of 22.5 mg 
(or 11.25 mg in some Asian countries) at 12-week intervals for 48 weeks.  Patients treated with 
leuprolide acetate will also receive an antiandrogen for 4 weeks or longer if indicated in the 
opinion of the investigator. 
The study is designed to allow for global approvals, however, different regulatory agencies 
require different criteria for the demonstration of efficacy.  The United States (US) Food and 
Drug Administration (FDA) requires, for approval, a primary efficacy criterion to determine 
whether the sustained castration rate (defined as the cumulative probability of testosterone 
≤ 50 ng/dL [1.7 nmol/L] while on relugolix study treatment from Week 5 Day 1 through Week 
49 Day 1) is greater than or equal to 90%.  The lower bound of the 95% confidence interval for 
the cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion.  The 
study includes a leuprolide acetate arm to meet the regulatory requirement of other regions to 
establish the non-inferiority of relugolix compared to leuprolide acetate 3-M depot injection as 
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assessed by the cumulative probability of sustained testosterone suppression.  The lower bound 
of the 95% confidence interval for the difference in the cumulative probability of sustained 
testosterone suppression between the 2 treatment groups will be calculated and must be greater 
than or equal to the non-inferiority margin of -10% to meet this criterion. 
The dose of relugolix selected is based on data from phase 1 and 2 studies demonstrating that 
oral doses of 80 mg and 120 mg once daily following an oral loading dose of 320 mg were able 
to suppress testosterone to castrate levels (see Section 2.2.4.2 and the Investigator Brochure).  A 
loading dose of 360 mg (three 120-mg tablets) was selected for phase 3 so that only one tablet 
size was required.  Leuprolide acetate 3-M depot injection was selected as the comparator as this 
is the GnRH agonist used most commonly as standard of care in the population under evaluation.  
Degarelix, an injectable GnRH antagonist, was considered, but was not used as it has limited 
market uptake attributed at least in part to a significant number of injection site reactions. 
4.3. 
Selection of Study Population 
Approximately 1125 men with advanced prostate cancer requiring androgen deprivation therapy 
will be enrolled in this study from approximately 200 study centers in North and South America, 
Europe, and the Asia-Pacific region.  Enrollment is defined as the time at which a patient is 
randomized to a treatment group and receives at least one dose of study drug. 
Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor prior 
to randomizing the patient. 
4.3.1. 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following inclusion criteria 
are met prior to randomization, unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
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4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer with 
one of the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention 
with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency 
ultrasound and not a candidate for salvage treatment by surgery (radiotherapy, 
cryotherapy, or high frequency ultrasound are allowed after 2 months of androgen 
deprivation therapy); or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease not suitable for local primary surgical intervention with 
curative intent (radiotherapy, cryotherapy, or high frequency ultrasound are allowed after 
2 months of androgen deprivation therapy); 
5. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (5.2 nmol/L); 
6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 µg/L), or, when 
applicable, post radical prostatectomy of > 0.2 ng/mL (0.2 µg/L) or post radiotherapy, 
cryotherapy, or high frequency ultrasound > 2.0 ng/mL (2.0 µg/L) above the post 
interventional nadir; 
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial 
screening and at baseline (refer to Appendix 1); 
8. Is a male patient who, even if surgically sterilized (ie, status post vasectomy): 
a. Agrees to use a male condom if having sex with a woman of childbearing age or a 
pregnant woman, during the entire study Treatment Period and through 4 months after the 
last dose of study drug; or 
b. Agrees to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner) and withdrawal are not acceptable methods 
of contraception; 
9. Must agree not to donate sperm from first dose of study drug through 4 months after the last 
dose of study drug; 
10. A randomization authorization form has been signed by a study medical monitor approving 
the patient for randomization into the trial. 
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4.3.2. 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. In the investigator’s opinion, is likely to require chemotherapy or surgical therapy for 
symptomatic disease management within 2 months of initiating androgen deprivation 
therapy; 
2. Previously received GnRH analog or other form of androgen deprivation therapy (estrogen or 
antiandrogen) for > 12 months total duration.  If androgen deprivation therapy was received 
for ≤ 12 months total duration, then that therapy must have been completed at least 
12 months prior to baseline; 
3. Previous treatment for prostate cancer with a taxane-based regimen; 
4. Metastases to brain per prior clinical evaluation; 
5. Features of the patient’s medical condition that make life expectancy due to other medical 
conditions of less than 5 years; 
6. Scheduled for major surgery after baseline; 
7. History of surgical castration; 
8. Diagnosis of or treatment for another malignancy within the 2 years before baseline, or 
presence of another malignancy with evidence of residual disease.  Patients with non-
melanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.  Patients with Stage 0 or Stage 1 melanoma or superficial 
Stage 0 or Stage 1 bladder cancer, if curatively managed prior to screening, are not excluded.  
The medical monitor should be contacted for any questions regarding this exclusion criterion; 
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable 
underlying disease, or the following laboratory values: 
a. Serum gamma-glutamyl transferase > 2.0 x ULN; 
b. Serum ALT and/or AST > 1.0 x ULN; 
c. Total bilirubin > 1.0 x ULN (unless secondary to Gilbert’s syndrome or the pattern is 
consistent with a diagnosis of Gilbert’s syndrome) or; 
d. Serum creatinine > 2.0 mg/dL; 
10. Uncontrolled diabetes with HbA1c > 10% or previously undiagnosed diabetes mellitus with 
screening HbA1c > 8% (such excluded patients may be rescreened after referral and evidence 
of improved control of their condition); 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(hepatitis A virus IgM positive), hepatitis B (HBsAg positive), or hepatitis C (HCV antibody 
positive, confirmed by HCV ribonucleic acid); 
12. Known human immunodeficiency virus infection; 
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13. Within 6 months before baseline, a history of myocardial infarction, angina, unstable 
symptomatic ischemic heart disease, or congestive heart failure, or any history of clinically 
significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or 
torsades de pointes, or history of Mobitz II second degree or third degree heart block without 
permanent pacemaker in place or untreated supraventricular tachycardia (heart rate ≥ 120 
beats per minute); thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, 
or symptomatic cerebrovascular events); or any other significant cardiac condition (eg, 
pericardial effusion, restrictive cardiomyopathy).  Patients with chronic stable atrial 
fibrillation on stable anticoagulant therapy or patients with stable cardiac rhythm controlled 
by a pacemaker are allowed; 
14. The following ECG abnormalities are excluded: 
a. Q-wave infarction, unless identified 6 or more months before the Screening visit; 
b. QTc > 470 msec.  If the QTc is prolonged in a patient with a pacemaker, the patient may 
be enrolled in the study upon discussion with the medical monitor; or 
c. Congenital long QT syndrome; 
15. Uncontrolled hypertension despite appropriate medical therapy (sitting blood pressure of 
greater than 160 mmHg systolic and/or 100 mmHg diastolic at 2 separate measurements no 
more than 45 minutes apart during the Screening visit).  Patients may be re-screened after 
referral and further management of hypertension; 
16. Hypotension, as indicated by systolic blood pressure < 84 mmHg on 2 repeat measures at 
least 15 minutes apart, or treated ongoing symptomatic orthostatic hypotension with 
> 20 mmHg decrease in systolic blood pressure one minute or more after assuming upright 
position; 
17. Bradycardia as indicated by a heart rate of < 45 beats per minute on the ECG at the Screening 
or Baseline Day 1 visit; 
18. Treatment for prostate cancer with any investigational products within 12 months before the 
first dose of study drug (approved products under investigation for an alternative condition, 
not directly related to therapy for prostate cancer, may be allowed); 
19. Treatment with an investigational product for indications other than prostate cancer within 
3 months; 
20. Previous treatment with relugolix in a clinical study; 
21. Patient is a study site employee or is a primary family member (spouse, parent, child, or 
sibling) of a site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets; 
23. Use of any medication listed in the prohibited medications table (see Section 5.10.1) without 
the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
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25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form); 
26. Any serious medical condition that limits life expectancy to less than 5 years, or any other 
medical or psychiatric condition that, in opinion of investigator, would interfere with 
completion of treatment according to this protocol. 
4.4. 
Other Eligibility Criteria Considerations 
Patient eligibility may require additional or repeat assessments such as safety labs, vital signs, or 
ECG during the Screening Period. 
To assess any potential impact on patient eligibility with regard to safety, the investigator is 
referred to the Investigator Brochure for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the investigational 
product(s) used in this study. 
4.5. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the Screening Period.  Study site personnel will access the interactive voice/web 
recognition system (IWRS) to assign a screening identification number to a potential patient. 
For patients who provide informed consent and subsequently do not meet eligibility criteria, or 
withdraw consent are considered screen failures and are not randomized.  Study site personnel 
should ensure that the source record includes documentation for the screen failure (eg, medical 
history, eligibility criteria, procedures performed). 
Patient numbers assigned to patients who become screen failures are not to be reused.  Patient 
identification numbers will be assigned to eligible patients at randomization, as described in 
Section 4.6. 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number 
After a patient is screened and the investigator determines that the patient is eligible for 
enrollment, the site staff will complete the Randomization Authorization Form and send it to the 
sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the Study 
Reference Manual.  The sponsor (or designee) will approve the patient’s enrollment in writing.  
Once the site has received approval, the patient may undergo the Baseline Day 1 visit.  The site 
will randomize the patient to treatment by using the IWRS during the patient’s Baseline Day 1 
visit.  The IWRS will assign the patient identification (ID) number.  This number will identify 
the patient for the duration of the study.  A study treatment kit number will be available at the 
site according to the randomization code. 
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4.7. 
Removal of Patients from Therapy 
Patients may withdraw consent to participate in the study and discontinue treatment at any time 
for any reason.  Investigators or the medical monitor may remove patients from therapy under 
this protocol for reasons of safety and/or lack of compliance as discussed below.  Patients 
removed from therapy for any reason will undergo the assessments for the Week 49 visit on the 
Schedule of Activities.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
Follow-up visits to assess safety will be performed in all study patients.  If the patient plans to 
start alternative androgen deprivation therapy less than 30 days after the End of Treatment visit, 
the Safety Follow-up visit may occur earlier, before the start of the alternative androgen 
deprivation therapy.  Testosterone recovery will be evaluated in the first 100 patients randomized 
to relugolix and 50 patients to leuprolide acetate who complete 48 weeks of study drug treatment 
and, in the opinion of the investigator, are candidates for intermittent androgen deprivation 
therapy and will not be offered alternative androgen deprivation therapy upon completion of 
study therapy.  These patients will return for the 60- and 90-day follow-up Testosterone 
Recovery visits. 
The safety and/or compliance events shown in Table 4-1 will result in the removal of patients 
from therapy either permanently or until the etiology of the problem has been identified and 
resolved. 
Table 4-1 
Removal of Patients from Treatment 
Reason 
Comment 
Adverse event or intercurrent illness 
Any intolerable adverse event to the patient that cannot be 
ameliorated by the use of adequate medical intervention, or that 
in the opinion of the investigator or medical monitor would lead 
to undue risk to the patient if dosing continued 
Failed to meet eligibility criteria 
post randomization 
If it is discovered after randomization that a patient failed to 
meet protocol entry criteria and continued participation poses 
an unacceptable risk to the patient’s health 
Dose hold 
Relugolix dose hold that exceeds 10 consecutive days 
Patient not meeting criteria for 
testosterone suppression to castrate 
level 
Patients with disease progression while on study drug, assuming 
adequate testosterone suppression (testosterone level 
≤ 50 ng/dL [1.7 nmol/L]), may receive additional systemic 
antineoplastic therapy and may stay on study. 
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Reason 
Comment 
Laboratory abnormality defined by 
protocol: 
ALT or AST > 8 x ULN; or 
ALT or AST > 5 x ULN and persists 
for more than 2 weeks; or 
ALT or AST > 3 x ULN in 
conjunction with elevated total 
bilirubin > 2 x ULN or INR > 1.5; or 
ALT or AST > 3 x ULN with 
appearance of fatigue, nausea, 
vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or 
eosinophilia (> 5%) 
If any of these liver test abnormalities develop, study drug 
should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a patient’s 
laboratory profile has returned to normal/baseline status). 
Confirmed QTc prolongation of 
more than 500 msec, in the absence 
of a pacemaker, as read by a 
cardiologist 
If QTc prolongation of > 500 msec in the absence of a 
pacemaker occurs, the ECG must be repeated.  Confirmed QTc 
prolongation will result in removal of the patient from 
treatment. 
Patients who have a clinically 
significant decrease in visual acuity 
as evaluated by an ophthalmologist 
that may be related to study drug 
treatment 
 
Gross noncompliance with protocol 
Patients who are, in the opinion of the investigator or the 
medical monitor, non-compliant with the protocol’s 
requirements 
Patient decision 
Patients may permanently discontinue study treatment at any 
time for any reason.  Following study drug discontinuation, 
patients should attend the protocol-required safety follow-up 
visit. 
Sponsor discontinuation of study 
The sponsor reserves the right to terminate the study anytime as 
described in Section 10.3.3.  The sponsor will terminate this 
study following completion of study objectives, or earlier if 
deemed necessary. 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; INR, 
international normalized ratio; QTc, QT interval corrected for heart rate; ULN, upper limit of normal 
 
Once study drug has been discontinued, all study procedures outlined for the Week 49 visit will 
be completed as specified in the Schedule of Activities (Section 1.1).  The primary reason for 
study drug discontinuation will be recorded on the eCRF. 
Patients who withdraw from treatment will not be replaced. 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
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possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  Patients randomized to relugolix should be counseled to notify the 
investigator in the event of intercurrent illness to determine if the study drug treatment can be 
continued.  Every effort should be made to ensure the patient’s compliance with study drug 
treatment, including calling patients to reschedule missed visits. 
In cases where the patient does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the patient.  
The site should attempt at least 3 documented telephone calls and, if necessary, a certified letter 
to the patient’s last known mailing address so that they can appropriately be withdrawn from the 
study with a primary reason of “Lost to Follow-up.” 
4.8. 
Contraception/Pregnancy Avoidance 
It is not known what effects relugolix has on human pregnancy or development of the embryo or 
fetus.  Therefore, male patients should avoid impregnating a female partner. 
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 4 months after the last dose of study drug. 
Nonsterilized male patients should use a male condom, either alone or in addition to effective 
methods of contraception used by a female partner of childbearing potential, through defined 
periods during and after study treatment as specified below.  Examples of effective contraceptive 
methods include condoms, hormonal contraceptives, and intrauterine devices. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following: 
• Use a male condom if having sex with a woman of childbearing age or a pregnant 
woman, during the entire study Treatment Period and through 4 months after the last dose 
of study drug; or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods for the female partner, and withdrawal are not acceptable methods 
of contraception. 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg following 
a loading dose of 360 mg on Day 1, or leuprolide acetate 22.5 mg (or 11.25 mg in some Asian 
countries) 3-M depot injection (plus antiandrogen for the first 4 weeks or longer if indicated in 
the opinion of the investigator).  Randomization will be stratified by geographic region, presence 
of metastatic disease, and age. 
Approximately 1125 patients will be enrolled in the study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region. 
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Study treatment is defined as either oral relugolix or leuprolide acetate injection (see Table 5-1). 
Table 5-1 
Description of MVT-601-3201 Study Drugs 
 
Study Treatment 
Product name: 
Relugolix 
Leuprolide Acetate 3-M Depot 
Formulation description: 
Round film coated pink tablet 
 
Dosage form: 
Tablet 
 
Unit dose strength and dosage 
level: 
120 mg, following a single-
loading dose of 360 mg 
22.5 mg (11.25 mg in some 
Asian countries) 
Route of Administration / 
Duration 
Oral / 48 weeksa 
Subcutaneous or intramuscular / 
48 weeksa 
a. 
Duration of treatment is 48 weeks during the Treatment Period; the last leuprolide acetate injection occurs 
12 weeks before the end of the Treatment Period. 
 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-
methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using the US 
Pharmacopeia and the National Formulary excipients. 
5.3. 
Randomization and Stratification 
Patients are assigned to one of 2 treatment arms in accordance with the randomization schedule 
using an integrated randomization system (IWRS). 
At Baseline Day 1, patients will be randomized in a 2:1 ratio to one of the following treatment 
arms: 
Treatment Arm 
Randomized Treatment 
Approximate 
Number of Patients 
Arm A 
Relugolix 360 mg (three 120 mg tablets) single oral 
loading dose on Day 1 followed by 120 mg orally once 
daily 
744 
Arm B 
Leuprolide acetate, 22.5 mg 3-M depota injection 
(or 11.25 mg in some Asian countries) 
371 
a. 
Antiandrogen is administered for the first 4 weeks or longer if indicated, in the opinion of the investigator. 
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Randomization will be stratified by geographic region, presence of metastatic disease, and age 
age as follows: 
• Geographic Region 
o Europe; 
o North and South America; or 
o Asia and Rest of World. 
• Presence of Metastatic Disease 
o Metastatic disease diagnosed on locally-read imaging by abdominopelvic 
computed tomography (CT) or magnetic resonance imaging (MRI) or bone scan 
at the time of the Baseline Day 1 visit; or 
o No evidence of metastatic disease by locally-read imaging. 
• Baseline Age 
o ≤ 75 years old; or 
o > 75 years old. 
5.4. 
Directions for Administration 
Relugolix 
Relugolix 120-mg tablet strength will be available as immediate-release film-coated tablets.  
These tablets will be presented in 45-tablet bottle packaging and dispensed to patients every 
4 weeks at scheduled study visits. 
All protocol-specific criteria for administration of study drug must be met and documented prior 
to study drug administration.  Study drug will be dispensed by study personnel only to eligible 
patients who are under the supervision of the investigator or identified subinvestigator(s).  If a 
blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence, followed by the blood draw, and then the meal. 
At the Baseline Day 1 visit, the site will administer a single loading dose of oral relugolix 
360 mg (3 tablets). 
Patients randomized to relugolix will be instructed to take one tablet on an empty stomach at 
least 1 hour before breakfast once daily.  If the dose is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
Patients may consume water ad libitum.  Patients should swallow the study medication whole 
and not chew it or manipulate it in any way before swallowing. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
Leuprolide Acetate 
Leuprolide acetate 3-M depot injection, 22.5 mg (or 11.25 in some Asian countries), will be 
administered every 12 weeks.  Leuprolide acetate 3-M depot will be administered on Day 1 at 
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the clinic, then at 12-week intervals (see Schedule of Activities, Section 1.1) and investigators 
should follow product instructions provided by the manufacturer.  An antiandrogen may be 
administered for the first 4 weeks or longer if indicated, as determined by the investigator, and/or 
as indicated by disease status (eg, in patients with extensive localized symptomatic disease or 
with metastatic disease). 
Possible antiandrogen options include, but are not limited to, bicalutamide, flutamide, and 
nilutamide. 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that is related to study drug and cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted if the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing until the toxicity improves to a 
grade 2 or lower severity.  Study drug can be held for a period of up to 10 consecutive days for 
evaluation and treatment of an adverse event.  Patients may subsequently be re-started on study 
drug, with the written approval of the sponsor (or designee). 
5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption 
Neither dose escalations nor dose reductions are allowed in the study. 
Every effort should be made to continue relugolix administration through treatment-emergent 
adverse events unless they are grade 3 or 4 and related to study drug, or the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing.  Of note, patients on leuprolide 
acetate 3-M depot injection continue to receive GnRH agonist therapy because it is impossible to 
discontinue treatment. 
If the grade 3 or 4 adverse event improves to grade 0, 1, or 2 after holding the dose, or if the 
adverse event is no longer believed to be related to study drug, the patient may be rechallenged at 
the same dose at the discretion of the investigator and medical monitor.  If the adverse event 
remains grade 3 or grade 4 after treatment discontinuation and the investigator continues to 
believe the adverse event is related to study drug, study drug treatment should be discontinued 
permanently. 
5.7. 
Storage, Packaging, and Labeling 
Relugolix will be packaged in bottles containing 45 120-mg tablets of relugolix.  Additional 
details regarding the packaging of relugolix are provided in the Investigator Brochure and Study 
Reference Manual. 
Leuprolide acetate 11.25 mg or 22.5 mg 3-M depot injection will be packaged and labeled for 
clinical trial use. 
Relugolix medication should be stored in an appropriate, limited-access, secure location, 
protected from light, in the original bottles and within a temperature range at 20°C to 25°C 
(68°F to 77°F) with excursions permitted to 15 to 30°C (59 to 86°F) as indicated on the label. 
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A daily temperature log of the drug storage area must be maintained every working day. 
Study drug must be stored under the conditions specified on the label, and remain in the original 
container until dispensed.  Only patients enrolled in the study may receive study drug, and only 
authorized site staff may supply or administer study drug.  Patients will be instructed to store 
study drug at room temperature out of the reach of children. 
Further guidance and information for final disposition of unused study drug are provided in the 
Study Reference Manual.  The investigator is responsible for study drug accountability, 
reconciliation, and record maintenance, including receipt, reconciliation, and final disposition 
records and their secure storage. 
Refer to the leuprolide acetate product labeling for information regarding the proper storage and 
handling of leuprolide acetate. 
5.8. 
Blinding 
Blinding is not applicable; this is a randomized open-label study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused study drug to each study visit.  Study drug accountability will be 
conducted and results will be recorded as the primary source of study drug accountability.  If a 
patient is persistently noncompliant with the study treatment, it may be appropriate to withdraw 
the patient from the study. 
All patients should be reinstructed regarding dosing compliance during study contacts.  The 
authorized study personnel conducting the re-education must document the process in the 
patient’s source records. 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-2 provides examples of medications that are prohibited prior to the first dose of study 
medication until the End of Treatment visit and the Follow-up Period is complete.  This list is not 
a comprehensive list of all restricted medications.  Consult the medical monitor if there is any 
uncertainty regarding patient use of a particular drug or drug class.  Patients may “wash out” of 
these prohibited medications prior to dosing based on the periods provided in Table 5-2. 
Any investigational agent for the treatment of prostate cancer, including agents that are 
commercially available for indications other than prostate cancer that are under investigation for 
the treatment of prostate cancer, are also prohibited for at least 12 months prior to the first dose 
of study medication. 
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Table 5-2 
Prohibited Medications and Washout Periods 
Drug Class 
Examples 
Minimum Washout 
Period 
GnRH analogues 
Leuprolide acetate 
injectiona 
Goserelin acetate 
injection 
 
12 months 
GnRH antagonists 
Degarelix 
 
12 months 
Antiandrogensa 
Bicalutamide 
Flutamide 
Nilutamide 
Enzalutamideb 
12 months 
CYP17 inhibitors 
Abiraterone acetate + 
prednisone 
 
12 months 
Other androgen 
suppressing agents 
Estrogens 
Ketoconazole 
Megestrol acetate 
Progestogens 
12 months 
Class IA an III 
antiarrhythmics 
Amiodarone 
Procainamide 
Quinidine 
Sotalol 
2 weeks  
(3 months for amiodarone) 
Moderate and strong 
CYP3A and 
P-glycoprotein 
inducers 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifampin 
St John’s Wort 
Primidone 
Rifabutin 
Rifapentine 
2 weeks 
Moderate/strong 
P-glycoprotein 
inhibitors 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporin 
Diltiazem 
Dronedarone 
Eliglustat 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lapatinib 
Lopinavir/Ritonavir 
Quercetin 
Quinidine 
Ranolazine 
Ticagrelor 
Verapamil 
2 weeks 
(3 months for amiodarone) 
Herbal therapies 
Chinese herbs 
Ginkgo biloba 
Ginseng 
Kava kava 
Melatonin 
2 weeks 
Abbreviation:  CYP, cytochrome P450 
a. 
Unless randomized to leuprolide acetate control arm of this study.  Antiandrogen therapy is permitted for the 
first 4 weeks or longer of leuprolide acetate treatment. 
b. Enzalutamide is allowed for the treatment of castration-resistant disease that occurs on study (rising prostate-
specific antigen in the setting of testosterone suppressed to castrate levels (≤ 50 ng/dL [1.7 nmol/L]). 
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5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded.  At a minimum, the drug 
generic name, dose amount, route of administration, start date, and stop date will be recorded in 
the source documents and the eCRF. 
If alternative androgen deprivation therapy is initiated prior to 30 days after the last relugolix 
dose, record the alternative androgen deprivation therapy as a concomitant medication. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive systemic antineoplastic and or radiotherapy. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities 
(see Section 1.1).  Study procedures are briefly described within Section 6.6.  Further details of 
the procedures are provided in the Study Reference Manual. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 3 periods:  Screening Period, Treatment 
Period, and Follow-up Period.  Unscheduled visits may also occur as needed to evaluate patients. 
6.2. 
Screening Period (Day -28 to Day -1) 
The Screening Period will be from Day -28 through Day -1.  At the Screening visit, study site 
personnel must explain to potential study participants all aspects of the study, including all 
scheduled visits and activities.  Study site personnel must obtain signed informed consent before 
any study-specific procedures are conducted, unless the procedures are part of routine standard 
of care.  The informed consent process must be documented in the patient’s clinical record. 
The investigator will assess and confirm the eligibility of each patient and determine that each 
patient will maintain study drug compliance during the treatment period.  All screening 
procedures results and relevant medical history must be available before eligibility can be 
determined.  All inclusion criteria must be met and none of the exclusion criteria may apply.  No 
eligibility waivers will be granted. 
The following assessments will be performed: 
• Complete medical history, including detailed prostate cancer history; 
• Vital signs, weight, and height; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
• Abdominopelvic CT or MRI and bone scan if not previously done in the preceding 
2 months prior to the Baseline Day 1 visit; 
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• Demographics; 
• Laboratory data collection (see Section 1.1); 
• Verify inclusion/exclusion criteria; and 
• Concomitant medications and adverse events. 
A Randomization Authorization Form must be submitted to the sponsor for approval prior to 
conducting the Baseline Day 1 visit. 
6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) 
Baseline Day 1 Visit 
Study site personnel should ensure that an approved Randomization Authorization Form is in the 
patient’s file before proceeding with the randomization and Day 1 visit procedures.  Patients will 
be randomized to either relugolix or leuprolide acetate 3-M depot injection 22.5 mg (or 11.25 mg 
in some Asian countries) (see Section 5.3). 
The following assessments will be performed: 
• Patient-reported outcome questionnaires (EQ-5D-5L, EORTC-QLQ-PR25, and EORTC-
QLQ-C30) 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Medical history; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); 
• Verify inclusion/exclusion criteria; 
• Concomitant medications and adverse events; 
• Randomize the patient; and 
• Study drug management: 
o If study drug administration is not logistically feasible on the same day as 
randomization, the patient must come to the clinic within 3 days of randomization 
for the required procedures and initiation of treatment. Day 1 will be defined as 
the day of randomization regardless of the first dose. 
o If the patient is randomized to relugolix, site personnel will administer a single 
loading dose of oral relugolix 360 mg (3 tablets) and then dispense study drug to 
the patient and instruct on daily dosing of 120 mg (1 tablet) and the importance of 
medication compliance (see Section 5.4); 
o If the patient is randomized to leuprolide acetate, site personnel will administer 
the injection in the clinic. 
Day 4 and Weeks 2, 3, and 4 Visits (Visit Window ± 1 day) 
The following assessments will be performed: 
• Vitals signs; 
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• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 Visits (Visit Window ± 7 Days) 
Importantly, patients randomized to relugolix should be called 7 days before each visit to ensure 
the patient is compliant with study drug medication. 
The following assessments will be performed: 
• Patient-reported questionnaires will be completed on the electronic tablet provided 
(Weeks 5, 13, 25, and 37 only) 
o Patients will complete the questionnaires before other study procedures, such as 
blood draws and physical examinations, are performed; 
• Vital signs, weight 
o Weight will be collected only on Weeks 13 and 25; 
• 12-lead ECG (Weeks 5, 13, and 25 only); 
• ECOG performance assessment (Week 25 only); 
• Symptom-based physical examination (except Week 25); 
• Complete physical exam and visual acuity assessment (Week 25 only); 
• Laboratory collection (see Section 1.1) 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm.  Samples will be collected predose; patients will be 
required to arrive at the clinic on an empty stomach; 
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability; 
 Dispense study drug to patient, ensure the patient takes their daily 120 mg 
dose at the clinic under fasting conditions, at least 1 hour before or 2 hours 
after eating a meal and remind patient on importance of medication 
compliance. 
o For patients randomized to leuprolide acetate, 
 Site will administer leuprolide acetate in clinic every 12 weeks (Weeks 13, 
25, and 37). 
Week 49 or (Early Termination of Study Drug) (Visit Window ± 7 Days) 
• For patients receiving relugolix, a member of the site team will call the patient 7 days 
before the Week 49 visit to remind the patient of the need for compliance with their study 
medication; 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs, weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
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• Laboratory collection (see Section 1.1); 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm.  Samples will be collected predose; patients will be 
required to arrive at the clinic on an empty stomach; 
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability. 
6.4. 
Follow-up Period 
The study day in which the Follow-up visit occurs is relative to when the patient takes his last 
dose of study drug.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
30-Day Safety Follow-up Visit (Visit Window ± 7 Days) 
A Safety Follow-up visit should occur 30 days after the End of Treatment and may occur earlier 
for patients who are starting alternative androgen deprivation therapy or do not complete 
12 weeks of study treatment.  Adverse events should continue to be collected and recorded 
through 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events and concomitant medications will be collected from the signing of the 
informed consent form until the Safety Follow-up visit approximately 30 days after the last dose 
of study drug. 
All other study procedures should be completed before the start of alternative androgen 
deprivation therapy. 
The following assessments will be performed: 
• Patient-reported questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
Testosterone Recovery Visit (Visit Window ± 7 Days) 
Patients who have started alternative androgen deprivation therapy will not participate in the 
60- and 90-day follow-up visits.  The first 100 patients randomized to receive relugolix and 
50 patients randomized to receive leuprolide acetate who complete the 48 weeks of study drug 
treatment and, in the opinion of the investigator, are candidates for intermittent androgen 
deprivation therapy will be included in the Testosterone Recovery 60- and 90-day Follow-up 
visits.  These patients will discontinue relugolix after 48 weeks of treatment and will be offered a 
period off androgen deprivation therapy. 
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The following assessments will be performed: 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications. 
Health Status Survey 
During the final weeks prior to database lock, sites will be asked to contact all study participants 
or their immediate family regarding the current health status of previously enrolled/completed 
study patients.  If the site is unsuccessful in contacting the patient and/or immediate family, the 
site may access hospital records or publicly available sources such as national registries, 
newspaper obituaries, and social networking websites. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
investigator.  The date and reason for the Unscheduled visit should be recorded in the patient’s 
source documentation.  The following activities should be completed at an Unscheduled visit 
conducted to evaluate adverse events:  vital signs, weight, symptom-directed brief physical 
examination, central safety laboratory assessment and collection of a PK sample if indicated, 
12-lead ECG, recording of concomitant medications, and study drug compliance. 
6.6. 
Study Procedures 
6.6.1. 
Efficacy-Related Procedures 
6.6.1.1. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, testosterone, 
dihydrotestosterone, sex hormone binding globulin, and PSA will be collected predose at the 
visits indicated in the Schedule of Activities in the protocol synopsis (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory.  Testosterone samples may 
be analyzed at a second laboratory to confirm non-castrate levels (Section 1.1). 
Serum LH, FSH, dihydrotestosterone, sex hormone binding globulin, and PSA samples will be 
analyzed at a central laboratory. 
PSA will also be used to evaluate biochemical progression per Prostate Cancer Clinical Trials 
Working Group 3 guidelines [Scher, 2016]. 
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Analysis of serum samples for testosterone is detailed below:  
Testosterone Assessment 
Serum concentrations of testosterone will be obtained as indicated in the Schedule of Activities 
(see Section 1.1). 
Testosterone will be assayed using a liquid chromatography-tandem mass spectrometry method 
sensitive at least as low as 5 ng/dL (0.17 nmol/L) for all measurements.  
Between Week 5 and Week 49 visits (inclusive), testosterone samples that are above castrate 
level (> 50 ng/dL) will be reported to the investigator at the respective study site.  Testosterone 
samples may be subject to reanalysis by liquid chromatography/mass spectrometry and/or 
immunoassay sensitive to at least as low as 10 ng/dL. 
Instructions for collection and processing of blood specimens are provided in the Study 
Reference Manual. 
6.6.1.2. 
Relugolix Pharmacokinetic Sample Collection 
Pharmacokinetic samples will only be collected in patients randomized to relugolix study drug. 
Blood samples for pharmacokinetic analysis of relugolix will be collected at the visits indicated 
in the study Schedule of Activities in the protocol synopsis (see Section 1.1).  The actual date 
and time of each blood sample collection will be recorded. 
Patients will be instructed to take their dose of study drug in the clinic at these visits.  Study drug 
will be administered on an empty stomach or at least 2 hours before food, and food will be 
withheld for 1 hour after dosing.  The date and time of their previous dose of study drug (ie, the 
dose the day before the clinic visit) will be accurately recorded.  If the study patient inadvertently 
took the study drug at home on the morning of the clinic visit, the date and time of that dose 
should also be accurately recorded and the pharmacokinetic sample collected, which may be 
used for population PK modeling. 
Plasma from the Week 5 and Week 13 visits in all patients will be analyzed for relugolix plasma 
concentration.  Analysis of other individual patient plasma samples will be performed on a case-
by-case basis (such as those patients with non-castrate testosterone levels). 
Collection, processing, storage, and shipping instructions will be provided in the Study 
Reference Manual.  Plasma analysis of relugolix will be performed by the sponsor (or designee). 
China and Japan Pharmacokinetic Subset 
In a subset of approximately 20 patients from China and approximately 20 patients from Japan 
that are randomized to relugolix, additional relugolix PK samples will be collected on Day 1, 
Day 4, and Week 2 visits (see Schedule of Activities in the protocol synopsis, Section 1.1).  The 
actual date and time of study drug administration and the date and time of each PK sample will 
be accurately recorded. 
All samples from the China and Japan subset will be analyzed for plasma relugolix 
concentrations.  Collection, processing, storage, and shipping instructions will be provided in the 
Study Reference Manual.  Plasma analysis of relugolix will be performed by the sponsor (or 
designee). 
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6.6.1.3. 
Pharmacogenomics Sample Collection 
Whole Blood Sample for Germline Deoxyribonucleic Acid 
Pharmacogenomic analysis may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety.  Participation of study patients in 
pharmacogenomic sample collection is optional.  A pharmacogenomics sample will be collected 
from patients at all participating study centers, with individual patient consent and per local 
ethics and regulatory standards.  The sample will be retained for germline deoxyribonucleic acid 
(DNA) analysis of potential genetic determinants of drug safety, drug efficacy or disease 
response, and drug metabolism. 
Every patient must sign informed consent/be consented in order to participate in the sampling of 
whole blood for DNA analysis.  This research may be used to develop a better understanding of 
the safety and efficacy of relugolix and other study drugs, to increase understanding of the 
disease/condition being studied, and for improving the efficiency, design and study methods of 
future research studies. 
Two venous whole blood sample (3 mL per sample) for the analysis of germline DNA will be 
collected at Day 1 from all patients who have provided informed consent.  The DNA samples are 
expected to be collected at the Day 1 visit, but if necessary, may be collected at any visit after 
randomization.  If necessary and feasible, a second aliquot of blood may be taken if isolation of 
DNA from the first sample was not successful or possible.  Germline DNA analysis may be 
conducted to investigate the contribution of genetic variance on drug response, for example, its 
efficacy and safety.  As pharmacogenomics is an evolving science, currently many genes and 
their function are not yet fully understood.  Future data may suggest a role of some of these 
genes in drug response or diseases, which may lead to additional hypothesis-generating 
exploratory research on stored samples. 
Individual blood samples for germline DNA analysis, including the result of any analyses and 
corresponding information will be identified only by a code in a computer database. 
The whole blood samples for DNA analysis will be stored securely at the sponsor’s location or 
its designated central laboratory vendor until 15 years after completion of this study (HERO, 
MVT-601-3201) and/or until the drug development of relugolix is no longer actively pursued by 
Myovant or its collaborators.  The storage period for these samples may be adjusted by country 
in accordance with local regulatory and/or legal requirements for the storage of research samples.  
Such changes will be reflected in the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) country-specific informed consent form.  After that time, the samples will be 
properly destroyed by the central laboratory or designee following approval by the sponsor.  The 
investigator will keep records linking the patient identity with the samples for the time required 
by applicable law.  Patients who consent and provide a pharmacogenomic sample for DNA 
analysis can withdraw their consent and request disposal of a stored sample at any time. 
Directions for sample collection and handling can be found in the Study Reference Manual. 
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6.6.1.4. 
Quality of Life 
European Quality of Life 5-Dimension 5-Level Assessment 
The EuroQol EQ-5D-5L comprises 5 scales and an overall assessment of health status on a 
visual analogue scale (Appendix 2).  The 5 scales include:  mobility, self-care, usual activities, 
pain and discomfort, and anxiety and depression.  The original version, the EQ-5D-3L, includes 
3 response options for each scale.  However, a new 5-level response-option version, the 
EQ-5D-5L, has been developed with the following response options:  no problems, slight 
problems, moderate problems, severe problems, and unable to/extreme problems.  It is believed 
that the EQ-5D-5L is superior to the EQ-5D-3L in terms of feasibility, ceiling effects, 
discriminatory power, and convergent validity.  The EQ-5D-5L index values will be calculated 
from the EQ-5D-5L descriptive system scores based on the Crosswalk value sets [EuroQol 
Group, 1990; Brooks, 1996; Herdman, 2011; Janssen, 2013]. 
European Organisation for Research and Treatment of Cancer Assessments 
The EORTC-QLQ-C30 [Fayers, 2001; Fayers, 2002] (Appendix 3) and the 25-item prostate 
cancer module EORTC-QLQ-PR25 [Spry, 2006] (Appendix 4) will be administered as specified 
in the Schedule of Activities (see Section 1.1). 
The EORTC QLQ-C30 core measurement will be used to capture distal outcomes, including 
physical, social functioning, and overall health-related quality of life.  The QLQ-C30 core 
questionnaire incorporates 30 questions comprising 9 multi-item scales:  5 functional scales 
(physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea 
and vomiting); and a global health and quality of life scale.  Several single-item symptom 
measures are also included.  It is a reliable and valid measure of health-related quality of life in 
patients with cancer and takes about 11 minutes to administer.  The instrument has been 
validated and used in many countries [Aaronson, 1993]. 
The EORTC-QLQ-PR25 is the 25-item Prostate Cancer module (P25) of the EORTC.  The 
EORTC-QLQ-PR25 contains 3 additional symptom scales (urinary, bowel, sexual) and 
5 treatment-related items. 
6.6.2. 
Safety-Related Procedures 
6.6.2.1. 
Weight, Height, and Body Mass Index 
Height and weight will be measured during screening (within 28 days before the first dose of 
study drug).  Weight will be obtained at additional time points as specified in the Schedule of 
Activities (see Section 1.1).  Patients should have weight and height measured while wearing 
indoor clothing and with shoes removed. 
6.6.2.2. 
Vital Signs 
Vital sign measurements include oral temperature, pulse rate, and seated measurement of 
diastolic and systolic blood pressure.  Patients should be sitting at rest for 5 minutes before blood 
pressure is measured.  When vital sign measurements are scheduled at the same time as an ECG 
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and blood draw, the vital signs will be obtained immediately prior to the ECG and blood draw, 
and the blood draw will be collected at the scheduled time. 
6.6.2.3. 
Physical Exams 
A complete physical examination will include head, ears, eyes, nose, mouth, thyroid, skin, heart, 
and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.  All 
subsequent physical examinations should focus on signs and symptoms reported by the patient to 
assess for clinically significant changes from the baseline assessment.  Visual acuity will be 
evaluated at Baseline Day 1, Week 25, and Week 49 by a standard visual eye chart.  The patient 
should wear any prescribed glasses or contacts during the visual acuity assessment. 
6.6.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities (see Section 1.1).  Laboratory 
requisition forms must be completed and samples must be clearly labelled with the patient ID 
number, protocol number, site/center number, and visit date.  Details for the preparation and 
shipment of samples will be provided.  Reference ranges for all safety parameters will be 
provided to the site by the central laboratory. 
The samples collected for clinical laboratory tests are listed in Table 6-1. 
Table 6-1 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Metabolic Panel 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Neutrophils and absolute 
neutrophil count 
Platelet (count) 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Creatinine 
Chloride 
Serum gamma-glutamyl 
transferase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Total cholesterol 
High density lipoprotein 
cholesterol 
Low density lipoprotein 
cholesterol 
Triglycerides 
Hemoglobin A1c 
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Endocrine Panel 
Diagnostic Screening 
(investigator’s discretion) 
 
Serum testosterone 
Serum LH 
Serum FSH 
Serum sex hormone binding 
globulin 
HIV test 
Hepatitis panel, including 
HBsAg and anti-HCV 
 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
LH, luteinizing hormone 
 
A separate sample will be collected at the Day 1 visit and will be banked and tested for presence 
of hepatitis A, B, and C (hepatitis A antibody, IgM, hepatitis B core antibody, IgM, hepatitis B 
surface antigen, and hepatitis C antibody) if requested by the medical monitor for evaluation of 
abnormal liver function tests. 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
plasma and serum hormone levels. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal and clinically 
significant results should be reported as adverse events. 
6.6.2.5. 
12-Lead Electrocardiograms 
A 12-lead ECG will be administered at the time points specified in the Schedule of Activities 
(Section 1.1).  When an ECG is scheduled at the same time as vital signs and a blood draw, the 
ECG will be obtained after the vital signs and prior to the blood draw; the blood draw will be 
collected at the scheduled time.  ECGs will be read locally by a qualified physician. 
If patients have a prolonged QTc (> 500 msec), the ECG should be repeated and confirmed.  
Patients with a confirmed QTc > 500 msec that develops during the trial should be withdrawn.  
All abnormal ECG findings must be documented by the investigator as clinically significant or 
not. 
6.6.2.6. 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the eCRF from the beginning of screening until 30 days after the last dose of 
relugolix or 12 weeks plus 30 days after the last leuprolide acetate injection.  See Section 5.10.1 
for a list of medications and therapies that are prohibited and/or allowed during the study. 
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6.6.2.7. 
Radiologic Assessment 
CT imaging or MRI of the abdominopelvic region with contrast and a bone scan must be 
obtained prior to randomization for each patient to determine the presence or absence of 
metastatic disease.  The scans should be read locally and do not need to be repeated if a scan 
exists within 60 days prior to the Baseline Day 1 visit. 
Radiologic assessment is not included as part of the Schedule of Activities after randomization. 
6.7. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of 5 mL of whole blood 
collected for pharmacogenomics testing (see Section 6.6.1.3) will be stored frozen at an 
appropriate vendor facility identified by the sponsor. 
The need to conduct pharmacogenomic analysis may be identified after this study (or 
additional studies) has been completed.  For this reason, the collected samples will be retained 
for up to 10 years after the last patient completes the study.  A patient may request the 
destruction of his sample at any time.  The sponsor may destroy the samples sooner than 
10 years after the study completes. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations including visual 
acuity assessment, vital signs, weight, ECGs, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or duration 
of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate medical 
events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 
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• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least one 
of the following criteria: 
o Induces clinical signs or symptoms; 
o Requires active intervention; or 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
o Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event; 
o The disease/disorder being studied, or expected progression; 
o Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; and 
o Situations where an untoward medical event has not occurred (eg, planned hospitalization 
for an elective procedure, with elective defined as known or planned at the time of 
signing of the informed consent). 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to CTCAE (Appendix 5).  Episodic adverse events, such as vomiting, or those that 
occur repeatedly over a period of consecutive days are “intermittent”.  All other events are 
“continuous”.  Additional information on detecting, documenting, and reporting adverse events 
and serious adverse events are provided below.  No toxicity-related dose reductions of study 
drug are permitted; however, study drug can be held for a period of up to 10 days for evaluation 
and treatment of an adverse event.  The study drug may be restarted if deemed safe for the 
patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study patient was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.  For example, drug-
induced hepatitis that resolved without evidence of hepatic failure would not be considered 
life-threatening even though drug-induced hepatitis can be fatal. 
c. 
Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
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d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local IRB/IEC. 
Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the patient is the preferred method to 
inquire about adverse event occurrence.  Appropriate questions include: 
• “How are you feeling?”  
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact? 
The patient’s answers to the EQ-5D-5L will not be used as a primary means to collect adverse 
events, however they should be reviewed by the study site personnel and the study monitors.  
Should the investigator or site staff become aware of a potential adverse event 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 adverse 
event not previously reported has been identified, normal reporting requirements should be 
applied. 
All patients who experience an adverse event will be evaluated at appropriate time intervals until 
the event resolves or has stabilized or become chronic.  At the conclusion of the study, the 
investigator and medical monitor will assess unresolved adverse events and determine if 
additional follow-up is warranted. 
All adverse events, whether or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
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each sign and symptom as an individual adverse event. 
Overdose and pregnancy in a partner will be reported as described in Section 7.7 and Section 7.8, 
respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events will be collected from the time the first dose of study drug is administered until 
the Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
Serious adverse events will be collected from the signing of the informed consent form until the 
safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection.  Serious adverse events reported to the 
investigator after the safety reporting period should be reported to the sponsor if the investigator 
assesses the event as related to the study drug treatment. 
Any event occurring between signing of the informed consent form and the first dose of study 
drug will be recorded as medical history and in the patient’s clinical record for any patient who 
continues to meet eligibility criteria and proceeds to dosing with study drug. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
definitions in Table 7-1 are to be used for the relationship of the adverse event to study drug. 
Table 7-1 
Causal Relationship to Study Drug 
Relationship 
Criteria 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely attributed to concurrent disease 
or other drugs or chemicals, and that follows a clinically reasonable response on 
re-administration (re-challenge) or withdrawal (de-challenge). 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but that could also be explained by 
concurrent disease or other drugs or chemicals.  Information on drug withdrawal 
may be lacking or unclear. 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable 
and/or in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
 
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All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE (see Appendix 5).  For terms not specified with the CTCAE, the criteria 
in Table 7-2 should be used to determine the grade severity. 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
7.5. 
Adverse Events of Clinical Interest Reporting 
Adverse events of clinical interest in this study are defined as any increase in ALT or AST 
≥ 3 x ULN. 
Any ALT or AST elevation of this degree or greater occurring during the randomized Treatment 
Period or the Follow-up visit should be reported to the sponsor using the serious adverse event 
form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), even 
if the event does not meet serious adverse event criteria.  Additional instructions for evaluating 
patients with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
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7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized ratio 
(INR) >1.5 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1) AST or ALT increases to ≥ 3 x ULN; AND 
2) Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3) Alkaline phosphatase value does not reach 2 x ULN; AND 
4) No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease; 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus); 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms; 
• Alcoholic hepatitis; 
• Nonalcoholic steatohepatitis; or 
• Autoimmune hepatitis. 
If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
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7.6. 
Serious Adverse Event Reporting 
Using a serious adverse event report form, all serious adverse events must be reported within 
24 hours of the study site personnel’s knowledge of the event, regardless of the investigator 
assessment of the relationship of the event to study drug.  Serious adverse events reported to the 
investigator after the safety reporting period should be reported to the sponsor if the investigator 
assesses the event as related to the study drug treatment. 
The contact information for submission of serious adverse events and events of overdose or 
pregnancy of partner is available on the serious adverse event report form and is as follows:   
Send completed Safety Report Forms to PRA Safety & Risk Management: 
Site Location 
Fax Number (Primary 
reporting method) 
E-mail (Secondary 
reporting method) 
North/South America: 
 
 
Europe, Asia, Pacific, and Africa: 
 
For questions on serious adverse event/adverse event of clinical interest reporting, please 
call: 
• North/South America:  
 or 
 
• Europe, Asia, Pacific, and Africa:  
 
The initial report should include: 
• Study number (MVT-601-3201); 
• Site name and number; 
• Investigator name; 
• Patient ID number, sex, and age; 
• Details of study drug administration; 
• The date of the report; 
• A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); and 
• Causal relationship to the study drug. 
If the patient died, the report should include the cause of death and whether or not the cause of 
death was related to study drug, as well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
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7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 240 mg within a 24-hour window is an overdose, except 
for the 360-mg loading dose on Day 1.  The sponsor does not recommend specific treatment for 
an overdose; supportive treatment should be provided as clinically applicable. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form, whether or not the overdose is associated with an 
adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); and 
• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If the partner of any patient becomes pregnant during the study or through 4 months after the last 
dose of study drug, the investigator must inform the sponsor of the pregnancy. 
The patient should remain on study drug treatment, unless otherwise indicated. 
If the patient agrees, the patient’s pregnant partner should be notified and requested to sign a 
Release of Information form, permitting transfer of information regarding the pregnancy and 
outcome to the sponsor. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy reporting forms.  The expected date of delivery or expected date 
of the end of the pregnancy, last menstruation, estimated conception date, pregnancy result, and 
neonatal data, etc, should be included in this information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
Benefit/Risk Assessment 
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
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The risk assessment and mitigation strategies for this protocol are outlined in Table 7-3. 
Table 7-3 
Relugolix Potential Risks and Mitigation 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Hepatic Enzyme Increases 
Isolated increases in hepatic enzymes have been 
observed in prior clinical studies.  Hepatic enzyme 
increases, considered an important potential risk of 
treatment with relugolix, are closely monitored in 
accordance with FDA guidelines for assessing drug-
induced liver injury [FDA, 2009] in all relugolix 
studies. 
Exclusion criteria for 
AST and ALT > 1 x 
the ULN; total 
bilirubin values > 1.0 
ULN unless consistent 
with Gilbert’s 
syndrome. 
Liver chemistry will be 
monitored during the 
study.  Appropriate 
liver stopping criteria 
and follow-up 
procedures are detailed 
in Section 7.5.2. 
Phospholipidosis 
Data from nonclinical studies in rats and monkeys 
showed histopathological changes consistent with 
PLD.  PLD by itself is not adverse.  No clinical 
evidence of relugolix-related PLD-associated toxicity 
has been observed nor was there a clinically 
meaningful increase in a biomarker of PLD assessed 
in phase 2 clinical studies. 
Patients with 
significant underlying 
medical conditions are 
excluded. 
Routine safety 
monitoring including 
laboratory assessments, 
ECGs, and assessment 
of adverse events; visual 
acuity will be evaluated 
during the study. 
Risks Associated with Medical Castration 
Acute and subsequent chronic symptoms of medical 
castration (reduction of testosterone to ≤ 50 ng/dL 
[1.7 nmol/L]) include vasomotor symptoms or hot 
flushes, disturbed sleep related to vasomotor 
symptoms, decreased libido, and fatigue or loss of 
energy.  These side effects are usually not severe and 
can be managed with anticipatory guidance. 
Long-term suppression of testosterone is associated 
with well-characterized risks including bone loss, 
decreased muscle mass, possible changes in insulin 
sensitivity with increased risk of diabetes, altered 
lipid metabolism, and possible increased risk of 
cardiovascular disease [Oefelein, 2002; Lopez, 
2005; Diamond,1998; Keating, 2006; Braga-
Basaria, 2006; Saigal, 2007; Tsai, 2007; D'Amico, 
2007; Efstathiou, 2009]. 
- 
Effects can usually be 
managed with 
appropriate 
anticipatory guidance 
(eg, diet and exercise 
programs) or 
supportive therapy 
when required (eg, 
lipid-lowering or bone-
sparing agents). 
Metabolic Changes 
Metabolic changes (insulin resistance, dyslipidemia, 
and increased weight) with increased risk of diabetes 
are a potential risk of the hypoestrogenic state 
induced by relugolix. 
- 
Fasting lipids and 
glucose will be 
monitored during the 
study. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Loss of Bone Mineral Density 
Loss of bone mineral density is considered a potential 
risk of treatment with relugolix in the prostate cancer 
indication. 
- 
Fractures will be 
assessed through 
adverse event 
monitoring.  Use of 
anti-resorptive bone 
therapy, such as 
bisphosphonates or 
denosumab, may be 
considered by the 
treating physician.  
Abbreviations:  ALT; alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; FDA, 
Food and Drug Administration; PLD, phospholipidoses; ULN, upper limit of normal 
8. 
DATA QUALITY ASSURANCE 
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the Study 
Reference Manual with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice regulations.  By signing this protocol, the investigator grants permission to 
Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-site 
monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and Good Clinical Practices.  The study monitor 
should have access to laboratory test results and any other source records and data needed to 
verify the entries on the eCRF.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved.  For this 
study, patient data will be entered into a sponsor-approved electronic database and combined 
with data provided from other sources in validated datasets then transmitted electronically to the 
sponsor (or designee). 
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Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
8.3. 
Independent Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board will review available safety data, as 
appropriate, on a periodic basis throughout the conduct of the study.  Details of the Data and 
Safety Monitoring Board will be captured in a charter prior to the start of the study. 
8.4. 
Steering Committee 
A Steering Committee consisting of experts in the field of prostate cancer and staff members of 
Myovant Sciences GmbH will be established to provide oversight for the clinical trial, study 
design, study conduct, data analysis, and presentation and publication of the study data.  Details 
of the Steering Committee responsibilities will be captured in a separate charter. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan will describe the detailed statistical methods and analyses for this 
study.  The statistical analysis plan will be prepared and finalized prior to database lock and 
analysis of the primary and secondary endpoints. 
All confidence intervals will be 2-sided at an alpha level of 0.05 unless otherwise specified.  The 
methodology to be used to maintain a study-wide type I error rate of 0.05 across primary and 
secondary endpoint testing will be described in the statistical analysis plan. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 2:1, relugolix to leuprolide 
acetate 3-M depot.  Randomization will be stratified by the following factors: 
• Geographic Region:  North and South America versus Europe versus Asia and Rest of 
World; 
• Presence of Metastatic Disease:  yes versus no; 
• Baseline Age:  ≤ 75 years old versus > 75 years old. 
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Stratified efficacy analyses will incorporate these 3 stratification factors unless otherwise 
specified. 
9.2. 
Analysis Populations 
The Intent-To-Treat (ITT) population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis.  Patients will be analyzed according to their randomized treatment assignment. 
The Per-Protocol population will consist of those members of the ITT population who have no 
major protocol deviations as defined in the statistical analysis plan, considering the following 
protocol deviations but not limited to: 
• Those who entered the study even though they did not satisfy the entry criteria; 
• Those who developed withdrawal criteria during the study but were not withdrawn; 
• Those who received the wrong treatment or incorrect dose; 
• Those who received an excluded concomitant treatment. 
The Per-Protocol population will not be analyzed if this population comprises more than 95% or 
less than 50% of the ITT population.  The Per-Protocol population will be used as a sensitivity 
analysis of the ITT population for the primary efficacy endpoint and secondary endpoints.  The 
Per-Protocol population will be identified prior to the database lock. 
The primary population for safety analyses will be the Safety population, defined as all patients 
who receive at least one dose of any study treatment.  Patients will be analyzed according to the 
treatment actually received, regardless of their randomized treatment assignment. 
9.3. 
Efficacy Analyses 
9.3.1. 
Primary Endpoint Analyses 
The primary efficacy endpoint is the sustained castration rate, defined as the cumulative 
probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 (Study Day 337).  This probability will be 
estimated for each treatment group using the Kaplan-Meier method with the confidence interval 
calculated using the exponential Greenwood formula via log-log transformation of the survival 
function.  Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL 
(1.7 nmol/L) will be censored at the last testosterone assessment prior to discontinuation.  
Detailed censoring rules will be described in the statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix is 
greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion. 
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• Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression.  The lower bound of the 95% confidence interval for the 
difference in the cumulative probability of sustained testosterone suppression between the 
2 treatment groups will be calculated and must be greater than or equal to the non-
inferiority margin of -10% to meet this criterion.  The confidence interval of the 
treatment difference will be calculated using the formula 𝑉෠ൣ𝑆1෡(𝑡) −𝑆2෡(𝑡)൧= 𝑉෠ൣ𝑆1෡(𝑡)൧+
𝑉෠ൣ𝑆2෡(𝑡)൧ , where each of the variance of the Kaplan-Meier estimate will be calculated 
using the Greenwood's formula 𝑉෠ൣ𝑆̂(𝑡)൧= 𝑆̂(𝑡)2 ൤∑
𝑑𝑗
𝑛𝑗൫𝑛𝑗−𝑑𝑗൯
𝑗:𝑡(𝑗)≤𝑡
൨ ; nj denote the 
number of patients at risk at time t(j) and dj denote the number of events observed at time 
t(j)) [Lachin, 2000]. 
The evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans.  The 2-sided type I error rates for the final analyses will be controlled at 0.05 separately 
for each regional analysis. 
9.3.2. 
Secondary Endpoint Analyses 
If the result of the primary endpoint is statistically significant, the secondary endpoints will be 
analyzed.  The methods and procedures necessary to maintain a study-wide 2-sided type I error 
rate of 0.05 across primary and secondary endpoint testing will be described in the statistical 
analysis plan. 
• Castration rate defined as the cumulative probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing at Week 1 Day 4, prior to dosing at Week 2 
Day 1, and prior to dosing at Week 3 Day1 will be summarized by treatment group using 
the Kaplan-Meier method; 
• Profound castration rate defined as the cumulative probability of testosterone suppression 
of ≤ 20 ng/dL (0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 
Day 1 will be estimated for each treatment group using the Kaplan-Meier method.  The 
difference in the cumulative probabilities between the relugolix group and the leuprolide 
acetate group will be provided, along with the 95% confidence interval calculated in the 
same manner as in the primary analysis of the primary endpoint; 
• PSA response and percent change from baseline in PSA at Week 2 and Week 5 will be 
summarized and compared between the relugolix group and the leuprolide acetate group; 
• Proportions of patients who have a PSA concentration < 0.2 ng/mL (0.2 µg/L) at 
Week 25 will be summarized by treatment group.  The proportions will be compared 
between the relugolix group and the leuprolide acetate group by constructing a 
95% confidence interval for the difference in proportions; 
• Time to testosterone recovery in the first 100 patients randomized to relugolix and the 
first 50 patients randomized to leuprolide acetate who complete 48 weeks of treatment 
and who do not start alternative androgen deprivation therapy within the following 
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12 weeks (or within 24 weeks following the last received leuprolide acetate 3-M depot 
injection) will be compared between the relugolix group and the leuprolide acetate group; 
• Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 global 
health domain and the EORTC-QLQ-PR25 sexual activity and hormonal-treatment-
related symptom subdomains will be summarized by treatment group.  The least square 
means at Week 49 will be compared between the relugolix group and the leuprolide 
acetate group by constructing a 95% confidence interval for the difference in the least 
square means using a mixed model for repeated measures; and 
• Absolute values and changes from baseline of the remaining domains in the EORTC 
QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L will be summarized by 
treatment group.  The least square means at Week 49 will be compared between the 
relugolix group and the leuprolide acetate group by constructing a 95% confidence 
interval for the difference in the least square means using a mixed model for repeated 
measures. 
Further details of the secondary analyses will be described in the statistical analysis plan. 
9.4. 
Safety Analyses 
The safety analyses will be based on the Safety population.  Safety will be assessed by 
summarizing and analyzing adverse events, laboratory analytes, vital signs, ECG parameters, and 
concomitant medications. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute’s CTCAE.  All adverse events will be coded to preferred term and system organ 
class using MedDRA 19.1 or higher.  The incidence of adverse events will be presented by 
MedDRA system organ class and preferred term, relationship to study drug treatment, and 
severity.  A patient reporting the same adverse event more than once is counted once, and at the 
maximum severity or strongest relationship to study drug treatment when calculating incidence. 
Laboratory data consist of chemistry, hematology, and hormonal tests.  Only data collected by 
the central laboratory will be used for analyses.  The National Cancer Institute CTCAE will be 
used to categorize toxicity grade for the laboratory parameters.  Shift tables will be provided for 
each gradable parameter to summarize baseline toxicity grade versus post-baseline toxicity 
grade.  For laboratory parameters that are not gradable by the CTCAE, a shift table based upon 
the normal range (low, normal, and high) will be provided for each parameter to summarize the 
baseline versus post-baseline results. 
9.5. 
Pharmacokinetic Analyses 
Plasma relugolix concentrations will be listed and summarized and included in the clinical study 
report. 
PK data will be pooled with data from other studies in healthy male patients and patients with 
prostate cancer for further population PK analysis, including evaluation of covariates of relugolix 
PK parameters, and for input into a population PK/pharmacodynamics models describing the 
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relationship between relugolix exposure and serum testosterone [Ahsman, 2016].  These 
population PK analyses will be detailed further in a separate statistical analysis plan and report. 
For patients from China and Japan in the PK subset, plasma relugolix PK parameters Cmax, 
AUC0-τ, and tmax from Day 1 and Day 14 of dosing will be determined.  Population PK or 
PK/pharmacodynamic analyses may be conducted to explore the factors that affect relugolix 
exposure or to contribute to the assessment of the relationships between exposure and 
testosterone. 
9.6. 
Endocrine Marker Analyses 
Endocrine markers will be analyzed to see effects of relugolix and leuprolide acetate as measured 
as absolute value and change from baseline for: 
• LH at Week 2, Week 3, Week 5, and then every 4 weeks until Week 49 and/or last 
follow-up visit; 
• FSH at Week 5, Week 13, Week 25, Week 37, and Week 49 visits; 
• Dihydrotestosterone at Week 5, Week 13, Week 25, Week 37, and Week 49 visits; and 
• Sex hormone binding globulin at Week 13, Week 25, and Week 49 visits. 
9.7. 
Exploratory Analyses 
Overall survival:  Overall survival defined as time from randomization to date of death prior to 
data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions for each 
treatment arm. 
Pharmacogenomic analyses may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety, pending availability of samples.  
Polymorphisms in germline genes related to the hypothalamic-pituitary-androgen pathway, 
prostate cancer risk, or to drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix.  These analyses will be 
detailed in a separate statistical analysis plan and associated reports. 
9.8. 
Interim Analyses 
There will be no planned interim efficacy analysis for the study. 
9.9. 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• True probabilities of sustained testosterone suppression are 94% and 96% for relugolix 
and leuprolide acetate, respectively; 
• 2:1 randomization ratio (relugolix:leuprolide acetate); and 
• Dropout rate of 15%. 
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The assumed probability of sustained testosterone suppression for relugolix arm is 94%.  It was 
estimated based on the predicted dose-response relationship for the effect of relugolix on 
testosterone suppression in patients with prostate cancer (data from phase 2 studies C27002 and 
C27003).  The assumed castration rate of 96% for leuprolide acetate was based on the results 
from degarelix phase 3 registration program [Shore, 2013]. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of < 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and an overall 2-sided type I 
error rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) 
will yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate.   
The final analysis will be performed separately for individual evaluation criterion using data 
collected through 48 weeks after enrollment of approximately 915 patients. 
Up to approximately 1125 patients will be randomized in order to fulfill the regulatory 
requirements of all participating countries.  This includes approximately 90 patients from Japan 
(60 relugolix, 30 leuprolide acetate) and approximately 200 patients (133 relugolix, 67 leuprolide 
acetate) from China PR. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR) Part 312, subpart D, “Responsibilities of 
sponsors and investigators,” 21 CFR Part 50, and 21 CFR Part 56, are adhered to.  These 
standards are consistent with the requirements of the European Community Directive 
2001/20/EC. 
Since this is a “covered” clinical study, the investigator will ensure that 21 CFR Part 54, is 
adhered to; a “covered” clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied.  This 
documentation must be provided before participation of the investigator and any sub-
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investigator.  The investigator and sub-investigator agree to notify the sponsor of any change in 
reportable interests during the study and for one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
A properly executed, written informed consent, in compliance with the Declaration of Helsinki, 
ICH Good Clinical Practice, US CFR for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27), and local regulations, will be obtained from each patient before entering the patient 
in the trial.  The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
The investigator will provide copies of the signed informed consent form to each patient (or to 
the patient’s legal representatives) and will maintain the signed original document within the 
patient’s record file per local requirements.  The investigator will also fully document the 
informed consent process in the patient’s source records. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator Brochure, protocol, eCRFs and other study forms, the investigational drug, 
and any other study information, remain the sole and exclusive property of the sponsor during 
the conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
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without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: 
1) Investigator’s study file:  The investigator’s study file will contain the Investigator Brochure, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents:  The required source data should include the following for 
each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and causality 
and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, US, Europe, or Japan) and until 
there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the sponsor.  The investigator must notify the sponsor 
before destroying any clinical study records. 
Clinical study documentation includes the Investigator Brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, curriculum vitae and all training records of study 
site personnel, and all correspondence pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
10.1.5. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on the 1572 form and/or other appropriate local health 
authority documents within a reasonable time period after data collection.  This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
Screening Period if an eCRF was initiated).  If a patient withdraws from the study, the reason 
must be noted on the eCRF.  If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.6. 
Investigational Product Accountability 
The investigator or investigator’s designee (ie, pharmacist) is responsible for ensuring adequate 
accountability including dates and lot numbers of all study drug.  This includes acknowledgment 
of receipt of each shipment of study product (quantity and condition), patient dispensing records, 
and returned or destroyed study product.  Dispensing records will document quantities received 
from the sponsor and quantities dispensed to patients, including lot number, date dispensed, 
patient ID number, and the initials of the person dispensing the medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements.  Drug may be returned or destroyed on an ongoing basis during the study 
if appropriate.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet the sponsor’s 
requirements for disposal, arrangements will be made between the site and the sponsor (or 
designee) for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
All records must be made available to the sponsor, authorized representatives, and appropriate 
regulatory agencies, upon request. 
Current ICH Good Clinical Practice guidelines require the investigator to ensure that study drug 
deliveries from the sponsor are received by a responsible person (eg, pharmacist), and the 
following: 
• That such deliveries are recorded, for example, on the sponsor-approved drug 
accountability log, or other sponsor-approved pharmacy log; 
• That study drug is handled and stored safely and properly in accordance with the label 
and the study protocol; 
• That study drug is only dispensed to study patients in accordance with the protocol; 
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• That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be documented.  
The following guidelines are therefore pertinent: 
• The investigator agrees not to supply study drug to any persons except the patients in this 
study; 
• The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs; 
• The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which patient; 
• The investigator/pharmacist agrees to conduct a final drug supply inventory on the drug 
accountability record at the conclusion or termination of the study.  It must be possible to 
reconcile delivery records with those of used and returned study drug.  Any discrepancies 
must be accounted for.  Appropriate forms of deliveries must be signed by the person 
responsible; 
• Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative.  Unused study drug 
not destroyed at the site must be returned to the sponsor-designated facility at the end of 
the study or upon expiration. 
10.1.7. 
Inspections 
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of the 
audit is to ensure that the study is (or was) conducted and monitored in compliance with the 
protocol as well as recognized Good Clinical Practice guidelines and regulations.  These audits 
will also increase the likelihood that the study data and all other study documentation can 
withstand a regulatory authority inspection.  If such audits are to occur, they will be arranged for 
a reasonable and agreed time.  By signing this protocol, the investigator grants permission to the 
sponsor or designee to conduct onsite audits of all appropriate facilities and study 
documentation. 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the sponsor or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 
10.1.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
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10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
(eg, http://www.clinicaltrials.gov) before enrollment of patients begins.  Results will be posted as 
required. 
10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct 
access to the investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
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10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  When the sponsor is aware of 
information on matters concerning the quality, efficacy, and safety of the study drugs, as well as 
other important information that may affect proper conduct of the clinical study, the sponsor may 
terminate the study and send a written notice of the termination along with the reasons to the 
investigator.  Should this be necessary, the sponsor will arrange discontinuation procedures and 
notify the appropriate regulatory authority(ies) and IRBs/IECs.  In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the protection of 
the study participants’ interests. 
If the investigator intends to terminate participation in the study, the investigator must 
immediately inform the sponsor and provide the reason to it. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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GnRH Antagonist TAK­385 and testosterone­lowering response in Prostate Cancer 
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Bosland MC. Testosterone treatment is a potent tumor promoter for the rat prostate. 
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Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, John M, Egan J, Basaria S. Metabolic 
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Cersosimo RJ, Carr D. Prostate cancer: current and evolving strategies. Am J Health Syst Pharm. 
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Conn PM, Crowley WF Jr. Gonadotropin-releasing hormone and its analogues. N Engl J Med. 
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Malone S, Ludgate C, Steigler A, Kantoff PW. Influence of androgen suppression 
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Clin Oncol. 2007 Jun 10;25(17):2420-5. 
Diamond T, Campbell J, Bryant C, Lynch W. The effect of combined androgen blockade on 
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Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, Smith MR. 
Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate 
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EuroQol Group.  EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy. 1990 Dec;16(3):199-208. 
Fayers P, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. EORTC QLQ-
C30 Scoring Manual. 3rd ed. Brussels: EORTC; 2001. 
Fayers P, Bottomley A; EORTC Quality of Life Group; Quality of Life Unit. Quality of life 
research within the EORTC-the EORTC QLQ-C30. European Organisation for Research 
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2009. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf. 
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Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer 
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Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 
2001 Jan-Feb;51(1):15-36. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life 
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Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, Busschbach 
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Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen 
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Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, Jensen JK, Olesen TK, 
Schröder FH. The efficacy and safety of degarelix: a 12-month, comparative, 
randomized, open-label, parallel-group phase III study in patients with prostate cancer. 
BJU Int. 2008 Dec;102(11):1531-8. 
Klotz L, O'Callaghan C, Ding K, Toren P, Dearnaley D, Higano CS, Horwitz E, Malone S, 
Goldenberg L, Gospodarowicz M, Crook JM. Nadir testosterone within first year of 
androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: 
a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin 
Oncol. 2015 Apr 1;33(10):1151-6. 
Kreis W. Current chemotherapy and future directions in research for the treatment of advanced 
hormone-refractory prostate cancer. Cancer Invest. 1995;13(3):296-312. 
Lachin J. Biostatistical Methods: The Assessment of Relative Risks. 2nd ed. Balding D, Cressie 
N, Fitzmaurice G, Johnstone I, Molenberghs G, Scott D, et al., editors: John Wiley & 
Sons, Inc.; 2010. 
Limonata P, Montagnani Marelli M, Moretti RM. LHRH analogues as anticancer agents: 
pituitary and extrapituitary sites of action. Expert Opin Investig Drugs. 2001 
Apr;10(4):709-20. 
Loblaw DA, Mendelson DS, Talcott JA, Virgo KS, Somerfield MR, Ben-Josef E, Middleton R, 
Porterfield H, Sharp SA, Smith TJ, Taplin ME, Vogelzang NJ, Wade JL Jr, Bennett CL, 
Scher HI; American Society of Clinical Oncology. American Society of Clinical 
Oncology recommendations for the initial hormonal management of androgen-sensitive 
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metastatic, recurrent, or progressive prostate cancer. J Clin Oncol. 2004 Jul 
15;22(14):2927-41. 
Lopez AM, Pena MA, Hernandez R, Val F, Martin B, Riancho JA. Fracture risk in patients with 
prostate cancer on androgen deprivation therapy. Osteoporos Int. 2005 Jun;16(6):707-11. 
Lupron Depot. Prescribing Information. AbbVie Inc., North Chicago, IL, USA. Revised 6/2016. 
Available at: http://www.lupron.com/prescribing-information.aspx. Accessed: 12 January 
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Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS; Urologic Diseases in 
America Project. Androgen deprivation therapy increases cardiovascular morbidity in 
men with prostate cancer. Cancer. 2007 Oct 1;110(7):1493-500. 
Schally AV, Coy DH, Arimura A. LH-RH agonists and antagonists. Int J Gynaecol Obstet. 
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Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
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Schwartz LH, Halabi S, Kantoff PW, Armstrong AJ; Prostate Cancer Clinical Trials 
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Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J 
Clin Oncol. 2016 Apr 20;34(12):1402-18. 
Shore ND. Experience with degarelix in the treatment of prostate cancer. Ther Adv Urol. 2013 
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Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-
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Spry NA, Kristjanson L, Hooton B, Hayden L, Neerhut G, Gurney H, Corica T, Korbel E, 
Weinstein S, McCaul K. Adverse effects to quality of life arising from treatment can 
recover with intermittent androgen suppression in men with prostate cancer. Eur J 
Cancer. 2006 May;42(8):1083-92. 
Tolis G, Ackman D, Stellos A, Mehta A, Labrie F, Fazekas AT, Comaru-Schally AM, Schally 
AV. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing 
hormone-releasing hormone agonists. Proc Natl Acad Sci U S A. 1982 Mar;79(5):1658-
62. 
Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, 
Kold Olesen T, Persson BE. Additional analysis of the secondary end point of 
biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus 
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leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 
2010 May;57(5):836-42. 
Tsai HK, D'Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for 
localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst. 
2007 Oct 17;99(20):1516-24. 
Waxman J, Man A, Hendry WF, Whitfield HN, Besser GM, Tiptaft RC, Paris AM, Oliver RT. 
Importance of early tumour exacerbation in patients treated with long acting analogues of 
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1985 Nov 16;291(6506):1387-8. 
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APPENDICES 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
Note:  Adapted from Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
 
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Appendix 2. EuroQol EQ-5D-5L Questionnaire 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
I have slight problems walking 
I have moderate problems walking 
I have severe problems walking 
I am unable to walk 
SELF-CARE 
Cl 
Cl 
Cl 
Cl 
Cl 
I have no problems washing or dressing myself 
Cl 
I have slight problems washing or dressing myself 
Cl 
I have moderate problems washing or dressing myseH 
Cl 
I have severe problems washing or dressing myself 
Cl 
I am unable to wash or dress myself 
Cl 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
I have no problems doing my usual activities 
Cl 
I have slight problems doing my usual activities 
Cl 
I have moderate problems doing my usual activities 
Cl 
I have severe problems doing my usual activities 
Cl 
I am unable to do my usual activities 
Cl 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
Cl 
Cl 
Cl 
Cl 
Cl 
Cl 
Cl 
Cl 
Cl 
Cl 
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Appendix 3. Quality of Life Questionnaire:  EORTC QLQ-C30 
 
., 
EORTC QLQ-C30 (m siou 3) 
We are. interested in some things about you and yotu· health. Please ru1swer all of the questions yourselfby circling the. 
uwuber that best applies to you There are uo "ri#lt" or "v.roug" answers. The. infouuatiou that you provide will 
remain strictly caufideutial. 
Please. fill in your initials: 
Your birthclate (Day, Month, Year): 
Toclay's date (Day, Mouth, Ye.,r): 
31 
Not at 
A 
Quite 
Yet} 
All 
Littl• 
a Bit 
Much 
1. 
Do you have any trouble doing strenuous activities, 
like c.rurying a hea\'y shopping bog or a suitcase? 
2 
3 
4 
2. 
Do you have auy trouble 
a jQgg wall.:? 
2 
3 
4 
3. 
Do you have auy trouble 
a short walk otlside of the botlSe? 
2 
3 
4 
4. 
Do you need to stay in bed or a chair during the clay? 
2 
3 
4 
5. 
Do you need help with eating, dressing, washillg 
yotu·self or using the toilet? 
2 
3 
4 
During the past week: 
Not at 
A 
Quit• 
YttJ 
All 
Littl• 
a Bit 
Much 
6. 
We,-. you limited in doing either your wod: or other daily activities? 
2 
3 
4 
7. 
We,-. you limited in ptu·suing your hobbies or other 
leisure ti.me activities? 
2 
3 
4 
8. 
We,-. you short of breath? 
2 
3 
4 
9. Ha,-. you had pain? 
2 
3 
4 
10. Did you need to rest? 
2 
3 
4 
11. Ha,-. you had trouble sleeping? 
2 
3 
4 
12. Ha,-. you felt weal'? 
2 
3 
4 
13. Ha,-. you lacked appetite? 
2 
3 
4 
14. Have you felt n<luseated? 
2 
3 
4 
15. Have you vomited? 
2 
3 
4 
16. Ha,-. you been constipated? 
2 
3 
4 
Please go ou to the next oage 
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Duriu& lbt p>SI wttk: 
.. " 
Qolt• 
\ "ny 
.-\11 
Uftl< 
• Bit 
Mor' 
I' 
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• 
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2 
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20 
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• 
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... _ 
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• 
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··-
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2 
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• 
f or lbt followiD& quu rioot plt>tt drdt lbt oumbtr btn,tto 1 >Dtl 7 lb>l 
btsl >pplits 10 you 
} 
6 
7 
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Appendix 4. Quality of Life Questionnaire:  EORTC QLQ-PR25 
 
 
EORTC QL Q - PR25 
Pataalls wm<tam.- rtp011 that they baH tht folk)\\ UlJ symp<oa" or problems Plta.e u>dtcat< tht 
extent to \\iucb you have cx.pcnmccd tbc\oC: 
or problmn dunn; tbc past wed: Please 
on"'"" by cm:bn' th• numb<r that bc>t opph« to you. 
During !Itt past wttk: 
A 
Qultt 
\"tl' 
It Ill 
IIttS. 
• bh 
mucb 
31 Hn• you bad to unnat• &.qumtly durtng tbt day'' 
2 
3 
4 
32 Hn• >""bad to unn>l< 6-oqumtly at ulgbr> 
2 
3 
4 
33 Wbtu >"" ftlt lbt urg< to ptiS unno did>"" 
to hwry to gttto tllt toll<(! 
2 
3 
4 
}4 Was 11 dllri<Uit for>"" to g<1 toCIU!l> sl«p btaoust 
)"OU -
to Jtl up fnqutntly at ntght to unnatt1 
2 
3 
4 
bad dtffirulty ,.,..., .... or lbt booM 
btaoust )"OU 
<lost to a 
2 
3 
4 
36 
)"OU bad Ill)' urunlmtaooal ..... (ltal:ogt} or ....... 
2 
3 
4 
37 Old )"OU 
patn wbm )"OU .,_,<dO 
2 
3 
4 
38 
tlus <JUP"""' ol1ly tf)-ou 
atd 
Has "-nnDI m 
11d- a p-obl<m for you" 
2 
3 
4 
39 
>..,..dally a<tn,.,.. -
hmlttd by your uruwy p-obl<ms• 
2 
3 
4 
40 
yow •lly .mv•bts bf.m 
by )"'Ur 
probkms" 
2 
) 
4 
41 Ha•-. )"OU bad any unUll<Dhoual 
{ltabg<) of stools' 
2 
3 
4 
42 Have>"" bad blood 10 )"Our stools" 
2 
3 
4 
43 Old )'OU 
bloattd r .. twgm )"Our abdom<o" 
2 
3 
4 
44 Old )'OU ba,-. hoi Ousb«• 
2 
3 
4 
)"OU 
or ftl1argtd wpplts or brta<ts" 
2 
3 
4 
46 
)"OU bad swtllulg ut >..,.. logs or anklo<• 
2 
3 
4 
Pkay: 80 'P d)ft nnl P'V 
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Appendix 5. 
Adverse Event Severity Grading 
When assessing adverse events, refer to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03, June 14, 2010 (available at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).  A 
copy of the National Cancer Institute CTCAE table will be provided in the Study Reference 
Manual. 
The National Cancer Institute CTCAE is a descriptive terminology that can be utilized for 
adverse event reporting.  A grading (severity) scale is provided for each adverse event term. 
Components and Organization of the National Cancer Institute CTCAE 
• System Organ Class (SOC).  SOC, the highest level of the Medical Dictionary for 
Regulatory Activities (MedDRA) hierarchy, is identified by anatomical or physiological 
system, etiology, or purpose (eg, SOC Investigations for laboratory test results).  CTCAE 
terms are grouped by MedDRA Primary SOCs.  Within each SOC, adverse events are 
listed and accompanied by descriptions of severity (grade). 
• CTAE Terms.  Each CTCAE term is a MedDRA LLT (Lowest Level Term). 
• Definitions.  A brief definition is provided to clarify the meaning of each adverse event 
term. 
• Grades.  Grade refers to the severity of the adverse event.  The CTCAE displays grades 1 
through 5 with unique clinical descriptions of severity for each adverse event based on 
this general guideline: 
o Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
o Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living; 
o Grade 4 Life-threatening consequences; urgent intervention indicated; and 
o Grade 5 Death related to adverse event. 
A semi-colon indicates “or” within the description of the grade.  A single dash (-) 
indicates a grade is not available.  Not all grades are appropriate for all adverse 
events.  Therefore, some adverse events are listed with fewer than 5 options for 
grade selection. 
• Grade 5.  Grade 5 (Death) is not appropriate for some adverse events and therefore is not 
an option. 
 
 
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Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes 
Study drug treatment should be withheld for any liver test abnormality listed in Section 7.5.1, 
pending investigation of alternative causes of liver injury.  Follow-up should continue until the 
liver test abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations 
in Appendix Table 2.  If close monitoring is not possible, study drug should be withheld, even if 
the results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, 
ALT, Bilirubin [Total and Direct]), 
Alkaline Phosphatase, and INR Testsa 
If AST or ALT ≥ 3 x ULN and total bilirubin 
> 2 x ULN or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
If ALT or AST ≥ 3 x ULN and total bilirubin 
and INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized 
ratio; ULN, upper limit of normal 
a. 
Review frequency of monitoring with medical monitor for an individual patient, in case of questions 
 
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Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
• 
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or 
coworkers, etc) and/or industrial chemical agents; 
• 
Prior and concurrent use of alcohol, recreational drugs, and special diets; 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants and mushrooms; 
• 
Physical examination. 
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
• 
Repeat liver tests as per Appendix Table 1a; 
• 
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat 
liver tests; 
• 
Complete blood count with differential to assess for eosinophilia; 
• 
Serum acetaminophen (paracetamol) concentration; 
• 
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus; 
• 
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune 
hepatitis, etc; 
• 
Serology for celiac disease; 
• 
Appropriate liver imaging; and 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
Abbreviations:  INR, international normalized ratio 
a. 
If the first follow-up testing does not confirm the initial abnormal liver test results, review any additional 
follow-up monitoring with the medical monitor. 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
HERO:  A Multinational Phase 3 Randomized, Open-label, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
Relugolix in Men with Advanced Prostate Cancer 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3201 
Indication: 
Advanced Prostate Cancer 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
IND Number: 
118736 
EudraCT Number: 
2017-000160-15 
Version / Effective Date: 
Version 02 Jan 2018 
Study Medical Monitor: 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
Principal Investigator Name (Printed)  
Signature 
 
 
 
 
 
Date 
 
Site 
 
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TABLE OF CONTENTS 
Sponsor Signature Page .............................................................................................................................. 2 
Investigator Statement ................................................................................................................................ 3 
List of Tables ............................................................................................................................................... 8 
List of Figures .............................................................................................................................................. 8 
List of Abbreviations .................................................................................................................................. 9 
1. 
Protocol Synopsis ......................................................................................................................... 11 
1.1. 
Schedule of Activities ................................................................................................................ 23 
2. 
Introduction .................................................................................................................................. 27 
2.1. 
Prostate Cancer .......................................................................................................................... 27 
2.2. 
Relugolix ................................................................................................................................... 28 
2.2.1. 
Indication .......................................................................................................................... 28 
2.2.2. 
Pharmacology ................................................................................................................... 28 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 29 
2.2.4. 
Previous Human Experience ............................................................................................. 29 
3. 
Study Objectives and Endpoints ................................................................................................. 36 
4. 
Investigational Plan ..................................................................................................................... 39 
4.1. 
Overall Study Design................................................................................................................. 39 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 41 
4.3. 
Selection of Study Population ................................................................................................... 42 
4.3.1. 
Inclusion Criteria .............................................................................................................. 42 
4.3.2. 
Exclusion Criteria ............................................................................................................. 43 
4.4. 
Other Eligibility Criteria Considerations ................................................................................... 46 
4.5. 
Screening ................................................................................................................................... 46 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification Number ............ 47 
4.7. 
Removal of Patients from Therapy ............................................................................................ 47 
4.8. 
Contraception/Pregnancy Avoidance ........................................................................................ 49 
5. 
Treatments .................................................................................................................................... 50 
5.1. 
Treatments Administered .......................................................................................................... 50 
5.2. 
Identity of Investigational Product ............................................................................................ 50 
5.2.1. 
Product Characteristics ..................................................................................................... 50 
5.3. 
Randomization and Stratification .............................................................................................. 50 
5.4. 
Directions for Administration .................................................................................................... 51 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 52 
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5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption ......................................................... 52 
5.7. 
Storage, Packaging, and Labeling ............................................................................................. 53 
5.8. 
Blinding ..................................................................................................................................... 53 
5.9. 
Study Drug Accountability and Treatment Compliance ........................................................... 53 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 54 
5.10.1. 
Prohibited Medications ..................................................................................................... 54 
5.10.2. 
Permitted Medications ...................................................................................................... 55 
6. 
Study Assessments and Procedures ............................................................................................ 56 
6.1. 
Schedule of Observations and Procedures ................................................................................. 56 
6.2. 
Screening Period (Day -28 to Day -1) ....................................................................................... 56 
6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) ........................................................... 57 
6.4. 
Follow-up Period ....................................................................................................................... 59 
6.5. 
Unscheduled Visits .................................................................................................................... 60 
6.6. 
Study Procedures ....................................................................................................................... 60 
6.6.1. 
Efficacy-Related Procedures ............................................................................................. 60 
6.6.2. 
Safety-Related Procedures ................................................................................................ 63 
6.7. 
Biological Sample Retention and Destruction ........................................................................... 66 
7. 
Safety Considerations .................................................................................................................. 67 
7.1. 
Adverse Event Definitions......................................................................................................... 67 
7.1.1. 
Adverse Event ................................................................................................................... 67 
7.1.2. 
Serious Adverse Event ...................................................................................................... 68 
7.2. 
Adverse Event Reporting........................................................................................................... 68 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 69 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 70 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 70 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 71 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 71 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 72 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 72 
7.7. 
Study Drug Overdose Management .......................................................................................... 73 
7.8. 
Pregnancy Reporting ................................................................................................................. 74 
7.9. 
Benefit/Risk Assessment ........................................................................................................... 74 
8. 
Data Quality Assurance ............................................................................................................... 76 
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8.1. 
Clinical Procedures .................................................................................................................... 76 
8.2. 
Monitoring ................................................................................................................................. 76 
8.3. 
Independent Data and Safety Monitoring Board ....................................................................... 76 
8.4. 
Steering Committee ................................................................................................................... 77 
9. 
Statistical Considerations and Data Analyses ........................................................................... 77 
9.1. 
Randomization Methods ............................................................................................................ 77 
9.2. 
Analysis Populations ................................................................................................................. 77 
9.3. 
Efficacy Analyses ...................................................................................................................... 78 
9.3.1. 
Primary Endpoint Analyses .............................................................................................. 78 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 79 
9.4. 
Safety Analyses ......................................................................................................................... 80 
9.5. 
Pharmacokinetic Analyses ......................................................................................................... 80 
9.6. 
Endocrine Marker Analyses ...................................................................................................... 80 
9.7. 
Exploratory Analyses ................................................................................................................ 81 
9.8. 
Interim Analyses ........................................................................................................................ 81 
9.9. 
Sample Size ............................................................................................................................... 81 
10. 
Responsibilities ............................................................................................................................. 82 
10.1. 
Investigator Responsibilities...................................................................................................... 82 
10.1.1. 
Good Clinical Practice ...................................................................................................... 82 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 82 
10.1.3. 
Informed Consent ............................................................................................................. 83 
10.1.4. 
Confidentiality .................................................................................................................. 83 
10.1.5. 
Electronic Case Report Forms .......................................................................................... 84 
10.1.6. 
Investigational Product Accountability ............................................................................. 85 
10.1.7. 
Inspections ........................................................................................................................ 86 
10.1.8. 
Protocol Compliance ......................................................................................................... 86 
10.2. 
Sponsor Responsibilities............................................................................................................ 86 
10.2.1. 
Protocol Modifications ..................................................................................................... 86 
10.2.2. 
Study Report ..................................................................................................................... 87 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ............................ 87 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 87 
10.3.1. 
Access to Information Monitoring .................................................................................... 87 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 87 
10.3.3. 
Study Discontinuation ....................................................................................................... 88 
10.3.4. 
Publications ....................................................................................................................... 88 
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References .................................................................................................................................................. 89 
Appendices ................................................................................................................................................. 93 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status .......................................... 93 
Appendix 2. 
EuroQol EQ-5D-5L Questionnaire ............................................................................... 94 
Appendix 3. 
Quality of Life Questionnaire:  EORTC QLQ-C30 ..................................................... 96 
Appendix 4. 
Quality of Life Questionnaire:  EORTC QLQ-PR25 ................................................... 98 
Appendix 5. 
Adverse Event Severity Grading ................................................................................ 100 
Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes .......................................................... 101 
 
 
 
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LIST OF TABLES 
 
Table 1-1 
Schedule of Activities for Study MVT-601-3201............................................................. 23 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks ...................... 31 
Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) ........................................... 33 
Table 4-1 
Removal of Patients from Treatment ................................................................................ 47 
Table 5-1 
Description of MVT-601-3201 Study Drugs .................................................................... 50 
Table 5-2 
Prohibited Medications and Washout Periods .................................................................. 54 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 65 
Table 7-1 
Causal Relationship to Study Drug ................................................................................... 70 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 71 
Table 7-3 
Relugolix Potential Risks and Mitigation ......................................................................... 74 
 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury ...... 101 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............ 102 
 
LIST OF FIGURES 
Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of Relugolix 
and Degarelix at Week 25 ................................................................................................. 32 
Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent Reduction 
by Dose of Relugolix at Week 25 Day 1 .......................................................................... 34 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent Reduction 
by Leuprolide Acetate at Week 25 Day 1 ......................................................................... 34 
Figure 4-1 
Schematic of Study Design ............................................................................................... 41 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
3-M 
3-month 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-τ 
area under the concentration-time curve from time 0 to the end of the dosing 
interval 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHT 
dihydrotestosterone 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organisation of Research and Treatment of Cancer 
EOT 
end of treatment 
EuroQol EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level Questionnaire 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonization 
ID 
identification 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat (population) 
IWRS 
interactive voice/web recognition system 
LH 
luteinizing hormone 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
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Term 
Explanation 
NOAEL 
NYHA 
no-observed-adverse-effect-level 
New York Heart Association 
Obs 
observed 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
PSA 
prostate-specific antigen 
Q12W 
once every 12 weeks 
Q4W 
once every 4 weeks 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
SHBG 
QTc corrected using Fridericia’s formula 
sex hormone binding globulin 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
HERO:  A Multinational Phase 3, Randomized, Open-label, Parallel-
group Study to Evaluate the Safety and Efficacy of Relugolix in Men 
With Advanced Prostate Cancer 
Protocol Number 
MVT-601-3201 
Location 
Multinational, including North and South America, Europe, and Asia-
Pacific 
Study Centers 
Approximately 200 sites 
Study phase 
Phase 3 
Target Population 
Men aged 18 or older diagnosed with androgen-sensitive advanced 
prostate cancer who are candidates for at least 1 year of continuous 
androgen deprivation therapy for the management of androgen-sensitive 
advanced prostate cancer and who are not be candidates for surgical 
therapy.  Patients previously treated with taxanes or expected to receive 
taxanes after initiation of androgen deprivation therapy are excluded, as 
are patients receiving androgen deprivation therapy adjuvant or 
neoadjuvant to radiotherapy as primary definitive therapy. 
Number of 
Patients Planned 
Approximately 915 total patients 
Study Objectives 
Primary: 
• 
To evaluate the ability of relugolix to achieve and maintain serum 
testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) 
in men with androgen-sensitive advanced prostate cancer. 
 
Secondary: 
• 
To evaluate the time course and change in serum testosterone during 
treatment with relugolix; 
• 
To evaluate the time course and magnitude of prostate-specific 
antigen (PSA) reduction during treatment with relugolix; 
• 
To evaluate testosterone recovery following discontinuation of 
relugolix; 
• 
To evaluate quality of life using validated patient-reported outcome 
instruments; 
• 
To evaluate the safety of relugolix 120 mg once daily in men with 
androgen-sensitive advanced prostate cancer; 
• 
To evaluate the effect of relugolix and leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
To collect relugolix plasma concentration data to further evaluate 
relugolix population pharmacokinetics (PK) and the relationship 
between relugolix exposure and serum testosterone; and 
• 
To characterize the relugolix plasma PK parameters in a subset of 
patients from China (if enrolled) and Japan; and  
• 
To describe  the time course and magnitude of PSA progression and 
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development of castration resistant prostate cancer during treatment 
with relugolix. 
 
Exploratory: 
• 
To explore the overall survival of patients treated with relugolix; and 
• 
To explore the contribution of genetic variance on drug response. 
Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 
22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3-months (3-M) will be administered 
to patients with prostate cancer who require androgen deprivation therapy.  This study will 
evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive 
advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local 
primary intervention with curative intent, newly diagnosed metastatic disease (excluding 
metastases to the brain), and/or advanced localized disease.  Patients may receive radiotherapy, 
cryotherapy or high frequency ultrasound no sooner than 2 months after initiation of androgen 
deprivation therapy.  Patients may be included if they have not previously received androgen 
deprivation therapy for more than 18 months, and if the androgen deprivation therapy was 
completed at least 3 months prior to the baseline visit. If the dosing interval of the depot is 
longer than 3 months, then the prior androgen deprivation therapy must have been completed at 
least as long as the dosing interval of the depot.  Patients previously treated with taxanes or 
expected to receive taxanes after initiation of androgen deprivation therapy are excluded, as are 
patients receiving androgen deprivation therapy adjuvant or neoadjuvant to radiotherapy as 
primary definitive therapy.  Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 
5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once 
daily following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg 
(or 11.25 mg in Japan, Taiwan, and China). After randomization, patients on the leuprolide 
acetate arm may receive an antiandrogen for the first 4 weeks or longer if indicated in the 
opinion of the investigator.  Randomization will be stratified by geographic region, presence of 
metastatic disease, and age. 
Approximately 915 patients will be enrolled in this study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-reported 
outcomes (European Organisation of Research and Treatment of Cancer [EORTC] QLQ-C30, 
European Quality of Life 5-Dimesion 5-Level questionnaire [EuroQol EQ-5D-5L]) will be 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
assessed approximately every 3 months during the Treatment Period and more frequently during 
the Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China (if 
enrolled) and Japan.  Safety assessments will include treatment-emergent adverse events, vital 
signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECG), and 
visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive radiotherapy as prescribed by the investigator. In the setting of rising 
PSA patients may also receive enzalutamide. For patients requiring other systemic 
antineoplastic therapy during the treatment period, the investigator should contact the medical 
monitor.  
 
 
 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
All of the following inclusion criteria must have been met prior to randomization unless 
otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
Version 2.0, 02 Jan 2018 
Myovant Sciences GmbH 
17 
CONFIDENTIAL 
sibling) of a site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets or conditions that may 
interfere with absorption at the level of the small intestine. Examples of such conditions 
include but are not limited to Crohn's disease, gastric bypass, active peptic ulcer disease, and 
gastrectomy. The medical monitor should be contacted for any questions regarding this 
exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see Section 
5.10.1) without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form [eCRF]); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would 
interfere with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
Dose and Route of 
Administration 
Test Product 
Relugolix 120 mg tablet strength will be available as immediate-release 
film-coated tablets, and 1 tablet (120 mg) will be administered once daily 
following an oral loading dose of 360 mg (three 120-mg tablets) on 
Day 1.  These tablets will be presented in 45-tablet bottles and dispensed 
to patients every 4 weeks at scheduled study visits. 
All protocol-specific inclusion criteria and none of the exclusion criteria 
must be met and documented prior to study drug administration.  Study 
drug will be dispensed only to eligible patients who are under the 
supervision of the investigator or identified subinvestigator(s). 
Reference Product 
Leuprolide acetate, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), 
3-M depot will be administered per the approved dose and method of 
dosing in the region where the patient is enrolled.  Leuprolide acetate 3-M 
depot injection will be administered on Day 1 (with an antiandrogen of 
choice, if indicated according to the investigator, for the first 4 weeks or 
longer), then at 12-week intervals thereafter for 48 weeks.  Preparation of 
the depot injection and administration should follow the instructions 
provided by the manufacturer. 
Duration of 
Treatment 
The duration of treatment will be 48 weeks.  The last dose of leuprolide 
acetate 3-M depot will be administered at the Week 37 visit. 
Criteria for 
Evaluation 
The following treatment arms will be evaluated after 48 weeks of study 
treatment: 
• 
Arm A:  Oral relugolix 120 mg once daily following a loading dose of 
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360 mg (three 120-mg tablets) on Day 1. 
• 
Arm B:  Leuprolide acetate 3-M depot injection, 22.5 mg (or 
11.25 mg in Japan, Taiwan, and China). 
 
Primary Endpoint 
• 
Sustained castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study 
treatment from Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
 
Secondary Endpoints 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) prior to 
dosing on Week 1 Day 4, prior to dosing on Week 3 Day 1; 
o Profound castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 20 ng/dL (0.7 nmol/L) while on 
study treatment from Week 25 Day 1 through Week 49 Day 1; 
o Time to testosterone recovery in approximately 100 patients 
randomized to relugolix and approximately 50 patients 
randomized to leuprolide acetate who complete 48 weeks of 
treatment and who do not plan to start alternative androgen 
deprivation therapy within the following 12 weeks (or within 24 
weeks following the last injection of leuprolide acetate 3-M 
depot); 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed PSA response by Prostate 
Cancer Clinical Trials Working Group 3 guidelines at the Week 3 
and Week 5 visits [Scher, 2016]; 
o Proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit;  
• 
Absolute values and changes from baseline in the scores of the 
EORTC-QLQ-C30 global health domain, and the EORTC-QLQ-
PR25 sexual activity and hormonal-treatment-related symptom 
subdomains, at regular intervals during treatment, and as applicable 
during the Follow-up and/or at End of Treatment visits; 
• 
Absolute values and changes from baseline of the remaining domains 
in the EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular intervals during 
treatment, and as applicable during the Follow-up visits; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical laboratory data; 
• 
Endocrine marker effects of relugolix and leuprolide acetate as 
measured as absolute value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 25, and Week 49 visits; 
and 
o Sex hormone binding globulin at the Week 5, Week 25, and Week 
49 visits; 
• 
Predose relugolix plasma concentrations; 
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• 
Single and repeat-dose plasma relugolix PK parameters such as 
maximum plasma concentration (Cmax), area under the concentration-
time curve from time 0 to the end of the dosing interval (AUC0-τ), and 
time to maximum plasma concentration (tmax) in a subset of patients 
from China (if enrolled) and Japan during the Day 1 visit. 
• 
Time-to PSA progression; 
• 
Proportion of patients with confirmed PSA progression among those 
who have achieved sustained testosterone suppression during the 48-
week treatment. 
 
 
Exploratory Endpoints 
• 
Overall survival defined as time from randomization to date of death 
prior to data cutoff date; and 
• 
The presence of polymorphisms in germline genes related to the 
hypothalamic-pituitary-androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix. 
These will be evaluated in a subset of patients. 
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Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) population defined as all 
randomized patients who have taken at least one dose of study treatment. Randomization will be 
stratified by geographic region (North and South America versus Europe versus Asia and Rest 
of World), presence of metastatic disease on baseline imaging (yes versus no), and age 
(≤ 75 years old versus > 75 years old).  The 2-sided type I error rate for this study is 0.05. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the sustained castration rate defined as the cumulative 
probability of achieving testosterone suppression to castrate levels of ≤ 50 ng/dL (1.7 nmol/L) 
while on study treatment from Week 5 Day 1 (Study Day 29) through Week 49 Day 1 (Study 
Day 337).  This probability will be estimated for each treatment group using the Kaplan-Meier 
method with the confidence interval calculated using the exponential Greenwood formula via 
log-log transformation of the survival function.  Patients who discontinue treatment prior to 
observing a testosterone level > 50 ng/dL (1.7 nmol/L) will be censored at the last testosterone 
assessment prior to discontinuation.  Detailed censoring rules will be prespecified in the 
statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• 
Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix 
is greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression to castrate levels in the 
relugolix treatment group will be calculated and must be greater than or equal to 90% to 
meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression to castrate levels.  The lower bound of the 95% confidence 
interval for the difference in the cumulative probability of sustained testosterone 
suppression to castrate levels between the 2 treatment groups will be calculated and 
must be greater than or equal to the non-inferiority margin of -10% to meet this 
criterion. 
The 2-sided type I error rate will be 0.05 for each individual evaluation criterion. 
Secondary Efficacy Endpoints: 
1. Castration rate:  the cumulative probability of testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) prior to dosing on Week 1 Day 4, and prior to dosing on Week 3 Day 1; 
2. Profound castration rate:  the cumulative probability of testosterone suppression to 
≤ 20 ng/dL (0.7 nmol/L) from Week 25 through Week 49; 
3. PSA response rate:  proportion of patients with a ≥ 50% decrease in PSA from baseline at 
Week 3 and confirmed at Week 5; 
4. Undetectable PSA rate:  proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit; 
5. Time to testosterone recovery in approximately 100 relugolix-treated and approximately 50 
leuprolide acetate-treated patients who complete 48 weeks of treatment and do not start 
alternative androgen deprivation therapy within 12 weeks after the last dose of relugolix or 
within 24 weeks following the last received injection of leuprolide acetate.  Kaplan-Meier 
methods will be used to describe survival distributions; 
6. Quality of Life:  absolute values and changes from baseline in the scores of the EORTC-
QLQ-C30 global health domain, and the EORTC-QLQ-PR25 sexual activity and hormonal-
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treatment-related symptom subdomains, at regular intervals during treatment, and as 
applicable at the Follow-up and/or End-of-Study visits will be presented.  Additionally, 
absolute values and changes from baseline of the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as EQ-5D-5L, at regular intervals during treatment, 
and as applicable during the Follow-up visits will be presented.  Change from baseline will 
be analyzed using mixed-model repeated measures methodology; 
7. Time to PSA progression; 
8. Proportion of patients with confirmed PSA progression among those who have achieved 
sustained testosterone suppression  during the 48-week treatment period.  
 
Exploratory Endpoints: 
1. Overall survival:  Overall survival defined as time from randomization to date of death prior 
to data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions; 
2. The effect of polymorphisms in germline genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or drug metabolizing enzymes and transporter 
proteins on the efficacy and safety of relugolix will be described in a separate statistical 
analysis plan. 
The methods and procedures needed to maintain a study-wide 2-sided type I error rate of 0.05 
across primary and secondary endpoint testing will be described in the statistical analysis plan. 
 
Pharmacokinetics 
Relugolix plasma concentrations will be summarized and described using population PK 
methods.  Plasma PK parameters in a subset of patients from China (if enrolled) and Japan will 
be determined using noncompartmental methods. 
 
Safety 
Safety assessments, including adverse events, vital signs, clinical laboratory tests, and ECGs, 
will be summarized for the treatment-emergent period.  The treatment-emergent period is 
defined as the time from first dose of study drug through 30 days after the last dose of relugolix 
or 12 weeks plus 30 days after the last dose of leuprolide acetate.  Safety analyses will be based 
on all randomized patients who receive any amount of study drug (Safety population).  Drug 
exposure will be summarized by descriptive statistics.  Severity of all treatment-emergent 
adverse events will be evaluated by the investigator based on the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred 
term, higher-level term, and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of patients with adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to study drug, and 
severity.  Descriptive rather than inferential statistics will be used.  Laboratory values also will 
be classified by toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory 
shift tables of baseline versus post baseline results will be produced. 
An independent Data and Safety Monitoring Board will monitor all available safety data on a 
periodic basis.  The roles and responsibilities of the Data and Safety Monitoring Board will be 
described in detail in a separate charter. 
 
 
 
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Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• 
True probabilities of sustained castration rates are 94% and 96% for relugolix and 
leuprolide acetate, respectively; 
• 
2:1 randomization ratio (relugolix:leuprolide acetate); 
• 
Dropout rate of 15%. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of ≤ 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and a 2-sided type I error 
rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) will 
yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate. 
The primary analysis of the primary efficacy endpoint will be performed after at least 
915 patients have had the opportunity to complete 48 weeks of study drug treatment.  The 
evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans. 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3201 
Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Informed 
Consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dispensation: 
Relugolix 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xr 
 
 
 
Study Drug 
Administration: 
Relugolix Once 
Daily 
 
X 
X 
Patients will receive a single loading dose of oral relugolix 360 mg on Day 1 in the clinic; 
Starting on Day 2, patients will take oral relugolix 120 mg once daily 
Xr 
 
 
 
Study Drug 
Administration: 
Leuprolide 
Acetate 3-M 
Depot 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Xr 
 
 
 
Phone call prior 
to visit and 
study drug 
accountabilityd 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including 
detailed prostate 
cancer history) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Weight, BMI 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
12-lead ECGg 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
ECOG 
Performance 
Assessment 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
Complete 
Physical Exam 
and Visual 
Acuityh 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
 
 
 
Symptom Based 
Physical Exam 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xr 
X 
X 
X 
Abdominopelvic 
CT or MRI and 
Bone Scani 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
EuroQol EQ-
5D-5L Health 
Questionnaire 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
EORTC-QLQ-
PR25 and 
EORTC-QLQ-
C30 Quality of 
Life 
Questionnaires 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Lipid & HbA1ck 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Serum 
Testosterone 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xr 
X 
X 
X 
LH/FSH 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
X 
X 
SHBG/DHT 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
 
 
X 
Blood Sample 
for Relugolix 
PKm,n 
 
Xm,n 
Xn 
Xn 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xr 
 
 
 
Blood Sample 
for DNAo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
Health Status 
Surveyp 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xr 
 
 
 
Abbreviations:  3-M, 3-month; BMI, body mass index; CT, computed tomography; DHT, dihydrotestosterone; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of 
treatment; EuroQol EQ-5D-5L, European Quality of Life 5-Dimension 5-Level; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; LH, luteinizing 
hormone; MRI, magnetic resonance imaging; PK, pharmacokinetics; PSA, prostate-specific antigen; SHBG, sex hormone binding globulin 
a. 
The study day in which the Follow-up visit occurs is not specified in the table because these visits occur relative to when the patient takes his last dose of 
study drug.  The End of Treatment (EOT) is defined as the last dose of relugolix or 12 weeks after the last leuprolide acetate injection. 
b. May occur earlier for patients who are starting alternative androgen deprivation therapy, or do not complete 12 weeks of study treatment.  Adverse events, 
serious adverse events, and concomitant medications should continue to be collected and recorded through 30 days after the End of Treatment.  All other 
study procedures should be completed before the start of alternative androgen deprivation therapy. 
c. 
Patients who have started alternative androgen deprivation therapy will not participate in the 60- and 90-day Follow-up visits.  For approximately 100 
patients receiving relugolix and approximately 50 patients receiving leuprolide acetate who complete 48 weeks of study drug treatment and, in the opinion of 
the investigator, can remain off androgen deprivation therapy for 90 days will be included in the testosterone recovery 60- and 90-day Follow-up visits. 
d. For patients assigned to the relugolix treatment arm, the patient should be called 7 days before their next visit to check on compliance with their study 
medication. Study drug accountability will be conducted at visits and results will be recorded as the primary source of study drug accountability. 
e. 
If patient terminates early from study treatment, the patient should be asked to come in as soon as possible and complete this visit. 
f. 
The informed consent form must be signed before any study-mandated procedures are performed. 
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g. 12-lead ECGs should be read locally by a qualified physician. 
h. A complete physical examination should be performed.  Visual acuity will be evaluated by a standard visual eye chart.  The patient should wear any 
prescribed glasses or contacts during the visual acuity assessment. Patients whose presenting visual acuity score is 90 or lower at the screening visit should 
be encouraged to obtain a diagnostic evaluation from an eye care provider, i.e., an ophthalmologist or an optometrist.  Any findings (i.e., diagnoses) from the 
eye examination should be recorded as medical history. Patients whose presenting visual acuity score at Week 25, Week 49, or Early Termination has 
decreased by 10 or more points from the screening visit should be referred to an ophthalmologist for a diagnostic evaluation.  A copy of the ophthalmology 
consultation must be submitted to the sponsor 
i. 
An abdominopelvic CT or MRI and a bone scan should be performed and read locally to determine the presence of metastatic disease within 60 days prior to 
randomization. However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not required. If metastatic disease is not present on CT or 
MRI, then a bone scan is also required.  
j. 
Collect serious adverse event information from the time of signed informed consent through the Safety Follow-up Visit, which is through 30 days after the 
last dose of relugolix or 12 weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or 
hormonal therapy or surgical intervention, whichever occurs first.  Collect nonserious adverse event information from the Baseline Day 1 visit (or from the 
time of signed informed consent if event was related to a screening study procedure through approximately 30 days after the last dose of relugolix or 12 
weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or hormonal therapy or surgical 
intervention, whichever occurs first. 
k. Blood samples must be obtained fasting; nothing to eat or drink (other than water) for at least 9 hours prior to obtaining the sample. 
l. 
All testosterone samples obtained from Week 5 and beyond are to be collected during a ± 7-day window. 
m. Blood samples for PK analysis will be collected for all patients assigned to the relugolix treatment arm.  Samples will be collected predose, approximately 24 
hours after the previous dose. Patients may be dosed in the clinic at these visits, provided the dose can be administered at least 2 hours after food; food 
should be withheld for 1 hour after dosing.  
n. A subset of patients from China (if enrolled) and Japan will have additional samples collected predose, and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on 
Day 1 and Week 2 visits. Patients will be dosed in the clinic at these visits. The dose will be administered at least 2 hours after food; food should be withheld 
for 1 hour after dosing. A predose sample (approximately 24 hours after the previous dose) also will be collected at the Day 4 visit.  Patients may be dosed in 
the clinic at the Day 4 visit, provided the dose can be administered at least 2 hours after food; food should be withheld for 1 hour after dosing.  
o. The blood sample for DNA should be collected at the Baseline Day 1 visit, but may be collected at any visit if it is missed at that visit. 
p. During the final weeks prior to database lock, sites will be asked to contact all study participants or their immediate family regarding the current health status 
of previously enrolled/completed study patients.  
q. Week 2 visit will only occur for patients who are part of the Japan or China subset for PK analysis.  
r. 
For an Unscheduled visit, these procedures will be performed as needed, based on the reason(s) for the Unscheduled visit.
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2. 
INTRODUCTION 
2.1. 
Prostate Cancer 
Prostate cancer is the most prevalent form of cancer in men and the second leading cause of 
death due to cancer in men in the US [Greenlee, 2001] and Europe [Ferlay, 2007].  The median 
age of diagnosis is 70 years, and diagnosis before the age of 40 years is rare [Cersosimo, 1996].  
In Japanese men, prostate cancer was the fourth leading cancer diagnosis in 2007 [Foundation 
for Promotion of Cancer Research, 2012].  The incidence of invasive prostate cancer increases 
with age; a clear increase is seen among men aged 60 years or older [Siegel, 2014]. 
If prostate cancer is diagnosed at a stage where it is confined to the prostate gland and immediate 
surroundings, it is generally treated by surgical removal of the prostate gland, or prostatectomy, 
or with radiation.  Often, these procedures are successful in curing men of their disease.  Men 
whose disease progresses after prostatectomy or radiation are said to have advanced prostate 
cancer.  Advanced prostate cancer is defined as either:  PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; newly diagnosed metastatic prostate 
cancer; or advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  The cure rate following surgery, depending on the stage of the cancer, is about 70% 
overall and, following radiation, about 50% to 60%. 
Approximately 25% to 30% of men will, therefore, progress to advanced disease, excluding 
those with metastatic disease at the time of diagnosis.  Androgens, such as testosterone and its 
more potent metabolite dihydrotestosterone, are strong tumor promoters for prostate cancer 
[Bosland, 2014].  Through the androgen receptor, they synergistically augment the effect of other 
tumor promoters or carcinogens.  Although prostate cancer is driven by presumed mutations in 
other tumor promoting pathways and/or by translocations leading to aberrant activation of the 
androgen receptor pathway, most early-stage prostate cancer cells remain either sensitive to or 
dependent upon circulating androgens.  Thus, for more than 60 years, androgen deprivation 
therapy with surgical or medical castration has been the foundational therapy for either advanced 
inoperable or metastatic cancer.  Increasingly, androgen deprivation therapy is used earlier as a 
neoadjuvant/adjuvant treatment to radiation therapy or for biochemical or clinical relapse after 
local therapies of curative or palliative intent.  More than 80% of men with progressive or 
advanced disease initially respond to androgen deprivation therapy with varying degrees of 
tumor regression or stabilization [Kreis, 1995].  The duration and depth of response to androgen 
deprivation therapy is presumably dependent on the underlying tumor biology and burden.  Thus, 
patients with metastases respond for an average of 2 years before any biochemical evidence of 
castration resistance occurs.  By contrast, patients with biochemical-only evidence of progressive 
disease may respond to androgen deprivation therapy for 5 years or more [Klotz, 2015]. 
Currently, most patients in developed countries receive medical rather than surgical castration.  
GnRH (or LH-releasing hormone) agonists (ie, long-acting leuprolide acetate depot injections) 
are the current mainstay of medical castration, causing long-term desensitization and down 
regulation of the hypothalamic-pituitary gonadal axis.  One disadvantage of the agonist form of 
GnRH is the initial stimulation of the axis lasting 1 to 3 weeks that occurs prior to 
desensitization.  This results in a rise in LH and testosterone levels and an increase in clinical 
symptoms.  In addition, at the time of repeat injection of GnRH agonist depot, microsurges of 
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LH and testosterone may occur, although the apparent incidence is low [Klotz, 2008].  The initial 
flare response may be managed with simultaneous antiandrogen administration, such as with 
bicalutamide. 
Recently, GnRH antagonists, in particular degarelix, [Firmagon, 2016], have become available as 
an alternative form of medical castration.  Degarelix, an injectable peptide, has been approved in 
some countries for the treatment of patients with advanced prostate cancer.  As a GnRH 
antagonist, degarelix achieves medical castration and PSA response with no initial agonist 
activity within the first 1 to 2 weeks of administration, and effectively can obviate the need for 
concomitant antiandrogen treatment.  Post-hoc analyses of degarelix trials [Tombal, 2010] 
suggest that it may have additional advantages regarding disease response or secondary relapse; 
however, such differences require confirmation in prospective studies.  Because of the need for 
monthly depot injections, with large volumes and accompanying local reactions, the use of 
degarelix in clinical practice has remained low. 
Relugolix, previously known as TAK-385, is a potent and highly selective oral small molecule 
antagonist for the human GnRH receptor.  For patients, relugolix may offer the advantages 
conferred by a direct receptor antagonist, including a more rapid onset of action and the absence 
of clinical flare or worsening of symptoms from the initial rise in androgens caused by GnRH 
agonists, as well as having the added convenience and relative comfort of oral dosing. 
2.2. 
Relugolix 
2.2.1. 
Indication 
Relugolix is being developed as a once daily oral medication for the treatment of advanced 
prostate cancer.  The proposed dose of relugolix is 120 mg administered orally once daily 
following a loading dose of 360 mg (three 120-mg tablets) on Day 1. 
2.2.2. 
Pharmacology 
Relugolix is an orally-active, potent, highly-selective, high-affinity small molecule GnRH 
receptor antagonist with a novel structure.  Relugolix was discovered and initially studied by 
Takeda Pharmaceutical Company, Limited, before development rights outside of Japan and 
certain East Asian countries were licensed to Myovant Sciences GmbH. 
Relugolix antagonizes the human GnRH receptors present on the gonadotrophin-secreting cells 
of the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
LH and FSH fall rapidly, followed by a decline over a few days in testosterone in men and 
estradiol and progesterone levels in women.  Relugolix acts as a potent and highly selective 
antagonist for the human GnRH receptor.  The affinity of relugolix for the human GnRH 
receptor in vitro was approximately 50-fold higher than that of GnRH in the presence of protein 
(40% fetal bovine serum).  Transgenic knock-in mice expressing the human GnRH receptor 
treated with relugolix had substantial reductions in reproductive organ weights of both female 
and male mice, suggesting that relugolix may suppress blood estrogen and testosterone levels, 
respectively.  Orally administered relugolix suppressed the hypothalamic-pituitary axis in 
castrated cynomolgus monkeys at doses of 1 mg/kg and higher. 
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2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level for liver findings in the 39-week monkey 
toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (area under the 
concentration-time curve [AUC]) in men receiving 120 mg once daily (0.469 μg⋅hr/mL), the 
dose of relugolix to be administered in this study.  Both the liver and PLD findings demonstrated 
evidence of reversibility following a 13-week recovery period in monkeys.  No evidence of PLD 
has been observed in clinical studies.  The relugolix toxicology program supports the conduct of 
clinical studies up to the NOAEL (15 mg/kg/day) exposure (5.2 μg·hr/mL) for liver toxicity in 
monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human Thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies have been completed.  In 
addition, 6 clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 
2 studies in men with prostate cancer (US and Europe), and 2 phase 3 studies in women with 
uterine fibroids in Japan.  More than 1380 patients and healthy volunteers have received at least 
one dose of relugolix, including 158 women receiving relugolix 40 mg once daily for at least 
28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg once daily for at 
least 24 weeks and for as long as 48 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of testosterone in male subjects and estradiol in female subjects.  After oral 
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administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The PK and pharmacodynamics of relugolix have been evaluated, and 
appear to be similar in Western and Asian volunteers, despite the lower mean body mass index 
observed in Asian volunteers. 
A relative bioavailability and food effect study was conducted using the global phase 3 prostate 
cancer formulation of 120 mg relugolix.  After administration with a high-fat, high-calorie 
breakfast, the Cmax and AUC of relugolix were reduced, on average, by 21.4% and 18.8%, 
respectively. 
In the phase 1 study C27001, serum LH, FSH, dihydrotestosterone, and testosterone 
concentrations were determined in healthy men following single and multiple oral doses of 
relugolix or placebo for up to 28 days.  Loading doses of ≥ 160 mg on Day 1 were used to 
shorten the time to testosterone suppression.  Relugolix caused an immediate and effective 
suppression of LH, FSH, and testosterone.  After 14 days of once daily dosing, mean LH and 
serum testosterone concentration profiles were similar for the 40, 80, and 180 mg relugolix dose 
cohorts.  LH, FSH, and testosterone concentrations began decreasing 2 to 6 hours postdose on 
Day 1 and remained suppressed through Day 14.  However, the relugolix once daily maintenance 
dose was a major determinant of sustained testosterone suppression.  Profound castration 
(defined as average testosterone levels < 20 ng/dL or 0.7 nmol/L) was achieved with 40, 80, or 
180 mg once daily for 14 days; however, 20 mg once daily was insufficient in maintaining 
adequate suppression of serum LH and testosterone concentration levels during the second week. 
In healthy, older men receiving 14 or 28 days of dosing, effective castration was consistently 
achieved over 14 and 28 days dosing at daily doses of 40 to 180 mg (14 days) and 80 to 160 mg 
(28 days).  Use of a loading dose for up to 3 days (or once daily doses of ≥ 160 mg) resulted in 
castration levels of testosterone (< 50 ng/dL or 1.7 nmol/L) within 24 to 48 hours.  Results 
obtained after 28 days of dosing suggested that the likely minimal, fully effective maintenance 
dose for sustained castration would be relugolix ≥ 80 mg once daily.  Doses of 80 mg and 
120 mg were moved forward into phase 2 development. 
Relugolix is to be administered in the fasted state (at least 1 hour before or 2 hours after a meal), 
as food decreases the extent of relugolix absorption by approximately 20%.  The exposure of 
relugolix is increased by inhibitors of P-glycoprotein up to 6-fold, but relugolix does not 
significantly impact the exposure of cytochrome P450 (CYP) 1A2, 2C9, 2D6, or 3A4 substrates.  
In a dedicated study, relugolix did not prolong QTc at single doses of 60 or 360 mg. 
2.2.4.2. 
Clinical Studies in Men with Prostate Cancer 
One phase 1 study and 2 phase 2 studies have been conducted evaluating relugolix in men with 
prostate cancer. 
Study TB-AK160108 is an ongoing multicenter phase 1, open-label, dose range-finding study 
conducted in hormone treatment-naïve Asian patients with non-metastatic prostate cancer.  The 
study consists of a dose-rising phase (Part A) and an expansion phase (Part B).  In Part A, a 
loading dose of relugolix (320 or 360 mg) was administered on Day 1 followed by once daily 
dosing on Days 2 through 28, with the dosage dependent on the individual cohort of 3 to 4 
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patients each.  In Part B, 30 patients receive a maximum of 96 weeks treatment at doses of 
80 and 120 mg once daily (N = 15 each arm, loading dose of 320 mg on Day 1).  Testosterone 
reduction by both doses of relugolix was rapid and sustained through 48 weeks.  Both the 80-
 and 120-mg once daily doses were evaluated in phase 2 clinical studies. 
Study C27003 is a phase 2 study that enrolled men in North America or the United Kingdom 
requiring 6 months of androgen deprivation therapy as neoadjuvant and adjuvant therapy to 
external beam radiation therapy.  Patients were randomized to relugolix 120 mg once daily 
following a single oral loading dose of 320 mg (N = 65) or to degarelix 80 mg subcutaneously 
every 4 weeks following a single loading dose of 240 mg (N = 38) for 24 weeks.  External beam 
radiation therapy was initiated for most patients between Week 13 and Week 15. 
Relugolix 120 mg administered orally once daily rapidly suppressed testosterone levels below 
the castration threshold (50 ng/dL [1.7 nmol/L]) within the first week of therapy and maintained 
those levels from the end of Week 4 through at least 24 weeks.  The levels of testosterone 
suppression achieved by relugolix were similar to those achieved by monthly injections of 
degarelix.  Profound castration rates below the lower testosterone threshold of < 20 ng/dL 
(0.7 nmol/L) were also similar in the relugolix and degarelix groups (Table 2-1). 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks 
 
Relugolix 
120 mg QDa 
N = 65 
Degarelix 
80 mg Q4Wb 
N = 38 
Castration rate over 24 weeks, % 
(95% CI) 
95% 
(87.1, 99.0) 
89% 
(75.2, 97.1) 
Note:  Castration rate is defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5, Day 1 to specific time point (Week 25, Day 1). 
Abbreviations:  CI, confidence interval; Q4W, once every 4 weeks; QD, once daily 
a. 
Loading dose of 320 mg on Day 1 
b. Loading dose of 240 mg on Day 1, then dosed every month 
 
The percentage PSA reductions and absolute PSA values over time were consistent with the 
rapid testosterone reductions observed with both therapies and were similar between the 
relugolix and degarelix treatment arms.  Prostate gland size was measured during screening and 
following 8 to12 weeks of study drug treatment.  In both treatment groups, the average reduction 
in estimated prostate volumes was similar, approximately 30%.  Following discontinuation of 
therapy at the end of 24 weeks, patients were followed for an additional 12 weeks to evaluate 
testosterone recovery and associated changes in PSA and quality of life.  At the end of the 
follow-up period, approximately half of the patients receiving relugolix had recovered either to 
the baseline testosterone value or to > 280 ng/dL, whichever was less, compared to only 6% of 
patients receiving degarelix (Figure 2-1). 
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Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of 
Relugolix and Degarelix at Week 25 
 
Note:  Y-axis shows testosterone value (ng/dL); x-axis shows study week. 
 
Study C27002 is a phase 2 study of relugolix and leuprolide acetate in patients with prostate 
cancer who require first-line androgen deprivation therapy, which is ongoing in North America.  
This study was designed to help plan the population, dosing, and assessment schedules for 
phase 3 studies in patients with advanced prostate cancer.  Eligible patients in C27002 have 
evidence of advanced prostate cancer including either:  1) PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; 2) newly diagnosed metastatic prostate 
cancer; or 3) advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  In this open-label, parallel group study, patients were randomized to receive 1 of 
2 dose levels of oral relugolix (80 or 120 mg [patients randomized to relugolix received a loading 
dose of 320 mg on Day 1], N = 50 per group) or to an observation cohort to receive standard 
GnRH therapy with leuprolide acetate 22.5 mg administered by intramuscular injection every 
12 weeks (N = 25).  Relugolix or leuprolide acetate was administered for up to 48 weeks with 
patients randomized to leuprolide acetate receiving their last on-study 12-week depot injection at 
Week 37. 
The primary objective of this phase 2 study was to evaluate the ability of relugolix to achieve 
and maintain testosterone suppression (< 50 ng/dL [1.7 nmol/L]) through Week 25.  Results 
from the completed study C27002 demonstrate that both doses of relugolix, 80 mg and 120 mg 
once daily, rapidly reduced testosterone levels below the castration threshold within the first 
week of therapy and maintained those levels in 91% of patients through 24 weeks of treatment 
(Table 2-2). 
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Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) 
 
Relugolix 
Leuprolide 
Acetate 
22.5 mg Q12W 
N = 24 
 
80 mg QD 
N = 56 
120 mg QD 
N = 54 
Total 
N = 110 
Patients with at least 1 dose of 
treatment, n 
56 
54 
110 
24 
Castration ratea over 24 weeks 
 
 
 
 
n (%) 
51 (91) 
49 (91) 
100 (91) 
23 (96) 
95% CIb 
80.4-97.0 
79.7-96.9 
83.9-95.6 
78.9-99.9 
Profound castration ratec over 24 weeks 
 
 
 
 
n (%) 
39 (70) 
41 (76) 
80 (73) 
18 (75) 
95% CIb 
55.9-81.2 
62.4-86.5 
63.4-80.8 
53.3-90.2 
Abbreviations:  CI, confidence interval; Q12W, once every 12 weeks; QD, daily 
a. 
Castration rate was defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5 Day 1 to specific time point. 
b. The 2-sided 95% CI was calculated using the normal approximation method, if the number of non-castration 
patients was = 5 in any treatment arm, the exact CI was presented. 
c. 
Profound castration rate was defined as the estimated proportion of patients who had testosterone concentrations 
< 20 ng/dL at all scheduled visits Week 13 Day 1 through specific time point. 
 
Castration to below the lower testosterone threshold of < 20 ng/dL was also similar in the 
2 relugolix arms and to that observed in the leuprolide acetate arm.  On average, in patients 
receiving relugolix, testosterone decreased to below the castration threshold of 50 ng/dL 
(1.7 nmol/L) by the Day 4 visit, and to below the profound castration threshold of 20 ng/dL 
(0.7 nmol/L) by the Week 5 visit.  In contrast, in patients receiving leuprolide acetate, 
testosterone levels rose during the first 1 to 2 weeks of therapy and then declined to castrate 
levels by Week 5.  PSA responses between the 2 relugolix arms and leuprolide acetate were 
similar as demonstrated by PSA waterfall plots showing the reduction in PSA from baseline for 
individual patients (Figure 2-2 [relugolix] and Figure 2-3 [leuprolide acetate]). 
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Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent 
Reduction by Dose of Relugolix at Week 25 Day 1 
 
 
Note:  Last observation carried forward method was used to impute percent prostate-specific antigen reductions for 
patients without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen; QD, once 
daily; TAK-385, relugolix 
 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent 
Reduction by Leuprolide Acetate at Week 25 Day 1 
 
Notes: 
The leuprolide acetate dose was 22.5 mg every 12 weeks. 
Last observation carried forward method was used to impute percent prostate-specific antigen reductions for patients 
without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen 
 
A more detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Visit
Obs on Week 25 Day 1
LOCF by Week 25 Day 1
PSA Percent Reduction
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Investigator Brochure, Version 9.0, dated 09 November 2016, along with a full discussion of the 
safety profile of relugolix. 
2.2.4.3. 
Clinical Safety of Relugolix in Men with Prostate Cancer 
A full description of the safety data for relugolix from clinical trials is available in the 
Investigator Brochure.  Overall, approximately 632 healthy volunteers (330 women, 302 men), 
535 female patients with uterine fibroids (N = 229) or endometriosis (N = 306), and 218 male 
patients with prostate cancer received at least 1 dose of relugolix.  Data from the 175 patients 
with prostate cancer who received relugolix in randomized, open-label, parallel-group phase 2 
studies, C27002 and C27003, provide the basis for the frequency of expected adverse events 
associated with relugolix in the prostate cancer indication.  The adverse drug reactions in the 
prostate cancer indication observed in the phase 2 studies include hot flush (59%), fatigue (26%), 
arthralgia (10%), nausea (5%), and gynecomastia (3%).  No clinical evidence of PLD has 
observed in any relugolix clinical study. 
Leuprolide Acetate 3-Month Depot 
Leuprolide acetate depot is indicated for the palliative treatment of advanced prostatic cancer. 
Leuprolide acetate acts as an agonist at pituitary GnRH (gonadotropin-releasing hormone) 
receptors.  Leuprolide acetate has greater receptor affinity, reduced susceptibility to enzymatic 
degradation, and is approximately 100-fold more potent than the natural GnRH molecule.  GnRH 
agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial 
release of both LH and FSH, which causes a subsequent increase in testosterone production from 
testicular Leydig cells.  Initially, leuprolide acetate stimulates LH production, which in turn 
causes a surge of testosterone and dihydrotestosterone for 5 to 12 days before the ultimate 
inhibition of LH.  This androgen surge of male hormones can cause a flare reaction (“clinical 
flare”), which may lead to an increase in bone pain, bladder obstruction, or other symptoms due 
to prostate cancer [Tolis, 1982; Schally, 1980; Waxman, 1985; Conn, 1991; Limonata, 2001]. 
Chronic stimulation by the GnRH agonist ultimately desensitizes the GnRH receptors, 
downregulating the secretion of gonadotropins, LH, and FSH, leading to hypogonadism and thus 
a dramatic reduction in testosterone and dihydrotestosterone, on which continued growth of 
prostate cancer cells depends.  The fall in serum LH leads to a decrease in serum testosterone to 
castrate levels within 3 to 4 weeks after the start of treatment.  Continued treatment maintains 
serum testosterone at castrate levels. 
The decrease in testosterone production is generally reversible over time upon cessation of 
GnRH agonist therapy.  However, testosterone production does not always return to baseline 
levels and may be related to the duration of GnRH agonist therapy, patient age, and other factors. 
The flare phenomenon can be effectively prevented with antiandrogen therapy, which blocks the 
effect of the increased serum testosterone [Loblaw, 2004].  First generation antiandrogens such 
as flutamide, bicalutamide, and nilutamide bind to androgen receptors and competitively inhibit 
their interaction with testosterone and dihydrotestosterone.  They are often used in an attempt to 
limit the clinical sequelae produced by the hormonal surge resulting from GnRH agonist 
treatment. 
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The most common adverse reactions (> 10%) reported for marketed formulations of leuprolide 
acetate depot in common use include the following examples: 
• Leuprolide (leuprorelin) acetate 11.25 mg:  weight fluctuation, hot flash, hyperhidrosis, 
muscle weakness, bone pain, decreased libido, erectile dysfunction, testicular atrophy, 
fatigue, injection site reaction [Prostap 3 DCS, 2016] 
• Leuprolide acetate 22.5 mg:  hot flashes, ecchymoses, erythema, fatigue, injection site 
burning, injection site paraesthesia [Eligard, 2017] 
In post marketing experience, mood swings, depression, rare reports of suicidal ideation and 
attempt, rare reports of pituitary apoplexy have been reported.  Leuprolide has been associated 
with mild liver enzyme elevations (generally transient and asymptomatic) during therapy in 3-
5% of patients; values above 3 times the upper limit of normal are rare, being reported in less 
than 1% of recipients.  A risk of developing or worsening diabetes has been reported in men 
receiving this class of drug. 
The package insert (approved labeling) for the leuprolide acetate study drug provided for this 
study should be referenced for warnings, precautions, and safety information. 
 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
This phase 3 trial has 2 separate evaluation criteria for the primary efficacy endpoint to support 
different regulatory requirements for assessing benefit as listed briefly below and described in 
detail in the statistical analysis plan.  Patients enrolled into this phase 3 trial will be randomized 
2:1 to either relugolix 120 mg once daily following an oral loading dose of 360 mg on Day 1, or 
to leuprolide acetate 22.5 mg (or 11.25 mg Japan, Taiwan, and China) 3-M depot injection.  
Patients randomized to leuprolide acetate will also receive an antiandrogen if indicated at the 
discretion of the investigator. 
The first criterion for the primary efficacy endpoint will evaluate only patients randomized to 
relugolix.  The second criterion for the primary efficacy endpoint will evaluate the non-
inferiority of patients randomized to relugolix to those randomized to leuprolide acetate as 
described below. 
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Objectives 
Endpoints 
Primary 
• 
To evaluate the ability of relugolix to achieve 
and maintain serum testosterone suppressed to 
castrate levels of ≤ 50 ng/dL (1.7 nmol/L) in 
patients with androgen-sensitive advanced 
prostate cancer. 
The primary endpoint is the sustained castration 
rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
• 
Evaluation Criterion 1:  to determine whether 
the sustained castration rate (defined as the 
cumulative probability of testosterone 
suppression to ≤ 50 ng/dL [1.7 nmol/L] while 
on study treatment from Week 5 Day 1 
through Week 49 Day 7) for relugolix is 
greater than or equal to 90%.  The lower 
bound of the 95% confidence interval for the 
cumulative probability of sustained 
testosterone suppression in the relugolix 
treatment group will be calculated and must be 
at least 90% to meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-
inferiority of relugolix compared to leuprolide 
acetate 3-M depot injection as assessed by the 
cumulative probability of sustained 
testosterone suppression.  The lower bound of 
the 95% confidence interval for the difference 
in the cumulative probability of sustained 
testosterone suppression between the 
2 treatment groups will be calculated and must 
be greater than or equal to the non-inferiority 
margin of -10% to meet this criterion. 
Secondary 
• 
To evaluate the time course and change in 
serum testosterone during treatment with 
relugolix; 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative 
probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing 
on Week 1 Day 4 and prior to dosing on 
Week 3 Day 1; 
o Profound castration rate defined as the 
cumulative probability of testosterone 
suppression to ≤ 20 ng/dL (0.7 nmol/L) 
while on treatment from Week 25 Day 1 
through Week 49 Day 1); 
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Objectives 
Endpoints 
• 
To evaluate the time course and magnitude of 
PSA reduction during treatment with 
relugolix; 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed 
PSA response (by Prostate Cancer 
Clinical Trials Working Group 3 
[Scher, 2016]) at the Week 3 and Week 5 
visits; 
o Proportion of patients with PSA 
concentration < 0.2 ng/mL [0.2 µg/L] at 
the Week 25 visit; 
• 
To evaluate testosterone recovery following 
discontinuation of relugolix; 
• 
Time to testosterone recovery in 
approximately 100 patients randomized to 
relugolix and approximately 50 patients 
randomized to leuprolide acetate who 
complete  48 weeks of treatment and who do 
not plan to start alternative androgen 
deprivation therapy within the following 12 
weeks (or within 24 weeks following the last 
injection of leuprolide acetate 3-M depot); 
• 
To evaluate quality of life using validated 
patient-reported outcome instruments; 
• 
Absolute values and changes from baseline in 
the scores of the EORTC-QLQ-C30 global 
health domain, and the EORTC-QLQ-PR25 
sexual activity and hormonal-treatment-related 
symptom subdomains, at regular intervals 
during treatment, and as applicable during the 
Follow-up and/or End of Treatment visits; 
• 
Absolute values and changes from baseline of 
the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular 
intervals during treatment, and as applicable 
during the Follow-up visits; 
• 
To evaluate the safety of relugolix 120 mg 
once daily in men with androgen-sensitive 
advanced prostate cancer; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical 
laboratory data; 
• 
To evaluate the effect of relugolix and 
leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
Endocrine marker effects of relugolix and 
leuprolide acetate as measured as absolute 
value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 
25, and Week 49 visits; 
o Sex hormone binding globulin at the 
Week 5, Week 25, and Week 49 visits; 
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Objectives 
Endpoints 
• 
To collect relugolix plasma concentration data 
to further evaluate relugolix population PK 
and the relationship between relugolix 
exposure and serum testosterone; and 
• 
Predose relugolix plasma concentrations; 
• 
To characterize the relugolix plasma PK 
parameters in a subset of patients from China 
(if enrolled) and Japan; 
• 
Single and repeat-dose plasma relugolix PK 
parameters such as Cmax, AUC0-τ, and tmax. 
• 
To describe the time course and magnitude of 
PSA progression and development of 
castration resistant prostate cancer during 
treatment with relugolix; 
• 
Time to PSA progression 
• 
Proportion of patients with confirmed PSA 
progression among those who have achieved 
sustained testosterone suppression during the 
48-week treatment   
 
 
Exploratory 
• 
To explore the overall survival of patients 
treated with relugolix; and 
• 
Overall survival defined as time from 
randomization to date of death prior to data 
cutoff date; 
• 
To explore the contribution of genetic 
variance on drug response. 
• 
The presence of polymorphisms in germline 
genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter 
proteins that might be implicated in the drug 
disposition, safety, or efficacy of relugolix. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension 
22.5 mg (or 11.25 mg in Japan, Taiwan, and China) every 3-months (3-M) will be administered 
to patients with prostate cancer who require androgen deprivation therapy.  This study will 
evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive 
advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
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sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local primary 
intervention with curative intent, newly diagnosed metastatic disease (excluding metastases to 
the brain), and/or advanced localized disease.  Patients may receive radiotherapy, cryotherapy or 
high frequency ultrasound no sooner than 2 months after initiation of androgen deprivation 
therapy.  Patients may be included if they have not previously received androgen deprivation 
therapy for more than 18 months, and if the androgen deprivation therapy was completed at least 
3 months prior to baseline. If the dosing interval of the depot is longer than 3 months, then the 
prior androgen deprivation therapy must have been completed at least as long as the dosing 
interval of the depot.  Patients previously treated with taxanes or expected to receive taxanes 
after initiation of androgen deprivation therapy are excluded, as are patients receiving androgen 
deprivation therapy adjuvant or neoadjuvant to radiotherapy as primary definitive therapy.  
Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once daily 
following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg (or 
11.25 mg in Japan, Taiwan, and China). After randomization, patients on the leuprolide acetate 
arm may receive an antiandrogen for the first 4 weeks or longer if indicated in the opinion of the 
investigator.  Randomization will be stratified by geographic region, presence of metastatic 
disease, and age. 
Approximately 915 patients will be enrolled in this study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-reported 
outcomes (EORTC-QLQ-C30, EORTC-QLQ-PR25, EuroQol EQ-5D-5L) will be assessed 
approximately every 3 months during the Treatment Period and more frequently during the 
Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China (if 
enrolled) and Japan.  Safety assessments will include treatment-emergent adverse events, vital 
signs, physical examinations, clinical laboratory tests, 12-lead ECG, and visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive radiotherapy as prescribed by the investigator. In the setting of rising PSA 
patients may also receive enzalutamide. For patients requiring other systemic antineoplastic 
therapy during the treatment period, the investigator should contact the medical monitor.  
A schematic of the overall study design is provided in Figure 4-1. 
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Figure 4-1 Schematic of Study Design 
 
 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is designed to establish the safety and efficacy of relugolix 120 mg orally 
once daily in men with advanced prostate cancer who require at least 1 year of continuous 
androgen deprivation therapy for androgen-sensitive disease.  This study will focus on the 
primary objective of evaluating the ability of relugolix to achieve and maintain suppression of 
serum testosterone to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) in patients with advanced prostate 
cancer.  During the Treatment Period of the study (Day 1 to Week 49 [Study Day 337]), patients 
will be randomized to one of the study treatment arms:  oral loading dose of relugolix (360 mg) 
followed by 120 mg once daily of relugolix or leuprolide acetate 3-M depot injection of 22.5 mg 
(or 11.25 mg Japan, Taiwan, and China) at 12-week intervals for 48 weeks.  Patients treated with 
leuprolide acetate will also receive an antiandrogen for 4 weeks or longer if indicated in the 
opinion of the investigator. 
The study is designed to allow for global approvals, however, different regulatory agencies 
require different criteria for the demonstration of efficacy.  The United States (US) Food and 
Drug Administration (FDA) requires, for approval, a primary efficacy criterion to determine 
whether the sustained castration rate (defined as the cumulative probability of testosterone 
≤ 50 ng/dL [1.7 nmol/L] while on relugolix study treatment from Week 5 Day 1 through Week 
49 Day 1) is greater than or equal to 90%.  The lower bound of the 95% confidence interval for 
the cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion.  The 
study includes a leuprolide acetate arm to meet the regulatory requirement of other regions to 
establish the non-inferiority of relugolix compared to leuprolide acetate 3-M depot injection as 
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assessed by the cumulative probability of sustained testosterone suppression.  The lower bound 
of the 95% confidence interval for the difference in the cumulative probability of sustained 
testosterone suppression between the 2 treatment groups will be calculated and must be greater 
than or equal to the non-inferiority margin of -10% to meet this criterion. 
The dose of relugolix selected is based on data from phase 1 and 2 studies demonstrating that 
oral doses of 80 mg and 120 mg once daily following an oral loading dose of 320 mg were able 
to suppress testosterone to castrate levels (see Section 2.2.4.2 and the Investigator Brochure).  A 
loading dose of 360 mg (three 120-mg tablets) was selected for phase 3 so that only one tablet 
size was required.  Leuprolide acetate 3-M depot injection was selected as the comparator as this 
is the GnRH agonist used most commonly as standard of care in the population under evaluation.  
Degarelix, an injectable GnRH antagonist, was considered, but was not used as it has limited 
market uptake attributed at least in part to a significant number of injection site reactions. 
4.3. 
Selection of Study Population 
Approximately 915 men with advanced prostate cancer requiring androgen deprivation therapy 
will be enrolled in this study from approximately 200 study centers in North and South America, 
Europe, and the Asia-Pacific region.  Enrollment is defined as the time at which a patient is 
randomized to a treatment group and receives at least one dose of study drug. 
Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor prior 
to randomizing the patient. 
4.3.1. 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following inclusion criteria 
are met prior to randomization, unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer with 
one of the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention 
with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency 
ultrasound and not a candidate for salvage treatment by surgery; or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease unlikely to be cured by  local primary intervention with 
either surgery or radiation with curative intent; 
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8. Active malignancy beyond prostate cancer with the exception of any of the following:  
• Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ carcinoma 
of any type 
• Adequately treated Stage I cancer from which the subject is currently in remission and 
has been in remission for ≥ 2 years  
• Any other cancer from which the subject has been disease-free for ≥ 5 years 
The medical monitor should be contacted for any questions regarding this exclusion criterion.  
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable 
underlying disease, or the following laboratory values: 
a. Serum gamma-glutamyl transferase > 2.0 x ULN; 
b. Serum ALT and/or AST > ULN; 
c. Total bilirubin > ULN (unless secondary to Gilbert’s syndrome or the pattern is 
consistent with a diagnosis of Gilbert’s syndrome) or; 
d. Serum creatinine > 2.0 mg/dL (176.8 µmol/L); 
e. Platelets < 100 x 103/μL or history of bleeding disorder; 
f. Hemoglobin < 10.0 g/dL (100 g/L); 
g. Leukocytes (WBC) < 3 x 103/μL (3 GI/L); 
h. Absolute neutrophil count < 1.5 x 103/μL (1.5 GI/L); 
10. Hemoglobin A1c (HbA1c) > 10% in patients previously diagnosed with diabetes mellitus. 
HbA1c > 8% in patients whose diabetes mellitus is previously undiagnosed. (Excluded 
patients may be rescreened after referral and evidence of improved control of their 
condition);  
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(hepatitis A virus IgM positive), hepatitis B (HBsAg positive), or hepatitis C (HCV antibody 
positive, confirmed by HCV ribonucleic acid); 
12. Known human immunodeficiency virus infection; 
13. Any of the following within 6 months before Baseline Day 1: 
a. Myocardial infarction; 
b. Unstable angina; 
c. Unstable symptomatic ischemic heart disease; 
d. New York Heart Association (NYHA) class III or IV heart failure 
e. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or 
symptomatic cerebrovascular events); 
f. Any other significant cardiac condition (e.g., pericardial effusion, restrictive 
cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease);   
14. The following ECG abnormalities are excluded: 
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22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets or conditions that may 
interfere with absorption at the level of the small intestine. Examples of such conditions 
include but are not limited to Crohn's disease, gastric bypass, active peptic ulcer disease, and 
gastrectomy. The medical monitor should be contacted for any questions regarding this 
exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see 
Section 5.10.1) without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would 
interfere with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
4.4. 
Other Eligibility Criteria Considerations 
Patient eligibility may require additional or repeat assessments such as safety labs, vital signs, or 
ECG during the Screening Period. 
To assess any potential impact on patient eligibility with regard to safety, the investigator is 
referred to the Investigator Brochure for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the investigational 
product(s) used in this study. 
4.5. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the Screening Period.  Study site personnel will access the interactive voice/web 
recognition system (IWRS) to assign a screening identification number to a potential patient. 
For patients who provide informed consent and subsequently do not meet eligibility criteria, or 
withdraw consent are considered screen failures and are not randomized.  Study site personnel 
should ensure that the source record includes documentation for the screen failure (eg, medical 
history, eligibility criteria, procedures performed). 
Patient numbers assigned to patients who become screen failures are not to be reused.  Patient 
identification numbers will be assigned to eligible patients at randomization, as described in 
Section 4.6. 
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4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number 
After a patient is screened and the investigator determines that the patient is eligible for 
enrollment, the site staff will complete the Randomization Authorization Form and send it to the 
sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the investigator 
site file.  The sponsor (or designee) will approve the patient’s enrollment in writing.  Once the 
site has received approval, the patient may undergo the Baseline Day 1 visit.  The site will 
randomize the patient to treatment by using the IWRS during the patient’s Baseline Day 1 visit.  
The IWRS will assign the patient identification (ID) number.  This number will identify the 
patient for the duration of the study.  A study treatment kit number will be available at the site 
according to the randomization code. 
4.7. 
Removal of Patients from Therapy 
Patients may withdraw consent to participate in the study and discontinue treatment at any time 
for any reason.  Investigators or the medical monitor may remove patients from therapy under 
this protocol for reasons of safety and/or lack of compliance as discussed below.  Patients 
removed from therapy for any reason will undergo the assessments for the Week 49 visit on the 
Schedule of Activities.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
Follow-up visits to assess safety will be performed in all study patients.  If the patient plans to 
start alternative androgen deprivation therapy less than 30 days after the End of Treatment visit, 
the Safety Follow-up visit may occur earlier, before the start of the alternative androgen 
deprivation therapy.  Testosterone recovery will be evaluated in approximately 100 patients 
randomized to relugolix and approximately 50 patients to leuprolide acetate who complete 48 
weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy and will not be offered alternative androgen 
deprivation therapy upon completion of study therapy.  These patients will return for the 60- and 
90-day follow-up Testosterone Recovery visits. 
The safety and/or compliance events shown in Table 4-1 will result in the removal of patients 
from therapy either permanently or until the etiology of the problem has been identified and 
resolved. 
Table 4-1 
Removal of Patients from Treatment 
Reason 
Comment 
Adverse event or intercurrent illness 
Any intolerable adverse event to the patient that cannot be 
ameliorated by the use of adequate medical intervention, or that 
in the opinion of the investigator or medical monitor would lead 
to undue risk to the patient if dosing continued 
Failed to meet eligibility criteria 
post randomization 
If it is discovered after randomization that a patient failed to 
meet protocol entry criteria and continued participation poses 
an unacceptable risk to the patient’s health 
Dose hold 
Relugolix dose hold that exceeds 10 consecutive days 
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Reason 
Comment 
Patient not meeting criteria for 
testosterone suppression to castrate 
level 
Patients with disease progression while on study drug, assuming 
adequate testosterone suppression (testosterone level 
≤ 50 ng/dL [1.7 nmol/L]), may receive radiotherapy as 
prescribed by the investigator. In the setting of rising PSA 
patients may also receive enzalutamide. For patients requiring 
other systemic antineoplastic therapy during the treatment 
period, the investigator should contact the medical monitor.  
Laboratory abnormality defined by 
protocol: 
ALT or AST > 8 x ULN; or 
ALT or AST > 5 x ULN and persists 
for more than 2 weeks; or 
ALT or AST > 3 x ULN in 
conjunction with elevated total 
bilirubin > 2 x ULN or INR > 1.5; or 
ALT or AST > 3 x ULN with 
appearance of fatigue, nausea, 
vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or 
eosinophilia (> 5%) 
If any of these liver test abnormalities develop, study drug 
should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a patient’s 
laboratory profile has returned to normal/baseline status). 
Confirmed QTc prolongation of 
more than 500 msec, in the absence 
of a pacemaker, as read by a 
cardiologist 
If QTc prolongation of > 500 msec in the absence of a 
pacemaker occurs, the ECG must be repeated.  Confirmed QTc 
prolongation, measured by Fridericia's formula [QTcF = 
QT/(RR^0.33)], will result in removal of the patient from 
treatment.  
Patients who have a clinically 
significant decrease in visual acuity 
as evaluated by an ophthalmologist 
that may be related to study drug 
treatment 
 
Gross noncompliance with protocol 
Patients who are, in the opinion of the investigator or the 
medical monitor, non-compliant with the protocol’s 
requirements 
Patient decision 
Patients may permanently discontinue study treatment at any 
time for any reason.  Following study drug discontinuation, 
patients should attend the protocol-required safety follow-up 
visit. 
Sponsor discontinuation of study 
The sponsor reserves the right to terminate the study anytime as 
described in Section 10.3.3.  The sponsor will terminate this 
study following completion of study objectives, or earlier if 
deemed necessary. 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; INR, 
international normalized ratio; QTc, QT interval corrected for heart rate; QTcF, QT interval corrected for heart rate 
using the Fridericia formula; ULN, upper limit of normal 
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Once study drug has been discontinued, all study procedures outlined for the Week 49 visit will 
be completed as specified in the Schedule of Activities (Section 1.1).  The primary reason for 
study drug discontinuation will be recorded on the eCRF. 
Patients who withdraw from treatment will not be replaced. 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  Patients randomized to relugolix should be counseled to notify the 
investigator in the event of intercurrent illness to determine if the study drug treatment can be 
continued.  Every effort should be made to ensure the patient’s compliance with study drug 
treatment, including calling patients to reschedule missed visits. 
In cases where the patient does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the patient.  
The site should attempt at least 3 documented telephone calls and, if necessary, a certified letter 
to the patient’s last known mailing address so that they can appropriately be withdrawn from the 
study with a primary reason of “Lost to Follow-up.” 
4.8. 
Contraception/Pregnancy Avoidance 
It is not known what effects relugolix has on human pregnancy or development of the embryo or 
fetus.  Therefore, male patients should avoid impregnating a female partner. 
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 4 months after the last dose of study drug. 
Nonsterilized male patients should use a male condom, either alone or in addition to effective 
methods of contraception used by a female partner of childbearing potential, through defined 
periods during and after study treatment as specified below.  Examples of effective contraceptive 
methods include condoms, hormonal contraceptives, and intrauterine devices. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following: 
• Use a male condom if having sex with a woman of childbearing age or a pregnant 
woman, during the entire study Treatment Period and through 4 months after the last dose 
of study drug; or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods for the female partner, and withdrawal are not acceptable methods 
of contraception.  
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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg following 
a loading dose of 360 mg on Day 1, or leuprolide acetate 22.5 mg (or 11.25 mg in Japan, Taiwan, 
and China) 3-M depot injection (plus antiandrogen for the first 4 weeks or longer if indicated in 
the opinion of the investigator).  Randomization will be stratified by geographic region, presence 
of metastatic disease, and age. 
Approximately 915 patients will be enrolled in the study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region. 
Study treatment is defined as either oral relugolix or leuprolide acetate injection (see Table 5-1). 
Table 5-1 
Description of MVT-601-3201 Study Drugs 
 
Study Treatment 
Product name: 
Relugolix 
Leuprolide Acetate 3-M Depot 
Formulation description: 
Round film coated pink tablet 
 
Dosage form: 
Tablet 
 
Unit dose strength and dosage 
level: 
120 mg, following a single-
loading dose of 360 mg 
22.5 mg (11.25 mg in Japan, 
Taiwan, and China) 
Route of Administration / 
Duration 
Oral / 48 weeksa 
Subcutaneous or intramuscular / 
48 weeksa 
a. 
Duration of treatment is 48 weeks during the Treatment Period; the last leuprolide acetate injection occurs 
12 weeks before the end of the Treatment Period. 
 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-
methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using the US 
Pharmacopeia and the National Formulary excipients. 
5.3. 
Randomization and Stratification 
Patients are assigned to one of 2 treatment arms in accordance with the randomization schedule 
using an integrated randomization system (IWRS). 
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At Baseline Day 1, patients will be randomized in a 2:1 ratio to one of the following treatment 
arms: 
Treatment Arm 
Randomized Treatment 
Approximate 
Number of Patients 
Arm A 
Relugolix 360 mg (three 120 mg tablets) single oral 
loading dose on Day 1 followed by 120 mg orally once 
daily 
610 
Arm B 
Leuprolide acetate, 22.5 mg 3-M depota injection 
(or 11.25 mg in Japan, Taiwan, and China) 
305 
a. 
Antiandrogen is administered for the first 4 weeks or longer if indicated, in the opinion of the investigator. 
Randomization will be stratified by geographic region, presence of metastatic disease, and age 
age as follows: 
• Geographic Region 
o Europe; 
o North and South America; or 
o Asia and Rest of World. 
• Presence of Metastatic Disease 
o Metastatic disease diagnosed on locally-read imaging by abdominopelvic 
computed tomography (CT) or magnetic resonance imaging (MRI) or bone scan 
at the time of the Baseline Day 1 visit; or 
o No evidence of metastatic disease by locally-read imaging. 
• Baseline Age 
o ≤ 75 years old; or 
o > 75 years old. 
5.4. 
Directions for Administration 
Relugolix 
Relugolix 120-mg tablet strength will be available as immediate-release film-coated tablets.  
These tablets will be presented in 45-tablet bottle packaging and dispensed to patients every 
4 weeks at scheduled study visits. 
All protocol-specific criteria for administration of study drug must be met and documented prior 
to study drug administration.  Study drug will be dispensed by study personnel only to eligible 
patients who are under the supervision of the investigator or identified subinvestigator(s).  If a 
blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence, followed by the blood draw, and then the meal. 
At the Baseline Day 1 visit, the site will administer a single loading dose of oral relugolix 
360 mg (3 tablets). 
Patients randomized to relugolix will be instructed to take one tablet on an empty stomach at 
least 1 hour before breakfast once daily.  If the dose is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
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Patients may consume water ad libitum.  Patients should swallow the study medication whole 
and not chew it or manipulate it in any way before swallowing. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
Leuprolide Acetate 
Leuprolide acetate 3-M depot injection, 22.5 mg (or 11.25 in Japan, Taiwan, and China), will be 
administered every 12 weeks.  Leuprolide acetate 3-M depot will be administered on Day 1 at 
the clinic, then at 12-week intervals (see Schedule of Activities, Section 1.1) and investigators 
should follow product instructions provided by the manufacturer.  An antiandrogen may be 
administered for the first 4 weeks or longer if indicated, as determined by the investigator, and/or 
as indicated by disease status (eg, in patients with extensive localized symptomatic disease or 
with metastatic disease). 
Possible antiandrogen options include, but are not limited to, bicalutamide, flutamide, and 
nilutamide. 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that is related to study drug and cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted if the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing until the toxicity improves to a 
grade 2 or lower severity.  Study drug can be held for a period of up to 10 consecutive days for 
evaluation and treatment of an adverse event.  Patients may subsequently be re-started on study 
drug, with the written approval of the sponsor (or designee). 
5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption 
Neither dose escalations nor dose reductions are allowed in the study. 
Every effort should be made to continue relugolix administration through treatment-emergent 
adverse events unless they are grade 3 or 4 and related to study drug, or the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing.  Of note, patients on leuprolide 
acetate 3-M depot injection continue to receive GnRH agonist therapy because it is impossible to 
discontinue treatment. 
If the grade 3 or 4 adverse event improves to grade 0, 1, or 2 after holding the dose, or if the 
adverse event is no longer believed to be related to study drug, the patient may be rechallenged at 
the same dose at the discretion of the investigator and medical monitor.  If the adverse event 
remains grade 3 or grade 4 after treatment discontinuation and the investigator continues to 
believe the adverse event is related to study drug, study drug treatment should be discontinued 
permanently. 
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5.7. 
Storage, Packaging, and Labeling 
Relugolix will be packaged in bottles containing 45 120-mg tablets of relugolix.  Additional 
details regarding the packaging of relugolix are provided in the Investigator Brochure and 
investigator site file. 
Leuprolide acetate 11.25 mg or 22.5 mg 3-M depot injection will be packaged and labeled for 
clinical trial use. 
Relugolix medication should be stored in an appropriate, limited-access, secure location, 
protected from light, in the original bottles and within a temperature range at 15°C to 25°C 
(59°F to 77°F) with excursions permitted up to 30°C (86°F). 
A daily temperature log of the drug storage area must be maintained every working day. 
Study drug must be stored under the conditions specifie, and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Patients will be instructed to store study drug at 
room temperature out of the reach of children. 
Further guidance and information for final disposition of unused study drug are provided in the 
investigator site file.  The investigator is responsible for study drug accountability, 
reconciliation, and record maintenance, including receipt, reconciliation, and final disposition 
records and their secure storage. 
Refer to the leuprolide acetate product labeling for information regarding the proper storage and 
handling of leuprolide acetate. 
5.8. 
Blinding 
Blinding is not applicable; this is a randomized open-label study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused study drug to each study visit.  Study drug accountability will be 
conducted and results will be recorded as the primary source of study drug accountability.  If a 
patient is persistently noncompliant with the study treatment, it may be appropriate to withdraw 
the patient from the study. 
All patients should be reinstructed regarding dosing compliance during study contacts.  The 
authorized study personnel conducting the re-education must document the process in the 
patient’s source records. 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible. The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  
 
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Patients randomized to relugolix should be counseled to notify the investigator in the event of 
intercurrent illness to determine if the study drug treatment can be continued. Should a patient 
need a surgery of any kind, please contact the medical monitor. Every effort should be made to 
ensure the patient’s compliance with study drug treatment, including calling patients to 
reschedule missed visits.  
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-2 provides examples of systemic medications that are prohibited prior to the first dose of 
study medication until the End of Treatment visit and the Follow-up Period is complete.  This list 
is not a comprehensive list of all restricted medications.  Consult the medical monitor if there is 
any uncertainty regarding patient use of a particular drug or drug class.  Patients may “wash out” 
of these prohibited medications prior to dosing based on the periods provided in Table 5-2. 
Any investigational agent for the treatment of prostate cancer where the mechanism of action is 
testosterone lowering, including agents that are commercially available for indications other than 
prostate cancer that are under investigation for the treatment of prostate cancer, are also 
prohibited for at least 12 months prior to the first dose of study medication. 
Table 5-2 
Prohibited Medications and Washout Periods 
Drug Class 
Examples 
Minimum Washout Periodc 
GnRH analogues 
Leuprolide acetate 
injectiona 
Goserelin acetate 
injection 
 
At least one dosing interval of 
the depot preparation; minimum 
of 3 monthsd 
GnRH antagonists 
Degarelix 
 
At least one dosing interval of 
the depot preparation; minimum 
of 3 monthsd 
Antiandrogensa 
Bicalutamide 
Flutamide 
Nilutamide 
Enzalutamideb 
3 months 
CYP17 inhibitors 
Abiraterone acetate + 
prednisone 
 
3 months 
Other androgen 
suppressing agents 
or androgens 
Estrogens 
Ketoconazole 
Testosterones 
Megestrol acetate 
Progestogens 
3 months 
5-alpha reductase 
inhibitors 
Finasteride 
Dutasteride 
 
4 weeks 
6 months 
Class IA an III 
antiarrhythmics 
Amiodarone 
Procainamide 
Quinidine 
Sotalol 
2 weeks  
(3 months for amiodarone) 
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Drug Class 
Examples 
Minimum Washout Periodc 
Moderate and strong 
CYP3A and 
P-glycoprotein 
inducers 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifampin 
St John’s Wort 
Primidone 
Rifabutin 
Rifapentine 
1 week 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
Moderate/strong 
P-glycoprotein 
inhibitors 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporin 
Diltiazem 
Dronedarone 
Eliglustat 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lapatinib 
Lopinavir/Ritonavir 
Quercetin 
Quinidine 
Ranolazine 
Ticagrelor 
Verapamil 
1 week 
(3 months for amiodarone) 
(3 months for ketoconazole) 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
Herbal therapies 
Chinese herbs 
Ginkgo biloba 
Kava kava 
Ginseng  
2 weeks or 5 half-lives 
(whichever is shorter) 
Abbreviation:  CYP, cytochrome P450 
a. 
Unless randomized to leuprolide acetate control arm of this study.  After randomization, antiandrogen therapy is 
permitted for the first 4 weeks or longer of leuprolide acetate treatment. 
b. Enzalutamide is allowed for the treatment of castration-resistant disease that occurs on study (rising prostate-
specific antigen in the setting of testosterone suppressed to castrate levels (≤ 50 ng/dL [1.7 nmol/L]). 
c. 
Minimum washout period is calculated from the date of last dose of prohibited medication to the first day of 
study drug. 
d. Patients with cumulative previous androgen deprivation therapy > 18 months are excluded, regardless of 
washout period. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded.  At a minimum, the drug 
generic name, dose amount, route of administration, start date, and stop date will be recorded in 
the source documents and the eCRF. 
If alternative androgen deprivation therapy is initiated prior to 30 days after the last relugolix 
dose, record the alternative androgen deprivation therapy as a concomitant medication. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive radiotherapy as prescribed by the investigator. In the setting 
of rising PSA patients may also receive enzalutamide. For patients requiring other systemic 
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antineoplastic therapy during the treatment period, the investigator should contact the medical 
monitor. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities 
(see Section 1.1).  Study procedures are briefly described within Section 6.6.  Further details of 
the procedures are provided in the investigator site file. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 3 periods:  Screening Period, Treatment 
Period, and Follow-up Period.  Unscheduled visits may also occur as needed to evaluate patients. 
6.2. 
Screening Period (Day -28 to Day -1) 
The Screening Period will be from Day -28 through Day -1.  At the Screening visit, study site 
personnel must explain to potential study participants all aspects of the study, including all 
scheduled visits and activities.  Study site personnel must obtain signed informed consent before 
any study-specific procedures are conducted, unless the procedures are part of routine standard 
of care.  The informed consent process must be documented in the patient’s clinical record. 
The investigator will assess and confirm the eligibility of each patient and determine that each 
patient will maintain study drug compliance during the treatment period.  All screening 
procedures results and relevant medical history must be available before eligibility can be 
determined.  All inclusion criteria must be met and none of the exclusion criteria may apply.  No 
eligibility waivers will be granted. 
The following assessments will be performed: 
• Complete medical history, including detailed prostate cancer history; 
• Vital signs, weight, and height; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
• An abdominopelvic CT or MRI and a bone scan should be performed and read locally to 
determine the presence of metastatic disease within 60 days prior to randomization. 
However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not 
required. If metastatic disease is not present on CT or MRI, then a bone scan is also 
required.  
• Demographics; 
• Laboratory data collection (see Section 1.1); 
• Verify inclusion/exclusion criteria; and 
• Concomitant medications and adverse events. 
A Randomization Authorization Form must be submitted to the sponsor for approval prior to 
conducting the Baseline Day 1 visit. 
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6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) 
Baseline Day 1 Visit 
Study site personnel should ensure that an approved Randomization Authorization Form is in the 
patient’s file before proceeding with the randomization and Day 1 visit procedures.  Patients will 
be randomized to either relugolix or leuprolide acetate 3-M depot injection 22.5 mg (or 11.25 mg 
in Japan, Taiwan, and China) (see Section 5.3). 
The following assessments will be performed: 
• Patient-reported outcome questionnaires (EQ-5D-5L, EORTC-QLQ-PR25, and EORTC-
QLQ-C30) 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Medical history; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Verify inclusion/exclusion criteria; 
• Concomitant medications and adverse events; 
• Randomize the patient;  
• Laboratory collection (see Section 1.1); and 
• Study drug management: 
o If study drug administration is not logistically feasible on the same day as 
randomization, Day 1 will be defined as the day of the first dose. 
o If the patient is randomized to relugolix, site personnel will administer a single 
loading dose of oral relugolix 360 mg (3 tablets) and then dispense study drug to 
the patient and instruct on daily dosing of 120 mg (1 tablet) and the importance of 
medication compliance (see Section 5.4); 
o If the patient is randomized to leuprolide acetate, site personnel will administer 
the injection in the clinic. 
Day 4 and Weeks 2 and 3 Visits (Visit Window ± 2 days) 
The following assessments will be performed: 
• Vitals signs; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
 
Note: The Week 2 visit will only occur for patients who are part of the Japan or China subset for 
PK analysis. 
 
 
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Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 Visits (Visit Window ± 7 Days) 
Importantly, patients randomized to relugolix should be called 7 days before each visit to ensure 
the patient is compliant with study drug medication. 
The following assessments will be performed: 
• Patient-reported questionnaires will be completed on the electronic tablet provided 
(Weeks 5, 13, 25, and 37 only) 
o Patients will complete the questionnaires before other study procedures, such as 
blood draws and physical examinations, are performed; 
• Vital signs, weight 
o Weight will be collected only on Weeks 13 and 25; 
• 12-lead ECG (Weeks 5, 13, and 25 only); 
• ECOG performance assessment (Week 25 only); 
• Symptom-based physical examination (except Week 25); 
• Complete physical exam and visual acuity assessment (Week 25 only); 
• Laboratory collection (see Section 1.1) 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 24 
hours after the previous dose. Patients may be dosed in the clinic at these visits, 
provided the dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability; 
 Dispense study drug. Patients may be dosed in the clinic, provided the 
dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing; 
 Remind patients on importance of medication compliance. 
o For patients randomized to leuprolide acetate, 
 Site will administer leuprolide acetate in clinic every 12 weeks (Weeks 13, 
25, and 37). 
Week 49 or (Early Termination of Study Drug) (Visit Window ± 7 Days) 
• For patients receiving relugolix, a member of the site team will call the patient 7 days 
before the Week 49 visit to remind the patient of the need for compliance with their study 
medication; 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs, weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
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• Laboratory collection (see Section 1.1); 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 24 
hours after the previous dose.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability. 
6.4. 
Follow-up Period 
The study day in which the Follow-up visit occurs is relative to when the patient takes his last 
dose of study drug.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
30-Day Safety Follow-up Visit (Visit Window ± 7 Days) 
A Safety Follow-up visit should occur 30 days after the End of Treatment and may occur earlier 
for patients who are starting alternative androgen deprivation therapy or do not complete 
12 weeks of study treatment.  Adverse events should continue to be collected and recorded 
through 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events and concomitant medications will be collected from the signing of the 
informed consent form until the Safety Follow-up visit approximately 30 days after the last dose 
of study drug. 
All other study procedures should be completed before the start of alternative androgen 
deprivation therapy. 
The following assessments will be performed: 
• Patient-reported questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
Testosterone Recovery Visit (Visit Window ± 7 Days) 
Patients who have started alternative androgen deprivation therapy will not participate in the 
60- and 90-day follow-up visits.  Approximately 100 patients randomized to receive relugolix 
and approximately 50 patients randomized to receive leuprolide acetate who complete the 
48 weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy will be included in the Testosterone Recovery 60- and 
90-day Follow-up visits.  These patients will discontinue relugolix after 48 weeks of treatment 
and will be offered a period off androgen deprivation therapy. 
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The following assessments will be performed: 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications. 
Health Status Survey 
During the final weeks prior to database lock, sites will be asked to contact all study participants 
or their immediate family regarding the current health status of previously enrolled/completed 
study patients.  If the site is unsuccessful in contacting the patient and/or immediate family, the 
site may access hospital records or publicly available sources such as national registries, 
newspaper obituaries, and social networking websites. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
investigator.  The following activities should be completed at an Unscheduled visit: recording of 
the date and reason for the visit in the patient’s source documents, concomitant medication 
review and evaluation of adverse events.  In addition, procedures such as vital signs, weight, 
symptom-directed brief physical examination, central safety laboratory assessment and collection 
of a PK sample if indicated, 12-lead ECG, study drug compliance and dispensation, etc. may be 
conducted as needed.  See Schedule of Events (see Section 1.1) for tests that may be performed 
if indicated at an unscheduled visit.  Consult with the medical monitor, if needed, to discuss 
Unscheduled visit testing. 
6.6. 
Study Procedures 
6.6.1. 
Efficacy-Related Procedures 
6.6.1.1. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, testosterone, 
dihydrotestosterone, sex hormone binding globulin, and PSA will be collected predose at the 
visits indicated in the Schedule of Activities in the protocol synopsis (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory.  Testosterone samples may 
be analyzed at a second laboratory to confirm non-castrate levels (Section 1.1). 
Serum LH, FSH, dihydrotestosterone, sex hormone binding globulin, and PSA samples will be 
analyzed at a central laboratory. 
PSA will also be used to evaluate biochemical progression per Prostate Cancer Clinical Trials 
Working Group 3 guidelines [Scher, 2016]. 
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Analysis of serum samples for testosterone is detailed below:  
Testosterone Assessment 
Serum concentrations of testosterone will be obtained as indicated in the Schedule of Activities 
(see Section 1.1). 
Testosterone will be assayed using a liquid chromatography-tandem mass spectrometry method 
sensitive at least as low as 5 ng/dL (0.17 nmol/L) for all measurements.  
Between Week 5 and Week 49 visits (inclusive), testosterone samples that are above castrate 
level (> 50 ng/dL) will be reported to the investigator at the respective study site.  Testosterone 
samples may be subject to reanalysis by liquid chromatography/mass spectrometry and/or 
immunoassay sensitive to at least as low as 10 ng/dL. 
Instructions for collection and processing of blood specimens are provided in the investigator site 
file. 
6.6.1.2. 
Pharmacokinetic Sample Collection 
Relugolix  
Pharmacokinetic samples will only be collected in patients randomized to relugolix study drug. 
Blood samples for pharmacokinetic analysis of relugolix will be collected at the visits indicated 
in the study Schedule of Activities in the protocol synopsis (see Section 1.1).  The actual date 
and time of each blood sample collection will be recorded. 
Patients may take their dose of study drug in the clinic at these visits.  Study drug will be 
administered on an empty stomach or at least 2 hours before food, and food will be withheld for 
1 hour after dosing.  The date and time of their previous dose of study drug (ie, the dose the day 
before the clinic visit) will be accurately recorded.   
Ideally, predose samples should be collected approximately 24 hours (±6 hours) after the 
previous dose of relugolix, although samples collected outside of this window would not be 
considered a protocol deviation. 
If the study patient inadvertently took the study drug at home on the morning of the clinic visit, 
the date and time of that dose should also be accurately recorded and the pharmacokinetic 
sample collected, which may be used for population PK modeling. 
Plasma from the Week 5 and Week 13 visits in all patients will be analyzed for relugolix plasma 
concentration.  Analysis of other individual patient plasma samples will be performed on a case-
by-case basis (such as those patients with non-castrate testosterone levels). 
Collection, processing, storage, and shipping instructions will be provided in the investigator site 
file.  Plasma analysis of relugolix will be performed by the sponsor (or designee). 
Leuprolide Acetate  
For patients on leuprolide acetate, in the event of non-castrate testosterone levels, a blood sample 
may be taken for potential analysis of leuprolide acetate plasma concentration, following 
discussion with the medical monitor 
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China and Japan Pharmacokinetic Subset 
In a subset of patients from China (if enrolled) and approximately 20 patients from Japan that are 
randomized to relugolix, additional relugolix PK samples will be collected on Day 1, Day 4, and 
Week 2 visits (see Schedule of Activities in the protocol synopsis, Section 1.1).  The actual date 
and time of study drug administration and the date and time of each PK sample will be 
accurately recorded. 
All samples from the China and Japan subset will be analyzed for plasma relugolix 
concentrations.  Collection, processing, storage, and shipping instructions will be provided in the 
investigator site file.  Plasma analysis of relugolix will be performed by the sponsor (or 
designee). 
6.6.1.3. 
Pharmacogenomics Sample Collection 
Whole Blood Sample for Germline Deoxyribonucleic Acid 
Pharmacogenomic analysis may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety.  Participation of study patients in 
pharmacogenomic sample collection is optional.  A pharmacogenomics sample will be collected 
from patients at all participating study centers, with individual patient consent and per local 
ethics and regulatory standards.  The sample will be retained for germline deoxyribonucleic acid 
(DNA) analysis of potential genetic determinants of drug safety, drug efficacy or disease 
response, and drug metabolism. 
Every patient must sign informed consent/be consented in order to participate in the sampling of 
whole blood for DNA analysis.  This research may be used to develop a better understanding of 
the safety and efficacy of relugolix and other study drugs, to increase understanding of the 
disease/condition being studied, and for improving the efficiency, design and study methods of 
future research studies. 
Two venous whole blood sample (4 mL per sample) for the analysis of germline DNA will be 
collected at Day 1 from all patients who have provided informed consent.  The DNA samples are 
expected to be collected at the Day 1 visit, but if necessary, may be collected at any visit after 
randomization.  If necessary and feasible, a second aliquot of blood may be taken if isolation of 
DNA from the first sample was not successful or possible.  Germline DNA analysis may be 
conducted to investigate the contribution of genetic variance on drug response, for example, its 
efficacy and safety.  As pharmacogenomics is an evolving science, currently many genes and 
their function are not yet fully understood.  Future data may suggest a role of some of these 
genes in drug response or diseases, which may lead to additional hypothesis-generating 
exploratory research on stored samples. 
Individual blood samples for germline DNA analysis, including the result of any analyses and 
corresponding information will be identified only by a code in a computer database. 
The whole blood samples for DNA analysis will be stored securely at the sponsor’s location or 
its designated central laboratory vendor until 10 years after completion of this study (HERO, 
MVT-601-3201) and/or until the drug development of relugolix is no longer actively pursued by 
Myovant or its collaborators.  The storage period for these samples may be adjusted by country 
in accordance with local regulatory and/or legal requirements for the storage of research samples.  
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Such changes will be reflected in the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) country-specific informed consent form.  After that time, the samples will be 
properly destroyed by the central laboratory or designee following approval by the sponsor.  The 
investigator will keep records linking the patient identity with the samples for the time required 
by applicable law.  Patients who consent and provide a pharmacogenomic sample for DNA 
analysis can withdraw their consent and request disposal of a stored sample at any time. 
Directions for sample collection and handling can be found in the investigator site file. 
6.6.1.4. 
Quality of Life 
European Quality of Life 5-Dimension 5-Level Assessment 
The EuroQol EQ-5D-5L comprises 5 scales and an overall assessment of health status on a 
visual analogue scale (Appendix 2).  The 5 scales include:  mobility, self-care, usual activities, 
pain and discomfort, and anxiety and depression.  The original version, the EQ-5D-3L, includes 
3 response options for each scale.  However, a new 5-level response-option version, the 
EQ-5D-5L, has been developed with the following response options:  no problems, slight 
problems, moderate problems, severe problems, and unable to/extreme problems.  It is believed 
that the EQ-5D-5L is superior to the EQ-5D-3L in terms of feasibility, ceiling effects, 
discriminatory power, and convergent validity.  The EQ-5D-5L index values will be calculated 
from the EQ-5D-5L descriptive system scores based on the Crosswalk value sets [EuroQol 
Group, 1990; Brooks, 1996; Herdman, 2011; Janssen, 2013]. 
European Organisation for Research and Treatment of Cancer Assessments 
The EORTC-QLQ-C30 [Fayers, 2001; Fayers, 2002] (Appendix 3) and the 25-item prostate 
cancer module EORTC-QLQ-PR25 [Spry, 2006] (Appendix 4) will be administered as specified 
in the Schedule of Activities (see Section 1.1). 
The EORTC QLQ-C30 core measurement will be used to capture distal outcomes, including 
physical, social functioning, and overall health-related quality of life.  The QLQ-C30 core 
questionnaire incorporates 30 questions comprising 9 multi-item scales:  5 functional scales 
(physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea 
and vomiting); and a global health and quality of life scale.  Several single-item symptom 
measures are also included.  It is a reliable and valid measure of health-related quality of life in 
patients with cancer and takes about 11 minutes to administer.  The instrument has been 
validated and used in many countries [Aaronson, 1993]. 
The EORTC-QLQ-PR25 is the 25-item Prostate Cancer module (P25) of the EORTC.  The 
EORTC-QLQ-PR25 contains 3 additional symptom scales (urinary, bowel, sexual) and 
5 treatment-related items. 
6.6.2. 
Safety-Related Procedures 
6.6.2.1. 
Weight, Height, and Body Mass Index 
Height and weight will be measured during screening (within 28 days before the first dose of 
study drug).  Weight will be obtained at additional time points as specified in the Schedule of 
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Table 6-1 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Metabolic Panel 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Neutrophils and absolute 
neutrophil count 
Platelet (count) 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Creatinine 
Chloride 
Serum gamma-glutamyl 
transferase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Total cholesterol 
High density lipoprotein 
cholesterol 
Low density lipoprotein 
cholesterol 
Triglycerides 
Hemoglobin A1c 
Endocrine Panel 
Diagnostic Screening 
(investigator’s discretion) 
 
Serum testosterone 
Serum LH 
Serum FSH 
Serum sex hormone binding 
globulin 
Hepatitis panel, according to 
CDC criteria 
 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; LH, luteinizing hormone 
 
A separate sample will be collected at the Day 1 visit and will be banked and tested for presence 
of hepatitis A, B, and C (hepatitis A antibody, IgM, hepatitis B core antibody, IgM, hepatitis B 
surface antigen, and hepatitis C antibody) if requested by the medical monitor for evaluation of 
abnormal liver function tests. 
The central laboratory will perform laboratory tests for chemistry, hematology, and plasma and 
serum hormone levels. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal and clinically 
significant results should be reported as adverse events. 
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6.6.2.5. 
12-Lead Electrocardiograms 
A 12-lead ECG will be administered at the time points specified in the Schedule of Activities 
(Section 1.1).  When an ECG is scheduled at the same time as vital signs and a blood draw, the 
ECG, when possible, will be obtained after the vital signs and prior to the blood draw; the blood 
draw will be collected at the scheduled time.  ECGs will be read locally by a qualified physician. 
If patients have a prolonged QTc (> 500 msec) in the absence of a pacemaker, the ECG should 
be repeated and confirmed.  Patients with a confirmed QTc > 500 msec, measured by Fridericia's 
formula [QTcF = QT/(RR^0.33)], should be withdrawn.  All abnormal ECG findings must be 
documented by the investigator as clinically significant or not. 
6.6.2.6. 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient 30 days 
prior to the first dose of study drug until 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection will recorded in the eCRF (Exception: 
amiodarone will be reported if taken within 3 months prior to the first day of study drug).  See 
Section 5.10.1 for a list of medications and therapies that are prohibited and/or allowed during 
the study. 
 
6.6.2.7. 
Radiologic Assessment 
CT imaging or MRI of the abdominopelvic region with contrast and a bone scan must be 
obtained prior to randomization for each patient to determine the presence or absence of 
metastatic disease.  The scans should be read locally and do not need to be repeated if a scan 
exists within 60 days prior to the Baseline Day 1 visit. However, if CT or MRI demonstrates 
presence of metastatic disease, a bone scan is not required. If metastatic disease is not present on 
CT or MRI, then a bone scan is also required.  
Radiologic assessment is not included as part of the Schedule of Activities after randomization. 
6.7. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of 8 mL of whole blood 
for pharmacogenomics testing (see Section 6.6.1.3) will be collected. 
The need to conduct pharmacogenomic analysis may be identified after this study (or 
additional studies) has been completed.  For this reason, the collected samples will be retained 
for up to 10 years after the last patient completes the study.  A patient may request the 
destruction of his sample at any time.  The sponsor may destroy the samples sooner than 
10 years after the study completes. 
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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations including visual 
acuity assessment, vital signs, weight, ECGs, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or duration 
of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate medical 
events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least one 
of the following criteria: 
o Induces clinical signs or symptoms; 
o Requires active intervention; or 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
o Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event; 
o The disease/disorder being studied, or expected progression; 
o Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; and 
o Situations where an untoward medical event has not occurred (eg, planned hospitalization 
for an elective procedure, with elective defined as known or planned at the time of 
signing of the informed consent). 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to CTCAE (Appendix 5).  Episodic adverse events, such as vomiting, or those that 
occur repeatedly over a period of consecutive days are “intermittent”.  All other events are 
“continuous”.  Additional information on detecting, documenting, and reporting adverse events 
and serious adverse events are provided below.  No toxicity-related dose reductions of study 
drug are permitted; however, study drug can be held for a period of up to 10 days for evaluation 
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and treatment of an adverse event.  The study drug may be restarted if deemed safe for the 
patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study patient was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.  For example, drug-
induced hepatitis that resolved without evidence of hepatic failure would not be considered 
life-threatening even though drug-induced hepatitis can be fatal. 
c. 
Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local IRB/IEC. 
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Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the patient is the preferred method to 
inquire about adverse event occurrence.  Appropriate questions include: 
• “How are you feeling?”  
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact? 
The patient’s answers to the EQ-5D-5L will not be used as a primary means to collect adverse 
events, however they should be reviewed by the study site personnel and the study monitors.  
Should the investigator or site staff become aware of a potential adverse event 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 adverse 
event not previously reported has been identified, normal reporting requirements should be 
applied. 
All patients who experience an adverse event will be evaluated at appropriate time intervals until 
the event resolves or has stabilized or become chronic.  At the conclusion of the study, the 
investigator and medical monitor will assess unresolved adverse events and determine if 
additional follow-up is warranted. 
All adverse events, whether or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
each sign and symptom as an individual adverse event. 
Overdose and pregnancy in a partner will be reported as described in Section 7.7 and Section 7.8, 
respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events will be collected from the time the first dose of study drug is administered until 
the Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
Serious adverse events will be collected from the signing of the informed consent form until the 
Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events reported to the investigator after the safety reporting period should be 
reported to the sponsor if the investigator assesses the event as related to the study drug 
treatment. 
Any event occurring between signing of the informed consent form and the first dose of study 
drug will be recorded as medical history and in the patient’s clinical record for any patient who 
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continues to meet eligibility criteria and proceeds to dosing with study drug; the exception to this 
includes procedure-related pretreatment-emergent events which should be recorded as adverse 
events in the electronic data capture (EDC) system for those patients who remain eligible for 
study participation. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
definitions in Table 7-1 are to be used for the relationship of the adverse event to study drug. 
Table 7-1 
Causal Relationship to Study Drug 
Relationship 
Criteria 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely attributed to concurrent disease 
or other drugs or chemicals, and that follows a clinically reasonable response on 
re-administration (re-challenge) or withdrawal (de-challenge). 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but that could also be explained by 
concurrent disease or other drugs or chemicals.  Information on drug withdrawal 
may be lacking or unclear. 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable 
and/or in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE (see Appendix 5).  For terms not specified with the CTCAE, the criteria 
in Table 7-2 should be used to determine the grade severity. 
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Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
7.5. 
Adverse Events of Clinical Interest Reporting 
Adverse events of clinical interest in this study are defined as any increase in ALT or AST 
≥ 3 x ULN. 
Any ALT or AST elevation of this degree or greater occurring during the randomized Treatment 
Period or the Follow-up visit should be reported to the sponsor using the serious adverse event 
form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), even 
if the event does not meet serious adverse event criteria.  Additional instructions for evaluating 
patients with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized ratio 
(INR) >1.5 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
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For questions on Serious Adverse Event (SAE)/Adverse Event of Clinical Interest or 
events of overdose reporting, please call: 
• 
North/South America: 
  
• 
Regional toll-free phone and fax lines distributed separately.  Please refer to the 
investigator site file. 
The initial report should include: 
• Study number (MVT-601-3201); 
• Site address and number; 
• Investigator name; 
• Patient ID number, sex, and age; 
• Details of study drug administration; 
• The date of the report; 
• A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); and 
• Causal relationship to the study drug. 
If the patient died, the report should include the cause of death and whether or not the cause of 
death was related to study drug, as well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 240 mg within a 24-hour window is an overdose, except 
for the 360-mg loading dose.  The sponsor does not recommend specific treatment for an 
overdose; supportive treatment should be provided as clinically applicable. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form, whether or not the overdose is associated with an 
adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); and 
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• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If the partner of any patient becomes pregnant during the study or through 4 months after the last 
dose of study drug, the investigator must inform the sponsor of the pregnancy. 
The patient should remain on study drug treatment, unless otherwise indicated. 
If the patient agrees, the patient’s pregnant partner should be notified and requested to sign a 
Release of Information form, permitting transfer of information regarding the pregnancy and 
outcome to the sponsor. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the partner pregnancy report forms.  The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated conception date, pregnancy result, 
and neonatal data, etc, should be included in this information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
Benefit/Risk Assessment 
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategies for this protocol are outlined in Table 7-3. 
Table 7-3 
Relugolix Potential Risks and Mitigation 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Hepatic Enzyme Increases 
Isolated increases in hepatic enzymes have been 
observed in prior clinical studies.  Hepatic enzyme 
increases, considered an important potential risk of 
treatment with relugolix, are closely monitored in 
accordance with FDA guidelines for assessing drug-
induced liver injury [FDA, 2009] in all relugolix 
studies. 
Exclusion criteria for 
AST and ALT > ULN; 
total bilirubin values > 
ULN unless consistent 
with Gilbert’s 
syndrome. 
Liver chemistry will be 
monitored during the 
study.  Appropriate 
liver stopping criteria 
and follow-up 
procedures are detailed 
in Section 7.5.2. 
Phospholipidosis 
Data from nonclinical studies in rats and monkeys 
showed histopathological changes consistent with 
PLD.  PLD by itself is not adverse.  No clinical 
Patients with 
significant underlying 
medical conditions are 
excluded. 
Routine safety 
monitoring including 
laboratory assessments, 
ECGs, and assessment 
of adverse events; visual 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
evidence of relugolix-related PLD-associated toxicity 
has been observed nor was there a clinically 
meaningful increase in a biomarker of PLD assessed 
in phase 2 clinical studies. 
acuity will be evaluated 
during the study. 
Risks Associated with Medical Castration 
Acute and subsequent chronic symptoms of medical 
castration (reduction of testosterone to ≤ 50 ng/dL 
[1.7 nmol/L]) include vasomotor symptoms or hot 
flushes, disturbed sleep related to vasomotor 
symptoms, decreased libido, and fatigue or loss of 
energy.  These side effects are usually not severe and 
can be managed with anticipatory guidance. 
Long-term suppression of testosterone is associated 
with well-characterized risks including bone loss, 
decreased muscle mass, possible changes in insulin 
sensitivity with increased risk of diabetes, altered 
lipid metabolism, and possible increased risk of 
cardiovascular disease [Oefelein, 2002; Lopez, 
2005; Diamond,1998; Keating, 2006; Braga-
Basaria, 2006; Saigal, 2007; Tsai, 2007; D'Amico, 
2007; Efstathiou, 2009]. 
- 
Effects can usually be 
managed with 
appropriate 
anticipatory guidance 
(eg, diet and exercise 
programs) or 
supportive therapy 
when required (eg, 
lipid-lowering or bone-
sparing agents). 
Metabolic Changes 
Metabolic changes (insulin resistance, dyslipidemia, 
and increased weight) with increased risk of diabetes 
are a potential risk of the hypoestrogenic state 
induced by relugolix. 
- 
Fasting lipids and 
glucose will be 
monitored during the 
study. 
Loss of Bone Mineral Density 
Loss of bone mineral density is considered a potential 
risk of treatment with relugolix in the prostate cancer 
indication. 
- 
Fractures will be 
assessed through 
adverse event 
monitoring.  Use of 
anti-resorptive bone 
therapy, such as 
bisphosphonates or 
denosumab, may be 
considered by the 
treating physician.  
Abbreviations:  ALT; alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; FDA, 
Food and Drug Administration; PLD, phospholipidoses; ULN, upper limit of normal 
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8. 
DATA QUALITY ASSURANCE 
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the 
investigator site file with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice regulations.  By signing this protocol, the investigator grants permission to 
Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-site 
monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and Good Clinical Practices.  The study monitor 
should have access to laboratory test results and any other source records and data needed to 
verify the entries on the eCRF.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved.  For this 
study, patient data will be entered into a sponsor-approved electronic database and combined 
with data provided from other sources in validated datasets then transmitted electronically to the 
sponsor (or designee). 
Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
8.3. 
Independent Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board will review available safety data, as 
appropriate, on a periodic basis throughout the conduct of the study.  Details of the Data and 
Safety Monitoring Board will be captured in a charter prior to the start of the study. 
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8.4. 
Steering Committee 
A Steering Committee consisting of experts in the field of prostate cancer and staff members of 
Myovant Sciences GmbH will be established to provide oversight for the clinical trial, study 
design, study conduct, data analysis, and presentation and publication of the study data.  Details 
of the Steering Committee responsibilities will be captured in a separate charter. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan will describe the detailed statistical methods and analyses for this 
study.  The statistical analysis plan will be prepared and finalized prior to database lock and 
analysis of the primary and secondary endpoints. 
All confidence intervals will be 2-sided at an alpha level of 0.05 unless otherwise specified.  The 
methodology to be used to maintain a study-wide type I error rate of 0.05 across primary and 
secondary endpoint testing will be described in the statistical analysis plan. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 2:1, relugolix to leuprolide 
acetate 3-M depot.  Randomization will be stratified by the following factors: 
• Geographic Region:  North and South America versus Europe versus Asia and Rest of 
World; 
• Presence of Metastatic Disease:  yes versus no; 
• Baseline Age:  ≤ 75 years old versus > 75 years old. 
Stratified efficacy analyses will incorporate these 3 stratification factors unless otherwise 
specified. 
9.2. 
Analysis Populations 
The Intent-To-Treat (ITT) population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis.  Patients will be analyzed according to their randomized treatment assignment. 
The Per-Protocol population will consist of those members of the ITT population who have no 
major protocol deviations as defined in the statistical analysis plan, considering the following 
protocol deviations but not limited to: 
• Those who entered the study even though they did not satisfy the entry criteria; 
• Those who developed withdrawal criteria during the study but were not withdrawn; 
• Those who received the wrong treatment or incorrect dose; 
• Those who received an excluded concomitant treatment. 
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The Per-Protocol population will not be analyzed if this population comprises more than 95% or 
less than 50% of the ITT population.  The Per-Protocol population will be used as a sensitivity 
analysis of the ITT population for the primary efficacy endpoint and secondary endpoints.  The 
Per-Protocol population will be identified prior to the database lock. 
The primary population for safety analyses will be the Safety population, defined as all patients 
who receive at least one dose of any study treatment.  Patients will be analyzed according to the 
treatment actually received, regardless of their randomized treatment assignment. 
9.3. 
Efficacy Analyses 
9.3.1. 
Primary Endpoint Analyses 
The primary efficacy endpoint is the sustained castration rate, defined as the cumulative 
probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 (Study Day 337).  This probability will be 
estimated for each treatment group using the Kaplan-Meier method with the confidence interval 
calculated using the exponential Greenwood formula via log-log transformation of the survival 
function.  Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL 
(1.7 nmol/L) will be censored at the last testosterone assessment prior to discontinuation.  
Detailed censoring rules will be described in the statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix is 
greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion. 
• Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression.  The lower bound of the 95% confidence interval for the 
difference in the cumulative probability of sustained testosterone suppression between the 
2 treatment groups will be calculated and must be greater than or equal to the non-
inferiority margin of -10% to meet this criterion.  The confidence interval of the 
treatment difference will be calculated using the formula 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡) −𝑆𝑆2෡(𝑡𝑡)൧= 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡)൧+
𝑉𝑉෠ൣ𝑆𝑆2෡(𝑡𝑡)൧ , where each of the variance of the Kaplan-Meier estimate will be calculated 
using the Greenwood's formula 𝑉𝑉෠ൣ𝑆𝑆̂(𝑡𝑡)൧= 𝑆𝑆̂(𝑡𝑡)2 ൤∑
𝑑𝑑𝑗𝑗
𝑛𝑛𝑗𝑗൫𝑛𝑛𝑗𝑗−𝑑𝑑𝑗𝑗൯
𝑗𝑗:𝑡𝑡(𝑗𝑗)≤𝑡𝑡
൨ ; nj denote the 
number of patients at risk at time t(j) and dj denote the number of events observed at time 
t(j)) [Lachin, 2000]. 
The evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans.  The 2-sided type I error rates for the final analyses will be controlled at 0.05 separately 
for each regional analysis. 
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9.3.2. 
Secondary Endpoint Analyses 
If the result of the primary endpoint is statistically significant, the secondary endpoints will be 
analyzed.  The methods and procedures necessary to maintain a study-wide 2-sided type I error 
rate of 0.05 across primary and secondary endpoint testing will be described in the statistical 
analysis plan. 
• Castration rate defined as the cumulative probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing at Week 1 Day 4, and prior to dosing at Week 3 
Day 1 will be summarized by treatment group using the Kaplan-Meier method; 
• Profound castration rate defined as the cumulative probability of testosterone suppression 
of ≤ 20 ng/dL (0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 
Day 1 will be estimated for each treatment group using the Kaplan-Meier method.  The 
difference in the cumulative probabilities between the relugolix group and the leuprolide 
acetate group will be provided, along with the 95% confidence interval calculated in the 
same manner as in the primary analysis of the primary endpoint; 
• PSA response and percent change from baseline in PSA at Week 3 and Week 5 will be 
summarized and compared between the relugolix group and the leuprolide acetate group; 
• Proportions of patients who have a PSA concentration < 0.2 ng/mL (0.2 µg/L) at 
Week 25 will be summarized by treatment group.  The proportions will be compared 
between the relugolix group and the leuprolide acetate group by constructing a 
95% confidence interval for the difference in proportions; 
• Time to testosterone recovery in approximately 100 patients randomized to relugolix and 
approximately 50 patients randomized to leuprolide acetate who complete 48 weeks of 
treatment and who do not start alternative androgen deprivation therapy within the 
following 12 weeks (or within 24 weeks following the last received leuprolide acetate 
3-M depot injection) will be compared between the relugolix group and the leuprolide 
acetate group; 
• Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 global 
health domain and the EORTC-QLQ-PR25 sexual activity and hormonal-treatment-
related symptom subdomains will be summarized by treatment group.  The least square 
means at Week 49 will be compared between the relugolix group and the leuprolide 
acetate group by constructing a 95% confidence interval for the difference in the least 
square means using a mixed model for repeated measures; 
• Absolute values and changes from baseline of the remaining domains in the EORTC 
QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L will be summarized by 
treatment group.  The least square means at Week 49 will be compared between the 
relugolix group and the leuprolide acetate group by constructing a 95% confidence 
interval for the difference in the least square means using a mixed model for repeated 
measures; and 
• Time to PSA progression; 
• Proportion of patients with confirmed PSA progression among those who have achieved 
sustained testosterone suppression during the 48-week treatment. 
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Further details of the secondary analyses will be described in the statistical analysis plan. 
9.4. 
Safety Analyses 
The safety analyses will be based on the Safety population.  Safety will be assessed by 
summarizing and analyzing adverse events, laboratory analytes, vital signs, ECG parameters, and 
concomitant medications. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute’s CTCAE.  All adverse events will be coded to preferred term and system organ 
class using MedDRA 19.1 or higher.  The incidence of adverse events will be presented by 
MedDRA system organ class and preferred term, relationship to study drug treatment, and 
severity.  A patient reporting the same adverse event more than once is counted once, and at the 
maximum severity or strongest relationship to study drug treatment when calculating incidence. 
Laboratory data consist of chemistry, hematology, and hormonal tests.  Only data collected by 
the central laboratory will be used for analyses.  The National Cancer Institute CTCAE will be 
used to categorize toxicity grade for the laboratory parameters.  Shift tables will be provided for 
each gradable parameter to summarize baseline toxicity grade versus post-baseline toxicity 
grade.  For laboratory parameters that are not gradable by the CTCAE, a shift table based upon 
the normal range (low, normal, and high) will be provided for each parameter to summarize the 
baseline versus post-baseline results. 
9.5. 
Pharmacokinetic Analyses 
Plasma relugolix concentrations will be listed and summarized and included in the clinical study 
report. 
PK data may be pooled with data from other studies in healthy male patients and patients with 
prostate cancer for population PK analysis, including evaluation of covariates of relugolix PK 
parameters, and for input into a population PK/pharmacodynamics models describing the 
relationship between relugolix exposure and serum testosterone [Ahsman, 2016].  These 
population PK analyses will be detailed further in a separate statistical analysis plan and report. 
For patients from China (if enrolled) and Japan in the PK subset, plasma relugolix PK parameters 
Cmax, AUC0-τ, and tmax from Day 1 and Day 14 of dosing will be determined.  Population PK or 
PK/pharmacodynamic analyses may be conducted to explore the factors that affect relugolix 
exposure or to contribute to the assessment of the relationships between exposure and 
testosterone. 
9.6. 
Endocrine Marker Analyses 
Endocrine markers will be analyzed to see effects of relugolix and leuprolide acetate as measured 
as absolute value and change from baseline for: 
• LH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
• FSH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
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• Dihydrotestosterone at Week 5, Week 25, and Week 49 visits and/or follow-up visit(s);  
• Sex hormone binding globulin at Week 5, Week 25, and Week 49 visits and/or follow-up 
visit(s). 
9.7. 
Exploratory Analyses 
Overall survival:  Overall survival defined as time from randomization to date of death prior to 
data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions for each 
treatment arm. 
Pharmacogenomic analyses may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety, pending availability of samples.  
Polymorphisms in germline genes related to the hypothalamic-pituitary-androgen pathway, 
prostate cancer risk, or to drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix.  These analyses will be 
detailed in a separate statistical analysis plan and associated reports. 
9.8. 
Interim Analyses 
There will be no planned interim efficacy analysis for the study. 
9.9. 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• True probabilities of sustained testosterone suppression are 94% and 96% for relugolix 
and leuprolide acetate, respectively; 
• 2:1 randomization ratio (relugolix:leuprolide acetate); and 
• Dropout rate of 15%. 
The assumed probability of sustained testosterone suppression for relugolix arm is 94%.  It was 
estimated based on the predicted dose-response relationship for the effect of relugolix on 
testosterone suppression in patients with prostate cancer (data from phase 2 studies C27002 and 
C27003).  The assumed castration rate of 96% for leuprolide acetate was based on the results 
from degarelix phase 3 registration program [Shore, 2013]. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of < 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and an overall 2-sided type I 
error rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) 
will yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate.   
The final analysis will be performed separately for individual evaluation criterion using data 
collected through 48 weeks after enrollment of approximately 915 patients. 
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Approximately 915 patients will be randomized in order to fulfill the regulatory requirements of 
all participating countries. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR) Part 312, subpart D, “Responsibilities of 
sponsors and investigators,” 21 CFR Part 50, and 21 CFR Part 56, are adhered to.  These 
standards are consistent with the requirements of the European Community Directive 
2001/20/EC. 
Since this is a “covered” clinical study, the investigator will ensure that 21 CFR Part 54, is 
adhered to; a “covered” clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied.  This 
documentation must be provided before participation of the investigator and any sub-
investigator.  The investigator and sub-investigator agree to notify the sponsor of any change in 
reportable interests during the study and for one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
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10.1.3. 
Informed Consent 
A properly executed, written informed consent, in compliance with the Declaration of Helsinki, 
ICH Good Clinical Practice, US CFR for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27), and local regulations, will be obtained from each patient before entering the patient 
in the trial.  The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
The investigator will provide copies of the signed informed consent form to each patient (or to 
the patient’s legal representatives) and will maintain the signed original document within the 
patient’s record file per local requirements.  The investigator will also fully document the 
informed consent process in the patient’s source records. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator Brochure, protocol, eCRFs and other study forms, the investigational drug, 
and any other study information, remain the sole and exclusive property of the sponsor during 
the conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: 
1) Investigator’s study file:  The investigator’s study file will contain the Investigator Brochure, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents:  The required source data should include the following for 
each patient: 
• Patient identification (name, date of birth, gender); 
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• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and causality 
and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, US, Europe, or Japan) and until 
there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the sponsor.  The investigator must notify the sponsor 
before destroying any clinical study records. 
Clinical study documentation includes the Investigator Brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, curriculum vitae and all training records of study 
site personnel, and all correspondence pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
10.1.5. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on the 1572 form and/or other appropriate local health 
authority documents within a reasonable time period after data collection.  This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
Screening Period if an eCRF was initiated).  If a patient withdraws from the study, the reason 
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must be noted on the eCRF.  If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.6. 
Investigational Product Accountability 
The investigator or investigator’s designee (ie, pharmacist) is responsible for ensuring adequate 
accountability including dates and lot numbers of all study drug.  This includes acknowledgment 
of receipt of each shipment of study product (quantity and condition), patient dispensing records, 
and returned or destroyed study product.  Dispensing records will document quantities received 
from the sponsor and quantities dispensed to patients, including lot number, date dispensed, 
patient ID number, and the initials of the person dispensing the medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements.  Drug may be returned or destroyed on an ongoing basis during the study 
if appropriate.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet the sponsor’s 
requirements for disposal, arrangements will be made between the site and the sponsor (or 
designee) for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
All records must be made available to the sponsor, authorized representatives, and appropriate 
regulatory agencies, upon request. 
Current ICH Good Clinical Practice guidelines require the investigator to ensure that study drug 
deliveries from the sponsor are received by a responsible person (eg, pharmacist), and the 
following: 
• That such deliveries are recorded, for example, on the sponsor-approved drug 
accountability log, or other sponsor-approved pharmacy log; 
• That study drug is handled and stored safely and properly in accordance with the study 
protocol; 
• That study drug is only dispensed to study patients in accordance with the protocol; 
• That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be documented.  
The following guidelines are therefore pertinent: 
• The investigator agrees not to supply study drug to any persons except the patients in this 
study; 
• The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs; 
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• The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which patient; 
• The investigator/pharmacist agrees to conduct a final drug supply inventory on the drug 
accountability record at the conclusion or termination of the study.  It must be possible to 
reconcile delivery records with those of used and returned study drug.  Any discrepancies 
must be accounted for.  Appropriate forms of deliveries must be signed by the person 
responsible; 
• Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative.  Unused study drug 
not destroyed at the site must be returned to the sponsor-designated facility at the end of 
the study or upon expiration. 
10.1.7. 
Inspections 
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of the 
audit is to ensure that the study is (or was) conducted and monitored in compliance with the 
protocol as well as recognized Good Clinical Practice guidelines and regulations.  These audits 
will also increase the likelihood that the study data and all other study documentation can 
withstand a regulatory authority inspection.  If such audits are to occur, they will be arranged for 
a reasonable and agreed time.  By signing this protocol, the investigator grants permission to the 
sponsor or designee to conduct onsite audits of all appropriate facilities and study 
documentation. 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the sponsor or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 
10.1.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
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emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
(eg, http://www.clinicaltrials.gov) before enrollment of patients begins.  Results will be posted as 
required. 
10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct 
access to the investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
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10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  When the sponsor is aware of 
information on matters concerning the quality, efficacy, and safety of the study drugs, as well as 
other important information that may affect proper conduct of the clinical study, the sponsor may 
terminate the study and send a written notice of the termination along with the reasons to the 
investigator.  Should this be necessary, the sponsor will arrange discontinuation procedures and 
notify the appropriate regulatory authority(ies) and IRBs/IECs.  In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the protection of 
the study participants’ interests. 
If the investigator intends to terminate participation in the study, the investigator must 
immediately inform the sponsor and provide the reason to it. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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Weinstein S, McCaul K. Adverse effects to quality of life arising from treatment can 
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AV. Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing 
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Tombal B, Miller K, Boccon-Gibod L, Schröder F, Shore N, Crawford ED, Moul J, Jensen JK, 
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leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 
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APPENDICES 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
Note:  Adapted from Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
 
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Appendix 2. EuroQol EQ-5D-5L Questionnaire 
 
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Appendix 3. Quality of Life Questionnaire:  EORTC QLQ-C30 
 
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Appendix 4. Quality of Life Questionnaire:  EORTC QLQ-PR25 
 
 
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Appendix 5. 
Adverse Event Severity Grading 
When assessing adverse events, refer to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03, June 14, 2010 (available at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).  A 
copy of the National Cancer Institute CTCAE table will be provided in the investigator site file. 
The National Cancer Institute CTCAE is a descriptive terminology that can be utilized for 
adverse event reporting.  A grading (severity) scale is provided for each adverse event term. 
Components and Organization of the National Cancer Institute CTCAE 
• System Organ Class (SOC).  SOC, the highest level of the Medical Dictionary for 
Regulatory Activities (MedDRA) hierarchy, is identified by anatomical or physiological 
system, etiology, or purpose (eg, SOC Investigations for laboratory test results).  CTCAE 
terms are grouped by MedDRA Primary SOCs.  Within each SOC, adverse events are 
listed and accompanied by descriptions of severity (grade). 
• CTAE Terms.  Each CTCAE term is a MedDRA LLT (Lowest Level Term). 
• Definitions.  A brief definition is provided to clarify the meaning of each adverse event 
term. 
• Grades.  Grade refers to the severity of the adverse event.  The CTCAE displays grades 1 
through 5 with unique clinical descriptions of severity for each adverse event based on 
this general guideline: 
o Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
o Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living; 
o Grade 4 Life-threatening consequences; urgent intervention indicated; and 
o Grade 5 Death related to adverse event. 
A semi-colon indicates “or” within the description of the grade.  A single dash (-) 
indicates a grade is not available.  Not all grades are appropriate for all adverse 
events.  Therefore, some adverse events are listed with fewer than 5 options for 
grade selection. 
• Grade 5.  Grade 5 (Death) is not appropriate for some adverse events and therefore is not 
an option. 
 
 
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Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes 
Study drug treatment should be withheld for any liver test abnormality listed in Section 7.5.1, 
pending investigation of alternative causes of liver injury.  Follow-up should continue until the 
liver test abnormalities resolve to baseline. For this purpose, local labs can be used. However, 
duplicate samples should be taken for central analysis. 
 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations 
in Appendix Table 2.  If close monitoring is not possible, study drug should be withheld, even if 
the results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, 
ALT, Bilirubin [Total and Direct]), 
Alkaline Phosphatase, and INR Testsa,b 
If AST or ALT ≥ 3 x ULN and total bilirubin 
> 2 x ULN or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
If ALT or AST ≥ 3 x ULN and total bilirubin 
and INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized 
ratio; ULN, upper limit of normal 
a. 
Review frequency of monitoring with medical monitor for an individual patient, in case of questions 
b. Local labs can be used. However, duplicate samples should be taken for central analysis. 
 
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Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
• 
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or 
coworkers, etc) and/or industrial chemical agents; 
• 
Prior and concurrent use of alcohol, recreational drugs, and special diets; 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants and mushrooms; 
• 
Physical examination. 
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
• 
Repeat liver tests as per Appendix Table 1a; 
• 
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat 
liver tests; 
• 
Complete blood count with differential to assess for eosinophilia; 
• 
Serum acetaminophen (paracetamol) concentration; 
• 
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus; 
• 
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune 
hepatitis, etc; 
• 
Serology for celiac disease; 
• 
Appropriate liver imaging; and 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
Abbreviations:  INR, international normalized ratio 
a. 
If the first follow-up testing does not confirm the initial abnormal liver test results, review any additional 
follow-up monitoring with the medical monitor. 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
HERO:  A Multinational Phase 3 Randomized, Open-label, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
Relugolix in Men with Advanced Prostate Cancer 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3201 
Indication: 
Advanced Prostate Cancer 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
IND Number: 
118736 
EudraCT Number: 
2017-000160-15 
Version / Effective Date: 
Original:  13 January 2017 
Amendment 1:  02 January 2018 
Amendment 2:  18 January 2018 
Study Medical Monitor: 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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PPD


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INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
Principal Investigator Name (Printed)  
Signature 
 
 
 
 
 
Date 
 
Site 
 
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TABLE OF CONTENTS 
Sponsor Signature Page .............................................................................................................................. 2 
Investigator Statement ................................................................................................................................ 3 
List of Tables ............................................................................................................................................... 8 
List of Figures .............................................................................................................................................. 8 
List of Abbreviations .................................................................................................................................. 9 
1. 
Protocol Synopsis ......................................................................................................................... 11 
1.1. 
Schedule of Activities ................................................................................................................ 23 
2. 
Introduction .................................................................................................................................. 27 
2.1. 
Prostate Cancer .......................................................................................................................... 27 
2.2. 
Relugolix ................................................................................................................................... 28 
2.2.1. 
Indication .......................................................................................................................... 28 
2.2.2. 
Pharmacology ................................................................................................................... 28 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 29 
2.2.4. 
Previous Human Experience ............................................................................................. 29 
3. 
Study Objectives and Endpoints ................................................................................................. 36 
4. 
Investigational Plan ..................................................................................................................... 39 
4.1. 
Overall Study Design................................................................................................................. 39 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 41 
4.3. 
Selection of Study Population ................................................................................................... 42 
4.3.1. 
Inclusion Criteria .............................................................................................................. 42 
4.3.2. 
Exclusion Criteria ............................................................................................................. 43 
4.4. 
Other Eligibility Criteria Considerations ................................................................................... 46 
4.5. 
Screening ................................................................................................................................... 46 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification Number ............ 47 
4.7. 
Removal of Patients from Therapy ............................................................................................ 47 
4.8. 
Contraception/Pregnancy Avoidance ........................................................................................ 49 
5. 
Treatments .................................................................................................................................... 50 
5.1. 
Treatments Administered .......................................................................................................... 50 
5.2. 
Identity of Investigational Product ............................................................................................ 50 
5.2.1. 
Product Characteristics ..................................................................................................... 50 
5.3. 
Randomization and Stratification .............................................................................................. 50 
5.4. 
Directions for Administration .................................................................................................... 51 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 52 
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5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption ......................................................... 52 
5.7. 
Storage, Packaging, and Labeling ............................................................................................. 53 
5.8. 
Blinding ..................................................................................................................................... 53 
5.9. 
Study Drug Accountability and Treatment Compliance ........................................................... 53 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 54 
5.10.1. 
Prohibited Medications ..................................................................................................... 54 
5.10.2. 
Permitted Medications ...................................................................................................... 55 
6. 
Study Assessments and Procedures ............................................................................................ 56 
6.1. 
Schedule of Observations and Procedures ................................................................................. 56 
6.2. 
Screening Period (Day -28 to Day -1) ....................................................................................... 56 
6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) ........................................................... 57 
6.4. 
Follow-up Period ....................................................................................................................... 59 
6.5. 
Unscheduled Visits .................................................................................................................... 60 
6.6. 
Study Procedures ....................................................................................................................... 60 
6.6.1. 
Efficacy-Related Procedures ............................................................................................. 60 
6.6.2. 
Safety-Related Procedures ................................................................................................ 63 
6.7. 
Biological Sample Retention and Destruction ........................................................................... 66 
7. 
Safety Considerations .................................................................................................................. 67 
7.1. 
Adverse Event Definitions......................................................................................................... 67 
7.1.1. 
Adverse Event ................................................................................................................... 67 
7.1.2. 
Serious Adverse Event ...................................................................................................... 68 
7.2. 
Adverse Event Reporting........................................................................................................... 68 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 69 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 70 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 70 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 71 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 71 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 72 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 72 
7.7. 
Study Drug Overdose Management .......................................................................................... 73 
7.8. 
Pregnancy Reporting ................................................................................................................. 74 
7.9. 
Benefit/Risk Assessment ........................................................................................................... 74 
8. 
Data Quality Assurance ............................................................................................................... 76 
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8.1. 
Clinical Procedures .................................................................................................................... 76 
8.2. 
Monitoring ................................................................................................................................. 76 
8.3. 
Independent Data and Safety Monitoring Board ....................................................................... 76 
8.4. 
Steering Committee ................................................................................................................... 77 
9. 
Statistical Considerations and Data Analyses ........................................................................... 77 
9.1. 
Randomization Methods ............................................................................................................ 77 
9.2. 
Analysis Populations ................................................................................................................. 77 
9.3. 
Efficacy Analyses ...................................................................................................................... 78 
9.3.1. 
Primary Endpoint Analyses .............................................................................................. 78 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 79 
9.4. 
Safety Analyses ......................................................................................................................... 80 
9.5. 
Pharmacokinetic Analyses ......................................................................................................... 80 
9.6. 
Endocrine Marker Analyses ...................................................................................................... 80 
9.7. 
Exploratory Analyses ................................................................................................................ 81 
9.8. 
Interim Analyses ........................................................................................................................ 81 
9.9. 
Sample Size ............................................................................................................................... 81 
10. 
Responsibilities ............................................................................................................................. 82 
10.1. 
Investigator Responsibilities...................................................................................................... 82 
10.1.1. 
Good Clinical Practice ...................................................................................................... 82 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 82 
10.1.3. 
Informed Consent ............................................................................................................. 83 
10.1.4. 
Confidentiality .................................................................................................................. 83 
10.1.5. 
Electronic Case Report Forms .......................................................................................... 84 
10.1.6. 
Investigational Product Accountability ............................................................................. 85 
10.1.7. 
Inspections ........................................................................................................................ 86 
10.1.8. 
Protocol Compliance ......................................................................................................... 86 
10.2. 
Sponsor Responsibilities............................................................................................................ 86 
10.2.1. 
Protocol Modifications ..................................................................................................... 86 
10.2.2. 
Study Report ..................................................................................................................... 87 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ............................ 87 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 87 
10.3.1. 
Access to Information Monitoring .................................................................................... 87 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 87 
10.3.3. 
Study Discontinuation ....................................................................................................... 88 
10.3.4. 
Publications ....................................................................................................................... 88 
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References .................................................................................................................................................. 89 
Appendices ................................................................................................................................................. 93 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status .......................................... 93 
Appendix 2. 
EuroQol EQ-5D-5L Questionnaire ............................................................................... 94 
Appendix 3. 
Quality of Life Questionnaire:  EORTC QLQ-C30 ..................................................... 96 
Appendix 4. 
Quality of Life Questionnaire:  EORTC QLQ-PR25 ................................................... 98 
Appendix 5. 
Adverse Event Severity Grading ................................................................................ 100 
Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes .......................................................... 101 
 
 
 
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LIST OF TABLES 
 
Table 1-1 
Schedule of Activities for Study MVT-601-3201............................................................. 23 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks ...................... 31 
Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) ........................................... 33 
Table 4-1 
Removal of Patients from Treatment ................................................................................ 47 
Table 5-1 
Description of MVT-601-3201 Study Drugs .................................................................... 50 
Table 5-2 
Prohibited Medications and Washout Periods .................................................................. 54 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 65 
Table 7-1 
Causal Relationship to Study Drug ................................................................................... 70 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 71 
Table 7-3 
Relugolix Potential Risks and Mitigation ......................................................................... 74 
 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury ...... 101 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............ 102 
 
LIST OF FIGURES 
Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of Relugolix 
and Degarelix at Week 25 ................................................................................................. 32 
Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent Reduction 
by Dose of Relugolix at Week 25 Day 1 .......................................................................... 34 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent Reduction 
by Leuprolide Acetate at Week 25 Day 1 ......................................................................... 34 
Figure 4-1 
Schematic of Study Design ............................................................................................... 41 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
3-M 
3-month 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-τ 
area under the concentration-time curve from time 0 to the end of the dosing 
interval 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHT 
dihydrotestosterone 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organisation of Research and Treatment of Cancer 
EOT 
end of treatment 
EuroQol EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level Questionnaire 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonization 
ID 
identification 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat (population) 
IWRS 
interactive voice/web recognition system 
LH 
luteinizing hormone 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
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Term 
Explanation 
NOAEL 
NYHA 
no-observed-adverse-effect-level 
New York Heart Association 
Obs 
observed 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
PSA 
prostate-specific antigen 
Q12W 
once every 12 weeks 
Q4W 
once every 4 weeks 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
SHBG 
QTc corrected using Fridericia’s formula 
sex hormone binding globulin 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
HERO:  A Multinational Phase 3, Randomized, Open-label, Parallel-
group Study to Evaluate the Safety and Efficacy of Relugolix in Men 
With Advanced Prostate Cancer 
Protocol Number 
MVT-601-3201 
Location 
Multinational, including North and South America, Europe, and Asia-
Pacific 
Study Centers 
Approximately 200 sites 
Study phase 
Phase 3 
Target Population 
Men aged 18 or older diagnosed with androgen-sensitive advanced 
prostate cancer who are candidates for at least 1 year of continuous 
androgen deprivation therapy for the management of androgen-sensitive 
advanced prostate cancer and who are not be candidates for surgical 
therapy.  Patients previously treated with taxanes or expected to receive 
taxanes after initiation of androgen deprivation therapy are excluded, as 
are patients receiving androgen deprivation therapy adjuvant or 
neoadjuvant to radiotherapy as primary definitive therapy. 
Number of 
Patients Planned 
Approximately 915 total patients 
Study Objectives 
Primary: 
• 
To evaluate the ability of relugolix to achieve and maintain serum 
testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) 
in men with androgen-sensitive advanced prostate cancer. 
 
Secondary: 
• 
To evaluate the time course and change in serum testosterone during 
treatment with relugolix; 
• 
To evaluate the time course and magnitude of prostate-specific 
antigen (PSA) reduction during treatment with relugolix; 
• 
To evaluate testosterone recovery following discontinuation of 
relugolix; 
• 
To evaluate quality of life using validated patient-reported outcome 
instruments; 
• 
To evaluate the safety of relugolix 120 mg once daily in men with 
androgen-sensitive advanced prostate cancer; 
• 
To evaluate the effect of relugolix and leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
To collect relugolix plasma concentration data to further evaluate 
relugolix population pharmacokinetics (PK) and the relationship 
between relugolix exposure and serum testosterone; 
• 
To characterize the relugolix plasma PK parameters in a subset of 
patients from China (if enrolled) and Japan; and  
• 
To describe  the time course and magnitude of PSA progression and 
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development of castration resistant prostate cancer during treatment 
with relugolix. 
 
Exploratory: 
• 
To explore the overall survival of patients treated with relugolix; and 
• 
To explore the contribution of genetic variance on drug response. 
Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension, 
22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3-months (3-M) will be administered 
to patients with prostate cancer who require androgen deprivation therapy.  This study will 
evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive 
advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local 
primary intervention with curative intent, newly diagnosed metastatic disease (excluding 
metastases to the brain), and/or advanced localized disease.  Patients may receive radiotherapy, 
cryotherapy or high frequency ultrasound no sooner than 2 months after initiation of androgen 
deprivation therapy.  Patients may be included if they have not previously received androgen 
deprivation therapy for more than 18 months, and if the androgen deprivation therapy was 
completed at least 3 months prior to the baseline visit. If the dosing interval of the depot is 
longer than 3 months, then the prior androgen deprivation therapy must have been completed at 
least as long as the dosing interval of the depot.  Patients previously treated with taxanes or 
expected to receive taxanes after initiation of androgen deprivation therapy are excluded, as are 
patients receiving androgen deprivation therapy adjuvant or neoadjuvant to radiotherapy as 
primary definitive therapy.  Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 
5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once 
daily following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg 
(or 11.25 mg in Japan, Taiwan, and China). After randomization, patients on the leuprolide 
acetate arm may receive an antiandrogen for the first 4 weeks or longer if indicated in the 
opinion of the investigator.  Randomization will be stratified by geographic region, presence of 
metastatic disease, and age. 
Approximately 915 patients will be enrolled in this study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-reported 
outcomes (European Organisation of Research and Treatment of Cancer [EORTC] QLQ-C30, 
European Quality of Life 5-Dimesion 5-Level questionnaire [EuroQol EQ-5D-5L]) will be 
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assessed approximately every 3 months during the Treatment Period and more frequently during 
the Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China (if 
enrolled) and Japan.  Safety assessments will include treatment-emergent adverse events, vital 
signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms (ECG), and 
visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive radiotherapy as prescribed by the investigator. In the setting of rising 
PSA patients may also receive enzalutamide. For patients requiring other systemic 
antineoplastic therapy during the treatment period, the investigator should contact the medical 
monitor.  
 
 
 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
All of the following inclusion criteria must have been met prior to randomization unless 
otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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sibling) of a site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets or conditions that may 
interfere with absorption at the level of the small intestine. Examples of such conditions 
include but are not limited to Crohn's disease, gastric bypass, active peptic ulcer disease, and 
gastrectomy. The medical monitor should be contacted for any questions regarding this 
exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see Section 
5.10.1) without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form [eCRF]); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would 
interfere with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
Dose and Route of 
Administration 
Test Product 
Relugolix 120 mg tablet strength will be available as immediate-release 
film-coated tablets, and 1 tablet (120 mg) will be administered once daily 
following an oral loading dose of 360 mg (three 120-mg tablets) on 
Day 1.  These tablets will be presented in 45-tablet bottles and dispensed 
to patients every 4 weeks at scheduled study visits. 
All protocol-specific inclusion criteria and none of the exclusion criteria 
must be met and documented prior to study drug administration.  Study 
drug will be dispensed only to eligible patients who are under the 
supervision of the investigator or identified subinvestigator(s). 
Reference Product 
Leuprolide acetate, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), 
3-M depot will be administered per the approved dose and method of 
dosing in the region where the patient is enrolled.  Leuprolide acetate 3-M 
depot injection will be administered on Day 1 (with an antiandrogen of 
choice, if indicated according to the investigator, for the first 4 weeks or 
longer), then at 12-week intervals thereafter for 48 weeks.  Preparation of 
the depot injection and administration should follow the instructions 
provided by the manufacturer. 
Duration of 
Treatment 
The duration of treatment will be 48 weeks.  The last dose of leuprolide 
acetate 3-M depot will be administered at the Week 37 visit. 
Criteria for 
Evaluation 
The following treatment arms will be evaluated after 48 weeks of study 
treatment: 
• 
Arm A:  Oral relugolix 120 mg once daily following a loading dose of 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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360 mg (three 120-mg tablets) on Day 1. 
• 
Arm B:  Leuprolide acetate 3-M depot injection, 22.5 mg (or 
11.25 mg in Japan, Taiwan, and China). 
 
Primary Endpoint 
• 
Sustained castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study 
treatment from Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
 
Secondary Endpoints 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) prior to 
dosing on Week 1 Day 4, prior to dosing on Week 3 Day 1; 
o Profound castration rate defined as the cumulative probability of 
testosterone suppression to ≤ 20 ng/dL (0.7 nmol/L) while on 
study treatment from Week 25 Day 1 through Week 49 Day 1; 
o Time to testosterone recovery in approximately 100 patients 
randomized to relugolix and approximately 50 patients 
randomized to leuprolide acetate who complete 48 weeks of 
treatment and who do not plan to start alternative androgen 
deprivation therapy within the following 12 weeks (or within 24 
weeks following the last injection of leuprolide acetate 3-M 
depot); 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed PSA response by Prostate 
Cancer Clinical Trials Working Group 3 guidelines at the Week 3 
and Week 5 visits [Scher, 2016]; 
o Proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit;  
• 
Absolute values and changes from baseline in the scores of the 
EORTC-QLQ-C30 global health domain, and the EORTC-QLQ-
PR25 sexual activity and hormonal-treatment-related symptom 
subdomains, at regular intervals during treatment, and as applicable 
during the Follow-up and/or at End of Treatment visits; 
• 
Absolute values and changes from baseline of the remaining domains 
in the EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular intervals during 
treatment, and as applicable during the Follow-up visits; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical laboratory data; 
• 
Endocrine marker effects of relugolix and leuprolide acetate as 
measured as absolute value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 25, and Week 49 visits; 
and 
o Sex hormone binding globulin at the Week 5, Week 25, and Week 
49 visits; 
• 
Predose relugolix plasma concentrations; 
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• 
Single and repeat-dose plasma relugolix PK parameters such as 
maximum plasma concentration (Cmax), area under the concentration-
time curve from time 0 to the end of the dosing interval (AUC0-τ), and 
time to maximum plasma concentration (tmax) in a subset of patients 
from China (if enrolled) and Japan during the Day 1 visit. 
• 
Time-to PSA progression; 
• 
Proportion of patients with confirmed PSA progression among those 
who have achieved sustained testosterone suppression during the 48-
week treatment. 
 
 
Exploratory Endpoints 
• 
Overall survival defined as time from randomization to date of death 
prior to data cutoff date; and 
• 
The presence of polymorphisms in germline genes related to the 
hypothalamic-pituitary-androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix. 
These will be evaluated in a subset of patients. 
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Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) population defined as all 
randomized patients who have taken at least one dose of study treatment. Randomization will be 
stratified by geographic region (North and South America versus Europe versus Asia and Rest 
of World), presence of metastatic disease on baseline imaging (yes versus no), and age 
(≤ 75 years old versus > 75 years old).  The 2-sided type I error rate for this study is 0.05. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the sustained castration rate defined as the cumulative 
probability of achieving testosterone suppression to castrate levels of ≤ 50 ng/dL (1.7 nmol/L) 
while on study treatment from Week 5 Day 1 (Study Day 29) through Week 49 Day 1 (Study 
Day 337).  This probability will be estimated for each treatment group using the Kaplan-Meier 
method with the confidence interval calculated using the exponential Greenwood formula via 
log-log transformation of the survival function.  Patients who discontinue treatment prior to 
observing a testosterone level > 50 ng/dL (1.7 nmol/L) will be censored at the last testosterone 
assessment prior to discontinuation.  Detailed censoring rules will be prespecified in the 
statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• 
Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix 
is greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression to castrate levels in the 
relugolix treatment group will be calculated and must be greater than or equal to 90% to 
meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression to castrate levels.  The lower bound of the 95% confidence 
interval for the difference in the cumulative probability of sustained testosterone 
suppression to castrate levels between the 2 treatment groups will be calculated and 
must be greater than or equal to the non-inferiority margin of -10% to meet this 
criterion. 
The 2-sided type I error rate will be 0.05 for each individual evaluation criterion. 
Secondary Efficacy Endpoints: 
1. Castration rate:  the cumulative probability of testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) prior to dosing on Week 1 Day 4, and prior to dosing on Week 3 Day 1; 
2. Profound castration rate:  the cumulative probability of testosterone suppression to 
≤ 20 ng/dL (0.7 nmol/L) from Week 25 through Week 49; 
3. PSA response rate:  proportion of patients with a ≥ 50% decrease in PSA from baseline at 
Week 3 and confirmed at Week 5; 
4. Undetectable PSA rate:  proportion of patients with PSA concentration < 0.2 ng/mL 
(0.2 µg/L) at the Week 25 visit; 
5. Time to testosterone recovery in approximately 100 relugolix-treated and approximately 50 
leuprolide acetate-treated patients who complete 48 weeks of treatment and do not start 
alternative androgen deprivation therapy within 12 weeks after the last dose of relugolix or 
within 24 weeks following the last received injection of leuprolide acetate.  Kaplan-Meier 
methods will be used to describe survival distributions; 
6. Quality of Life:  absolute values and changes from baseline in the scores of the EORTC-
QLQ-C30 global health domain, and the EORTC-QLQ-PR25 sexual activity and hormonal-
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treatment-related symptom subdomains, at regular intervals during treatment, and as 
applicable at the Follow-up and/or End-of-Study visits will be presented.  Additionally, 
absolute values and changes from baseline of the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as EQ-5D-5L, at regular intervals during treatment, 
and as applicable during the Follow-up visits will be presented.  Change from baseline will 
be analyzed using mixed-model repeated measures methodology; 
7. Time to PSA progression; 
8. Proportion of patients with confirmed PSA progression among those who have achieved 
sustained testosterone suppression during the 48-week treatment period.  
 
Exploratory Endpoints: 
1. Overall survival:  Overall survival defined as time from randomization to date of death prior 
to data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions; 
2. The effect of polymorphisms in germline genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or drug metabolizing enzymes and transporter 
proteins on the efficacy and safety of relugolix will be described in a separate statistical 
analysis plan. 
The methods and procedures needed to maintain a study-wide 2-sided type I error rate of 0.05 
across primary and secondary endpoint testing will be described in the statistical analysis plan. 
 
Pharmacokinetics 
Relugolix plasma concentrations will be summarized and described using population PK 
methods.  Plasma PK parameters in a subset of patients from China (if enrolled) and Japan will 
be determined using noncompartmental methods. 
 
Safety 
Safety assessments, including adverse events, vital signs, clinical laboratory tests, and ECGs, 
will be summarized for the treatment-emergent period.  The treatment-emergent period is 
defined as the time from first dose of study drug through 30 days after the last dose of relugolix 
or 12 weeks plus 30 days after the last dose of leuprolide acetate.  Safety analyses will be based 
on all randomized patients who receive any amount of study drug (Safety population).  Drug 
exposure will be summarized by descriptive statistics.  Severity of all treatment-emergent 
adverse events will be evaluated by the investigator based on the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred 
term, higher-level term, and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of patients with adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to study drug, and 
severity.  Descriptive rather than inferential statistics will be used.  Laboratory values also will 
be classified by toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory 
shift tables of baseline versus post baseline results will be produced. 
An independent Data and Safety Monitoring Board will monitor all available safety data on a 
periodic basis.  The roles and responsibilities of the Data and Safety Monitoring Board will be 
described in detail in a separate charter. 
 
 
 
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Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• 
True probabilities of sustained castration rates are 94% and 96% for relugolix and 
leuprolide acetate, respectively; 
• 
2:1 randomization ratio (relugolix:leuprolide acetate); 
• 
Dropout rate of 15%. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of ≤ 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and a 2-sided type I error 
rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) will 
yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate. 
The primary analysis of the primary efficacy endpoint will be performed after at least 
915 patients have had the opportunity to complete 48 weeks of study drug treatment.  The 
evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans. 
 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3201 
Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Informed 
Consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dispensation: 
Relugolix 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xr 
 
 
 
Study Drug 
Administration: 
Relugolix Once 
Daily 
 
X 
X 
Patients will receive a single loading dose of oral relugolix 360 mg on Day 1 in the clinic; 
Starting on Day 2, patients will take oral relugolix 120 mg once daily 
Xr 
 
 
 
Study Drug 
Administration: 
Leuprolide 
Acetate 3-M 
Depot 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Xr 
 
 
 
Phone call prior 
to visit and 
study drug 
accountabilityd 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including 
detailed prostate 
cancer history) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Weight, BMI 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
12-lead ECGg 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
ECOG 
Performance 
Assessment 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
Complete 
Physical Exam 
and Visual 
Acuityh 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
 
 
 
Symptom Based 
Physical Exam 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xr 
X 
X 
X 
Abdominopelvic 
CT or MRI and 
Bone Scani 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
EuroQol EQ-
5D-5L Health 
Questionnaire 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
EORTC-QLQ-
PR25 and 
EORTC-QLQ-
C30 Quality of 
Life 
Questionnaires 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 
17 
and 
21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 
and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 60 
days 
EOT + 90 
days 
Visit Window 
Not applicable 
±2 days 
± 7 days 
 
± 7 days 
Lipid & HbA1ck 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Serum 
Testosterone 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xr 
X 
X 
X 
LH/FSH 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
X 
X 
SHBG/DHT 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
 
 
X 
Blood Sample 
for Relugolix 
PKm,n 
 
Xm,n 
Xn 
Xn 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xr 
 
 
 
Blood Sample 
for DNAo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
Health Status 
Surveyp 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xr 
 
 
 
Abbreviations:  3-M, 3-month; BMI, body mass index; CT, computed tomography; DHT, dihydrotestosterone; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of 
treatment; EuroQol EQ-5D-5L, European Quality of Life 5-Dimension 5-Level; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; LH, luteinizing 
hormone; MRI, magnetic resonance imaging; PK, pharmacokinetics; PSA, prostate-specific antigen; SHBG, sex hormone binding globulin 
a. 
The study day in which the Follow-up visit occurs is not specified in the table because these visits occur relative to when the patient takes his last dose of 
study drug.  The End of Treatment (EOT) is defined as the last dose of relugolix or 12 weeks after the last leuprolide acetate injection. 
b. May occur earlier for patients who are starting alternative androgen deprivation therapy, or do not complete 12 weeks of study treatment.  Adverse events, 
serious adverse events, and concomitant medications should continue to be collected and recorded through 30 days after the End of Treatment.  All other 
study procedures should be completed before the start of alternative androgen deprivation therapy. 
c. 
Patients who have started alternative androgen deprivation therapy will not participate in the 60- and 90-day Follow-up visits.  For approximately 100 
patients receiving relugolix and approximately 50 patients receiving leuprolide acetate who complete 48 weeks of study drug treatment and, in the opinion of 
the investigator, can remain off androgen deprivation therapy for 90 days will be included in the testosterone recovery 60- and 90-day Follow-up visits. 
d. For patients assigned to the relugolix treatment arm, the patient should be called 7 days before their next visit to check on compliance with their study 
medication. Study drug accountability will be conducted at visits and results will be recorded as the primary source of study drug accountability. 
e. 
If patient terminates early from study treatment, the patient should be asked to come in as soon as possible and complete this visit. 
f. 
The informed consent form must be signed before any study-mandated procedures are performed. 
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g. 12-lead ECGs should be read locally by a qualified physician. 
h. A complete physical examination should be performed.  Visual acuity will be evaluated by a standard visual eye chart.  The patient should wear any 
prescribed glasses or contacts during the visual acuity assessment. Patients whose presenting visual acuity score is 90 or lower at the screening visit should 
be encouraged to obtain a diagnostic evaluation from an eye care provider, i.e., an ophthalmologist or an optometrist.  Any findings (i.e., diagnoses) from the 
eye examination should be recorded as medical history. Patients whose presenting visual acuity score at Week 25, Week 49, or Early Termination has 
decreased by 10 or more points from the screening visit should be referred to an ophthalmologist for a diagnostic evaluation.  A copy of the ophthalmology 
consultation must be submitted to the sponsor 
i. 
An abdominopelvic CT or MRI and a bone scan should be performed and read locally to determine the presence of metastatic disease within 60 days prior to 
randomization. However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not required. If metastatic disease is not present on CT or 
MRI, then a bone scan is also required.  
j. 
Collect serious adverse event information from the time of signed informed consent through the Safety Follow-up Visit, which is through 30 days after the 
last dose of relugolix or 12 weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or 
hormonal therapy or surgical intervention, whichever occurs first.  Collect nonserious adverse event information from the Baseline Day 1 visit (or from the 
time of signed informed consent if event was related to a screening study procedure through approximately 30 days after the last dose of relugolix or 12 
weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or hormonal therapy or surgical 
intervention, whichever occurs first. 
k. Blood samples must be obtained fasting; nothing to eat or drink (other than water) for at least 9 hours prior to obtaining the sample. 
l. 
All testosterone samples obtained from Week 5 and beyond are to be collected during a ± 7-day window. 
m. Blood samples for PK analysis will be collected for all patients assigned to the relugolix treatment arm.  Samples will be collected predose, approximately 24 
hours after the previous dose. Patients may be dosed in the clinic at these visits, provided the dose can be administered at least 2 hours after food; food 
should be withheld for 1 hour after dosing.  
n. A subset of patients from China (if enrolled) and Japan will have additional samples collected predose, and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on 
Day 1 and Week 2 visits. Patients will be dosed in the clinic at these visits. The dose will be administered at least 2 hours after food; food should be withheld 
for 1 hour after dosing. A predose sample (approximately 24 hours after the previous dose) also will be collected at the Day 4 visit.  Patients may be dosed in 
the clinic at the Day 4 visit, provided the dose can be administered at least 2 hours after food; food should be withheld for 1 hour after dosing.  
o. The blood sample for DNA should be collected at the Baseline Day 1 visit, but may be collected at any visit if it is missed at that visit. 
p. During the final weeks prior to database lock, sites will be asked to contact all study participants or their immediate family regarding the current health status 
of previously enrolled/completed study patients.  
q. Week 2 visit will only occur for patients who are part of the Japan or China subset for PK analysis.  
r. 
For an Unscheduled visit, these procedures will be performed as needed, based on the reason(s) for the Unscheduled visit.
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2. 
INTRODUCTION 
2.1. 
Prostate Cancer 
Prostate cancer is the most prevalent form of cancer in men and the second leading cause of 
death due to cancer in men in the US [Greenlee, 2001] and Europe [Ferlay, 2007].  The median 
age of diagnosis is 70 years, and diagnosis before the age of 40 years is rare [Cersosimo, 1996].  
In Japanese men, prostate cancer was the fourth leading cancer diagnosis in 2007 [Foundation 
for Promotion of Cancer Research, 2012].  The incidence of invasive prostate cancer increases 
with age; a clear increase is seen among men aged 60 years or older [Siegel, 2014]. 
If prostate cancer is diagnosed at a stage where it is confined to the prostate gland and immediate 
surroundings, it is generally treated by surgical removal of the prostate gland, or prostatectomy, 
or with radiation.  Often, these procedures are successful in curing men of their disease.  Men 
whose disease progresses after prostatectomy or radiation are said to have advanced prostate 
cancer.  Advanced prostate cancer is defined as either:  PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; newly diagnosed metastatic prostate 
cancer; or advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  The cure rate following surgery, depending on the stage of the cancer, is about 70% 
overall and, following radiation, about 50% to 60%. 
Approximately 25% to 30% of men will, therefore, progress to advanced disease, excluding 
those with metastatic disease at the time of diagnosis.  Androgens, such as testosterone and its 
more potent metabolite dihydrotestosterone, are strong tumor promoters for prostate cancer 
[Bosland, 2014].  Through the androgen receptor, they synergistically augment the effect of other 
tumor promoters or carcinogens.  Although prostate cancer is driven by presumed mutations in 
other tumor promoting pathways and/or by translocations leading to aberrant activation of the 
androgen receptor pathway, most early-stage prostate cancer cells remain either sensitive to or 
dependent upon circulating androgens.  Thus, for more than 60 years, androgen deprivation 
therapy with surgical or medical castration has been the foundational therapy for either advanced 
inoperable or metastatic cancer.  Increasingly, androgen deprivation therapy is used earlier as a 
neoadjuvant/adjuvant treatment to radiation therapy or for biochemical or clinical relapse after 
local therapies of curative or palliative intent.  More than 80% of men with progressive or 
advanced disease initially respond to androgen deprivation therapy with varying degrees of 
tumor regression or stabilization [Kreis, 1995].  The duration and depth of response to androgen 
deprivation therapy is presumably dependent on the underlying tumor biology and burden.  Thus, 
patients with metastases respond for an average of 2 years before any biochemical evidence of 
castration resistance occurs.  By contrast, patients with biochemical-only evidence of progressive 
disease may respond to androgen deprivation therapy for 5 years or more [Klotz, 2015]. 
Currently, most patients in developed countries receive medical rather than surgical castration.  
GnRH (or LH-releasing hormone) agonists (ie, long-acting leuprolide acetate depot injections) 
are the current mainstay of medical castration, causing long-term desensitization and down 
regulation of the hypothalamic-pituitary gonadal axis.  One disadvantage of the agonist form of 
GnRH is the initial stimulation of the axis lasting 1 to 3 weeks that occurs prior to 
desensitization.  This results in a rise in LH and testosterone levels and an increase in clinical 
symptoms.  In addition, at the time of repeat injection of GnRH agonist depot, microsurges of 
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LH and testosterone may occur, although the apparent incidence is low [Klotz, 2008].  The initial 
flare response may be managed with simultaneous antiandrogen administration, such as with 
bicalutamide. 
Recently, GnRH antagonists, in particular degarelix, [Firmagon, 2016], have become available as 
an alternative form of medical castration.  Degarelix, an injectable peptide, has been approved in 
some countries for the treatment of patients with advanced prostate cancer.  As a GnRH 
antagonist, degarelix achieves medical castration and PSA response with no initial agonist 
activity within the first 1 to 2 weeks of administration, and effectively can obviate the need for 
concomitant antiandrogen treatment.  Post-hoc analyses of degarelix trials [Tombal, 2010] 
suggest that it may have additional advantages regarding disease response or secondary relapse; 
however, such differences require confirmation in prospective studies.  Because of the need for 
monthly depot injections, with large volumes and accompanying local reactions, the use of 
degarelix in clinical practice has remained low. 
Relugolix, previously known as TAK-385, is a potent and highly selective oral small molecule 
antagonist for the human GnRH receptor.  For patients, relugolix may offer the advantages 
conferred by a direct receptor antagonist, including a more rapid onset of action and the absence 
of clinical flare or worsening of symptoms from the initial rise in androgens caused by GnRH 
agonists, as well as having the added convenience and relative comfort of oral dosing. 
2.2. 
Relugolix 
2.2.1. 
Indication 
Relugolix is being developed as a once daily oral medication for the treatment of advanced 
prostate cancer.  The proposed dose of relugolix is 120 mg administered orally once daily 
following a loading dose of 360 mg (three 120-mg tablets) on Day 1. 
2.2.2. 
Pharmacology 
Relugolix is an orally-active, potent, highly-selective, high-affinity small molecule GnRH 
receptor antagonist with a novel structure.  Relugolix was discovered and initially studied by 
Takeda Pharmaceutical Company, Limited, before development rights outside of Japan and 
certain East Asian countries were licensed to Myovant Sciences GmbH. 
Relugolix antagonizes the human GnRH receptors present on the gonadotrophin-secreting cells 
of the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
LH and FSH fall rapidly, followed by a decline over a few days in testosterone in men and 
estradiol and progesterone levels in women.  Relugolix acts as a potent and highly selective 
antagonist for the human GnRH receptor.  The affinity of relugolix for the human GnRH 
receptor in vitro was approximately 50-fold higher than that of GnRH in the presence of protein 
(40% fetal bovine serum).  Transgenic knock-in mice expressing the human GnRH receptor 
treated with relugolix had substantial reductions in reproductive organ weights of both female 
and male mice, suggesting that relugolix may suppress blood estrogen and testosterone levels, 
respectively.  Orally administered relugolix suppressed the hypothalamic-pituitary axis in 
castrated cynomolgus monkeys at doses of 1 mg/kg and higher. 
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2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level for liver findings in the 39-week monkey 
toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (area under the 
concentration-time curve [AUC]) in men receiving 120 mg once daily (0.469 μg⋅hr/mL), the 
dose of relugolix to be administered in this study.  Both the liver and PLD findings demonstrated 
evidence of reversibility following a 13-week recovery period in monkeys.  No evidence of PLD 
has been observed in clinical studies.  The relugolix toxicology program supports the conduct of 
clinical studies up to the NOAEL (15 mg/kg/day) exposure (5.2 μg·hr/mL) for liver toxicity in 
monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human Thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies have been completed.  In 
addition, 6 clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 
2 studies in men with prostate cancer (US and Europe), and 2 phase 3 studies in women with 
uterine fibroids in Japan.  More than 1380 patients and healthy volunteers have received at least 
one dose of relugolix, including 158 women receiving relugolix 40 mg once daily for at least 
28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg once daily for at 
least 24 weeks and for as long as 48 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of testosterone in male subjects and estradiol in female subjects.  After oral 
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administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The PK and pharmacodynamics of relugolix have been evaluated, and 
appear to be similar in Western and Asian volunteers, despite the lower mean body mass index 
observed in Asian volunteers. 
A relative bioavailability and food effect study was conducted using the global phase 3 prostate 
cancer formulation of 120 mg relugolix.  After administration with a high-fat, high-calorie 
breakfast, the Cmax and AUC of relugolix were reduced, on average, by 21.4% and 18.8%, 
respectively. 
In the phase 1 study C27001, serum LH, FSH, dihydrotestosterone, and testosterone 
concentrations were determined in healthy men following single and multiple oral doses of 
relugolix or placebo for up to 28 days.  Loading doses of ≥ 160 mg on Day 1 were used to 
shorten the time to testosterone suppression.  Relugolix caused an immediate and effective 
suppression of LH, FSH, and testosterone.  After 14 days of once daily dosing, mean LH and 
serum testosterone concentration profiles were similar for the 40, 80, and 180 mg relugolix dose 
cohorts.  LH, FSH, and testosterone concentrations began decreasing 2 to 6 hours postdose on 
Day 1 and remained suppressed through Day 14.  However, the relugolix once daily maintenance 
dose was a major determinant of sustained testosterone suppression.  Profound castration 
(defined as average testosterone levels < 20 ng/dL or 0.7 nmol/L) was achieved with 40, 80, or 
180 mg once daily for 14 days; however, 20 mg once daily was insufficient in maintaining 
adequate suppression of serum LH and testosterone concentration levels during the second week. 
In healthy, older men receiving 14 or 28 days of dosing, effective castration was consistently 
achieved over 14 and 28 days dosing at daily doses of 40 to 180 mg (14 days) and 80 to 160 mg 
(28 days).  Use of a loading dose for up to 3 days (or once daily doses of ≥ 160 mg) resulted in 
castration levels of testosterone (< 50 ng/dL or 1.7 nmol/L) within 24 to 48 hours.  Results 
obtained after 28 days of dosing suggested that the likely minimal, fully effective maintenance 
dose for sustained castration would be relugolix ≥ 80 mg once daily.  Doses of 80 mg and 
120 mg were moved forward into phase 2 development. 
Relugolix is to be administered in the fasted state (at least 1 hour before or 2 hours after a meal), 
as food decreases the extent of relugolix absorption by approximately 20%.  The exposure of 
relugolix is increased by inhibitors of P-glycoprotein up to 6-fold, but relugolix does not 
significantly impact the exposure of cytochrome P450 (CYP) 1A2, 2C9, 2D6, or 3A4 substrates.  
In a dedicated study, relugolix did not prolong QTc at single doses of 60 or 360 mg. 
2.2.4.2. 
Clinical Studies in Men with Prostate Cancer 
One phase 1 study and 2 phase 2 studies have been conducted evaluating relugolix in men with 
prostate cancer. 
Study TB-AK160108 is an ongoing multicenter phase 1, open-label, dose range-finding study 
conducted in hormone treatment-naïve Asian patients with non-metastatic prostate cancer.  The 
study consists of a dose-rising phase (Part A) and an expansion phase (Part B).  In Part A, a 
loading dose of relugolix (320 or 360 mg) was administered on Day 1 followed by once daily 
dosing on Days 2 through 28, with the dosage dependent on the individual cohort of 3 to 4 
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patients each.  In Part B, 30 patients receive a maximum of 96 weeks treatment at doses of 
80 and 120 mg once daily (N = 15 each arm, loading dose of 320 mg on Day 1).  Testosterone 
reduction by both doses of relugolix was rapid and sustained through 48 weeks.  Both the 80-
 and 120-mg once daily doses were evaluated in phase 2 clinical studies. 
Study C27003 is a phase 2 study that enrolled men in North America or the United Kingdom 
requiring 6 months of androgen deprivation therapy as neoadjuvant and adjuvant therapy to 
external beam radiation therapy.  Patients were randomized to relugolix 120 mg once daily 
following a single oral loading dose of 320 mg (N = 65) or to degarelix 80 mg subcutaneously 
every 4 weeks following a single loading dose of 240 mg (N = 38) for 24 weeks.  External beam 
radiation therapy was initiated for most patients between Week 13 and Week 15. 
Relugolix 120 mg administered orally once daily rapidly suppressed testosterone levels below 
the castration threshold (50 ng/dL [1.7 nmol/L]) within the first week of therapy and maintained 
those levels from the end of Week 4 through at least 24 weeks.  The levels of testosterone 
suppression achieved by relugolix were similar to those achieved by monthly injections of 
degarelix.  Profound castration rates below the lower testosterone threshold of < 20 ng/dL 
(0.7 nmol/L) were also similar in the relugolix and degarelix groups (Table 2-1). 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks 
 
Relugolix 
120 mg QDa 
N = 65 
Degarelix 
80 mg Q4Wb 
N = 38 
Castration rate over 24 weeks, % 
(95% CI) 
95% 
(87.1, 99.0) 
89% 
(75.2, 97.1) 
Note:  Castration rate is defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5, Day 1 to specific time point (Week 25, Day 1). 
Abbreviations:  CI, confidence interval; Q4W, once every 4 weeks; QD, once daily 
a. 
Loading dose of 320 mg on Day 1 
b. Loading dose of 240 mg on Day 1, then dosed every month 
 
The percentage PSA reductions and absolute PSA values over time were consistent with the 
rapid testosterone reductions observed with both therapies and were similar between the 
relugolix and degarelix treatment arms.  Prostate gland size was measured during screening and 
following 8 to12 weeks of study drug treatment.  In both treatment groups, the average reduction 
in estimated prostate volumes was similar, approximately 30%.  Following discontinuation of 
therapy at the end of 24 weeks, patients were followed for an additional 12 weeks to evaluate 
testosterone recovery and associated changes in PSA and quality of life.  At the end of the 
follow-up period, approximately half of the patients receiving relugolix had recovered either to 
the baseline testosterone value or to > 280 ng/dL, whichever was less, compared to only 6% of 
patients receiving degarelix (Figure 2-1). 
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Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of 
Relugolix and Degarelix at Week 25 
 
Note:  Y-axis shows testosterone value (ng/dL); x-axis shows study week. 
 
Study C27002 is a phase 2 study of relugolix and leuprolide acetate in patients with prostate 
cancer who require first-line androgen deprivation therapy, which is ongoing in North America.  
This study was designed to help plan the population, dosing, and assessment schedules for 
phase 3 studies in patients with advanced prostate cancer.  Eligible patients in C27002 have 
evidence of advanced prostate cancer including either:  1) PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; 2) newly diagnosed metastatic prostate 
cancer; or 3) advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  In this open-label, parallel group study, patients were randomized to receive 1 of 
2 dose levels of oral relugolix (80 or 120 mg [patients randomized to relugolix received a loading 
dose of 320 mg on Day 1], N = 50 per group) or to an observation cohort to receive standard 
GnRH therapy with leuprolide acetate 22.5 mg administered by intramuscular injection every 
12 weeks (N = 25).  Relugolix or leuprolide acetate was administered for up to 48 weeks with 
patients randomized to leuprolide acetate receiving their last on-study 12-week depot injection at 
Week 37. 
The primary objective of this phase 2 study was to evaluate the ability of relugolix to achieve 
and maintain testosterone suppression (< 50 ng/dL [1.7 nmol/L]) through Week 25.  Results 
from the completed study C27002 demonstrate that both doses of relugolix, 80 mg and 120 mg 
once daily, rapidly reduced testosterone levels below the castration threshold within the first 
week of therapy and maintained those levels in 91% of patients through 24 weeks of treatment 
(Table 2-2). 
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Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) 
 
Relugolix 
Leuprolide 
Acetate 
22.5 mg Q12W 
N = 24 
 
80 mg QD 
N = 56 
120 mg QD 
N = 54 
Total 
N = 110 
Patients with at least 1 dose of 
treatment, n 
56 
54 
110 
24 
Castration ratea over 24 weeks 
 
 
 
 
n (%) 
51 (91) 
49 (91) 
100 (91) 
23 (96) 
95% CIb 
80.4-97.0 
79.7-96.9 
83.9-95.6 
78.9-99.9 
Profound castration ratec over 24 weeks 
 
 
 
 
n (%) 
39 (70) 
41 (76) 
80 (73) 
18 (75) 
95% CIb 
55.9-81.2 
62.4-86.5 
63.4-80.8 
53.3-90.2 
Abbreviations:  CI, confidence interval; Q12W, once every 12 weeks; QD, daily 
a. 
Castration rate was defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5 Day 1 to specific time point. 
b. The 2-sided 95% CI was calculated using the normal approximation method, if the number of non-castration 
patients was = 5 in any treatment arm, the exact CI was presented. 
c. 
Profound castration rate was defined as the estimated proportion of patients who had testosterone concentrations 
< 20 ng/dL at all scheduled visits Week 13 Day 1 through specific time point. 
 
Castration to below the lower testosterone threshold of < 20 ng/dL was also similar in the 
2 relugolix arms and to that observed in the leuprolide acetate arm.  On average, in patients 
receiving relugolix, testosterone decreased to below the castration threshold of 50 ng/dL 
(1.7 nmol/L) by the Day 4 visit, and to below the profound castration threshold of 20 ng/dL 
(0.7 nmol/L) by the Week 5 visit.  In contrast, in patients receiving leuprolide acetate, 
testosterone levels rose during the first 1 to 2 weeks of therapy and then declined to castrate 
levels by Week 5.  PSA responses between the 2 relugolix arms and leuprolide acetate were 
similar as demonstrated by PSA waterfall plots showing the reduction in PSA from baseline for 
individual patients (Figure 2-2 [relugolix] and Figure 2-3 [leuprolide acetate]). 
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Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent 
Reduction by Dose of Relugolix at Week 25 Day 1 
 
 
Note:  Last observation carried forward method was used to impute percent prostate-specific antigen reductions for 
patients without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen; QD, once 
daily; TAK-385, relugolix 
 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent 
Reduction by Leuprolide Acetate at Week 25 Day 1 
 
Notes: 
The leuprolide acetate dose was 22.5 mg every 12 weeks. 
Last observation carried forward method was used to impute percent prostate-specific antigen reductions for patients 
without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen 
 
A more detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Visit
Obs on Week 25 Day 1
LOCF by Week 25 Day 1
PSA Percent Reduction
-100
-80
-60
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-20
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Investigator Brochure, Version 9.0, dated 09 November 2016, along with a full discussion of the 
safety profile of relugolix. 
2.2.4.3. 
Clinical Safety of Relugolix in Men with Prostate Cancer 
A full description of the safety data for relugolix from clinical trials is available in the 
Investigator Brochure.  Overall, approximately 632 healthy volunteers (330 women, 302 men), 
535 female patients with uterine fibroids (N = 229) or endometriosis (N = 306), and 218 male 
patients with prostate cancer received at least 1 dose of relugolix.  Data from the 175 patients 
with prostate cancer who received relugolix in randomized, open-label, parallel-group phase 2 
studies, C27002 and C27003, provide the basis for the frequency of expected adverse events 
associated with relugolix in the prostate cancer indication.  The adverse drug reactions in the 
prostate cancer indication observed in the phase 2 studies include hot flush (59%), fatigue (26%), 
arthralgia (10%), nausea (5%), and gynecomastia (3%).  No clinical evidence of PLD has 
observed in any relugolix clinical study. 
Leuprolide Acetate 3-Month Depot 
Leuprolide acetate depot is indicated for the palliative treatment of advanced prostatic cancer. 
Leuprolide acetate acts as an agonist at pituitary GnRH (gonadotropin-releasing hormone) 
receptors.  Leuprolide acetate has greater receptor affinity, reduced susceptibility to enzymatic 
degradation, and is approximately 100-fold more potent than the natural GnRH molecule.  GnRH 
agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial 
release of both LH and FSH, which causes a subsequent increase in testosterone production from 
testicular Leydig cells.  Initially, leuprolide acetate stimulates LH production, which in turn 
causes a surge of testosterone and dihydrotestosterone for 5 to 12 days before the ultimate 
inhibition of LH.  This androgen surge of male hormones can cause a flare reaction (“clinical 
flare”), which may lead to an increase in bone pain, bladder obstruction, or other symptoms due 
to prostate cancer [Tolis, 1982; Schally, 1980; Waxman, 1985; Conn, 1991; Limonata, 2001]. 
Chronic stimulation by the GnRH agonist ultimately desensitizes the GnRH receptors, 
downregulating the secretion of gonadotropins, LH, and FSH, leading to hypogonadism and thus 
a dramatic reduction in testosterone and dihydrotestosterone, on which continued growth of 
prostate cancer cells depends.  The fall in serum LH leads to a decrease in serum testosterone to 
castrate levels within 3 to 4 weeks after the start of treatment.  Continued treatment maintains 
serum testosterone at castrate levels. 
The decrease in testosterone production is generally reversible over time upon cessation of 
GnRH agonist therapy.  However, testosterone production does not always return to baseline 
levels and may be related to the duration of GnRH agonist therapy, patient age, and other factors. 
The flare phenomenon can be effectively prevented with antiandrogen therapy, which blocks the 
effect of the increased serum testosterone [Loblaw, 2004].  First generation antiandrogens such 
as flutamide, bicalutamide, and nilutamide bind to androgen receptors and competitively inhibit 
their interaction with testosterone and dihydrotestosterone.  They are often used in an attempt to 
limit the clinical sequelae produced by the hormonal surge resulting from GnRH agonist 
treatment. 
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The most common adverse reactions (> 10%) reported for marketed formulations of leuprolide 
acetate depot in common use include the following examples: 
• Leuprolide (leuprorelin) acetate 11.25 mg:  weight fluctuation, hot flash, hyperhidrosis, 
muscle weakness, bone pain, decreased libido, erectile dysfunction, testicular atrophy, 
fatigue, injection site reaction [Prostap 3 DCS, 2016] 
• Leuprolide acetate 22.5 mg:  hot flashes, ecchymoses, erythema, fatigue, injection site 
burning, injection site paraesthesia [Eligard, 2017] 
In post marketing experience, mood swings, depression, rare reports of suicidal ideation and 
attempt, rare reports of pituitary apoplexy have been reported.  Leuprolide has been associated 
with mild liver enzyme elevations (generally transient and asymptomatic) during therapy in 3-
5% of patients; values above 3 times the upper limit of normal are rare, being reported in less 
than 1% of recipients.  A risk of developing or worsening diabetes has been reported in men 
receiving this class of drug. 
The package insert (approved labeling) for the leuprolide acetate study drug provided for this 
study should be referenced for warnings, precautions, and safety information. 
 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
This phase 3 trial has 2 separate evaluation criteria for the primary efficacy endpoint to support 
different regulatory requirements for assessing benefit as listed briefly below and described in 
detail in the statistical analysis plan.  Patients enrolled into this phase 3 trial will be randomized 
2:1 to either relugolix 120 mg once daily following an oral loading dose of 360 mg on Day 1, or 
to leuprolide acetate 22.5 mg (or 11.25 mg Japan, Taiwan, and China) 3-M depot injection.  
Patients randomized to leuprolide acetate will also receive an antiandrogen if indicated at the 
discretion of the investigator. 
The first criterion for the primary efficacy endpoint will evaluate only patients randomized to 
relugolix.  The second criterion for the primary efficacy endpoint will evaluate the non-
inferiority of patients randomized to relugolix to those randomized to leuprolide acetate as 
described below. 
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Objectives 
Endpoints 
Primary 
• 
To evaluate the ability of relugolix to achieve 
and maintain serum testosterone suppressed to 
castrate levels of ≤ 50 ng/dL (1.7 nmol/L) in 
patients with androgen-sensitive advanced 
prostate cancer. 
The primary endpoint is the sustained castration 
rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
• 
Evaluation Criterion 1:  to determine whether 
the sustained castration rate (defined as the 
cumulative probability of testosterone 
suppression to ≤ 50 ng/dL [1.7 nmol/L] while 
on study treatment from Week 5 Day 1 
through Week 49 Day 7) for relugolix is 
greater than or equal to 90%.  The lower 
bound of the 95% confidence interval for the 
cumulative probability of sustained 
testosterone suppression in the relugolix 
treatment group will be calculated and must be 
at least 90% to meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-
inferiority of relugolix compared to leuprolide 
acetate 3-M depot injection as assessed by the 
cumulative probability of sustained 
testosterone suppression.  The lower bound of 
the 95% confidence interval for the difference 
in the cumulative probability of sustained 
testosterone suppression between the 
2 treatment groups will be calculated and must 
be greater than or equal to the non-inferiority 
margin of -10% to meet this criterion. 
Secondary 
• 
To evaluate the time course and change in 
serum testosterone during treatment with 
relugolix; 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative 
probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing 
on Week 1 Day 4 and prior to dosing on 
Week 3 Day 1; 
o Profound castration rate defined as the 
cumulative probability of testosterone 
suppression to ≤ 20 ng/dL (0.7 nmol/L) 
while on treatment from Week 25 Day 1 
through Week 49 Day 1); 
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Objectives 
Endpoints 
• 
To evaluate the time course and magnitude of 
PSA reduction during treatment with 
relugolix; 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed 
PSA response (by Prostate Cancer 
Clinical Trials Working Group 3 
[Scher, 2016]) at the Week 3 and Week 5 
visits; 
o Proportion of patients with PSA 
concentration < 0.2 ng/mL [0.2 µg/L] at 
the Week 25 visit; 
• 
To evaluate testosterone recovery following 
discontinuation of relugolix; 
• 
Time to testosterone recovery in 
approximately 100 patients randomized to 
relugolix and approximately 50 patients 
randomized to leuprolide acetate who 
complete 48 weeks of treatment and who do 
not plan to start alternative androgen 
deprivation therapy within the following 12 
weeks (or within 24 weeks following the last 
injection of leuprolide acetate 3-M depot); 
• 
To evaluate quality of life using validated 
patient-reported outcome instruments; 
• 
Absolute values and changes from baseline in 
the scores of the EORTC-QLQ-C30 global 
health domain, and the EORTC-QLQ-PR25 
sexual activity and hormonal-treatment-related 
symptom subdomains, at regular intervals 
during treatment, and as applicable during the 
Follow-up and/or End of Treatment visits; 
• 
Absolute values and changes from baseline of 
the remaining domains in the EORTC QLQ-
C30 and EORTC QLQ-PR25, as well as the 
EuroQol EQ-5D-5L questionnaire, at regular 
intervals during treatment, and as applicable 
during the Follow-up visits; 
• 
To evaluate the safety of relugolix 120 mg 
once daily in men with androgen-sensitive 
advanced prostate cancer; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical 
laboratory data; 
• 
To evaluate the effect of relugolix and 
leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
Endocrine marker effects of relugolix and 
leuprolide acetate as measured as absolute 
value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 
25, and Week 49 visits; 
o Sex hormone binding globulin at the 
Week 5, Week 25, and Week 49 visits; 
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Objectives 
Endpoints 
• 
To collect relugolix plasma concentration data 
to further evaluate relugolix population PK 
and the relationship between relugolix 
exposure and serum testosterone; and 
• 
Predose relugolix plasma concentrations; 
• 
To characterize the relugolix plasma PK 
parameters in a subset of patients from China 
(if enrolled) and Japan; 
• 
Single and repeat-dose plasma relugolix PK 
parameters such as Cmax, AUC0-τ, and tmax. 
• 
To describe the time course and magnitude of 
PSA progression and development of 
castration resistant prostate cancer during 
treatment with relugolix; 
• 
Time to PSA progression 
• 
Proportion of patients with confirmed PSA 
progression among those who have achieved 
sustained testosterone suppression during the 
48-week treatment   
 
 
Exploratory 
• 
To explore the overall survival of patients 
treated with relugolix; and 
• 
Overall survival defined as time from 
randomization to date of death prior to data 
cutoff date; 
• 
To explore the contribution of genetic 
variance on drug response. 
• 
The presence of polymorphisms in germline 
genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter 
proteins that might be implicated in the drug 
disposition, safety, or efficacy of relugolix. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension 
22.5 mg (or 11.25 mg in Japan, Taiwan, and China) every 3-months (3-M) will be administered 
to patients with prostate cancer who require androgen deprivation therapy.  This study will 
evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive 
advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
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sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local primary 
intervention with curative intent, newly diagnosed metastatic disease (excluding metastases to 
the brain), and/or advanced localized disease.  Patients may receive radiotherapy, cryotherapy or 
high frequency ultrasound no sooner than 2 months after initiation of androgen deprivation 
therapy.  Patients may be included if they have not previously received androgen deprivation 
therapy for more than 18 months, and if the androgen deprivation therapy was completed at least 
3 months prior to baseline. If the dosing interval of the depot is longer than 3 months, then the 
prior androgen deprivation therapy must have been completed at least as long as the dosing 
interval of the depot.  Patients previously treated with taxanes or expected to receive taxanes 
after initiation of androgen deprivation therapy are excluded, as are patients receiving androgen 
deprivation therapy adjuvant or neoadjuvant to radiotherapy as primary definitive therapy.  
Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once daily 
following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg (or 
11.25 mg in Japan, Taiwan, and China). After randomization, patients on the leuprolide acetate 
arm may receive an antiandrogen for the first 4 weeks or longer if indicated in the opinion of the 
investigator.  Randomization will be stratified by geographic region, presence of metastatic 
disease, and age. 
Approximately 915 patients will be enrolled in this study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region.  The study includes a 
Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up Period of 
up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 
48 weeks.  During that time, testosterone and PSA will be assessed monthly and patient-reported 
outcomes (EORTC-QLQ-C30, EORTC-QLQ-PR25, EuroQol EQ-5D-5L) will be assessed 
approximately every 3 months during the Treatment Period and more frequently during the 
Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China (if 
enrolled) and Japan.  Safety assessments will include treatment-emergent adverse events, vital 
signs, physical examinations, clinical laboratory tests, 12-lead ECG, and visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (testosterone level ≤ 50 ng/dL [1.7 nmol/L]), should remain on 
study and may receive radiotherapy as prescribed by the investigator. In the setting of rising PSA 
patients may also receive enzalutamide. For patients requiring other systemic antineoplastic 
therapy during the treatment period, the investigator should contact the medical monitor.  
A schematic of the overall study design is provided in Figure 4-1. 
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Figure 4-1 Schematic of Study Design 
 
 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is designed to establish the safety and efficacy of relugolix 120 mg orally 
once daily in men with advanced prostate cancer who require at least 1 year of continuous 
androgen deprivation therapy for androgen-sensitive disease.  This study will focus on the 
primary objective of evaluating the ability of relugolix to achieve and maintain suppression of 
serum testosterone to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) in patients with advanced prostate 
cancer.  During the Treatment Period of the study (Day 1 to Week 49 [Study Day 337]), patients 
will be randomized to one of the study treatment arms:  oral loading dose of relugolix (360 mg) 
followed by 120 mg once daily of relugolix or leuprolide acetate 3-M depot injection of 22.5 mg 
(or 11.25 mg Japan, Taiwan, and China) at 12-week intervals for 48 weeks.  Patients treated with 
leuprolide acetate will also receive an antiandrogen for 4 weeks or longer if indicated in the 
opinion of the investigator. 
The study is designed to allow for global approvals, however, different regulatory agencies 
require different criteria for the demonstration of efficacy.  The United States (US) Food and 
Drug Administration (FDA) requires, for approval, a primary efficacy criterion to determine 
whether the sustained castration rate (defined as the cumulative probability of testosterone 
≤ 50 ng/dL [1.7 nmol/L] while on relugolix study treatment from Week 5 Day 1 through Week 
49 Day 1) is greater than or equal to 90%.  The lower bound of the 95% confidence interval for 
the cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion.  The 
study includes a leuprolide acetate arm to meet the regulatory requirement of other regions to 
establish the non-inferiority of relugolix compared to leuprolide acetate 3-M depot injection as 
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assessed by the cumulative probability of sustained testosterone suppression.  The lower bound 
of the 95% confidence interval for the difference in the cumulative probability of sustained 
testosterone suppression between the 2 treatment groups will be calculated and must be greater 
than or equal to the non-inferiority margin of -10% to meet this criterion. 
The dose of relugolix selected is based on data from phase 1 and 2 studies demonstrating that 
oral doses of 80 mg and 120 mg once daily following an oral loading dose of 320 mg were able 
to suppress testosterone to castrate levels (see Section 2.2.4.2 and the Investigator Brochure).  A 
loading dose of 360 mg (three 120-mg tablets) was selected for phase 3 so that only one tablet 
size was required.  Leuprolide acetate 3-M depot injection was selected as the comparator as this 
is the GnRH agonist used most commonly as standard of care in the population under evaluation.  
Degarelix, an injectable GnRH antagonist, was considered, but was not used as it has limited 
market uptake attributed at least in part to a significant number of injection site reactions. 
4.3. 
Selection of Study Population 
Approximately 915 men with advanced prostate cancer requiring androgen deprivation therapy 
will be enrolled in this study from approximately 200 study centers in North and South America, 
Europe, and the Asia-Pacific region.  Enrollment is defined as the time at which a patient is 
randomized to a treatment group and receives at least one dose of study drug. 
Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor prior 
to randomizing the patient. 
4.3.1. 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following inclusion criteria 
are met prior to randomization, unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer with 
one of the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention 
with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency 
ultrasound and not a candidate for salvage treatment by surgery; or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease unlikely to be cured by  local primary intervention with 
either surgery or radiation with curative intent; 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
Amendment 2, 18 January 2018 
Myovant Sciences GmbH 
44 
CONFIDENTIAL 
8. Active malignancy beyond prostate cancer with the exception of any of the following:  
• Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ carcinoma 
of any type 
• Adequately treated Stage I cancer from which the subject is currently in remission and 
has been in remission for ≥ 2 years  
• Any other cancer from which the subject has been disease-free for ≥ 5 years 
The medical monitor should be contacted for any questions regarding this exclusion criterion.  
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable 
underlying disease, or the following laboratory values: 
a. Serum gamma-glutamyl transferase > 2.0 x ULN; 
b. Serum ALT and/or AST > ULN; 
c. Total bilirubin > ULN (unless secondary to Gilbert’s syndrome or the pattern is 
consistent with a diagnosis of Gilbert’s syndrome) or; 
d. Serum creatinine > 2.0 mg/dL (176.8 µmol/L); 
e. Platelets < 100 x 103/μL or history of bleeding disorder; 
f. Hemoglobin < 10.0 g/dL (100 g/L); 
g. Leukocytes (WBC) < 3 x 103/μL (3 GI/L); 
h. Absolute neutrophil count < 1.5 x 103/μL (1.5 GI/L); 
10. Hemoglobin A1c (HbA1c) > 10% in patients previously diagnosed with diabetes mellitus. 
HbA1c > 8% in patients whose diabetes mellitus is previously undiagnosed. (Excluded 
patients may be rescreened after referral and evidence of improved control of their 
condition);  
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(hepatitis A virus IgM positive), hepatitis B (HBsAg positive), or hepatitis C (HCV antibody 
positive, confirmed by HCV ribonucleic acid); 
12. Known human immunodeficiency virus infection; 
13. Any of the following within 6 months before Baseline Day 1: 
a. Myocardial infarction; 
b. Unstable angina; 
c. Unstable symptomatic ischemic heart disease; 
d. New York Heart Association (NYHA) class III or IV heart failure 
e. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or 
symptomatic cerebrovascular events); 
f. Any other significant cardiac condition (e.g., pericardial effusion, restrictive 
cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease);   
14. The following ECG abnormalities are excluded: 
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Myovant Sciences GmbH
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
Amendment 2, 18 January 2018 
Myovant Sciences GmbH 
46 
CONFIDENTIAL 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets or conditions that may 
interfere with absorption at the level of the small intestine. Examples of such conditions 
include but are not limited to Crohn's disease, gastric bypass, active peptic ulcer disease, and 
gastrectomy. The medical monitor should be contacted for any questions regarding this 
exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see 
Section 5.10.1) without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would 
interfere with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
4.4. 
Other Eligibility Criteria Considerations 
Patient eligibility may require additional or repeat assessments such as safety labs, vital signs, or 
ECG during the Screening Period. 
To assess any potential impact on patient eligibility with regard to safety, the investigator is 
referred to the Investigator Brochure for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the investigational 
product(s) used in this study. 
4.5. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the Screening Period.  Study site personnel will access the interactive voice/web 
recognition system (IWRS) to assign a screening identification number to a potential patient. 
For patients who provide informed consent and subsequently do not meet eligibility criteria, or 
withdraw consent are considered screen failures and are not randomized.  Study site personnel 
should ensure that the source record includes documentation for the screen failure (eg, medical 
history, eligibility criteria, procedures performed). 
Patient numbers assigned to patients who become screen failures are not to be reused.  Patient 
identification numbers will be assigned to eligible patients at randomization, as described in 
Section 4.6. 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number 
After a patient is screened and the investigator determines that the patient is eligible for 
enrollment, the site staff will complete the Randomization Authorization Form and send it to the 
sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the investigator 
site file.  The sponsor (or designee) will approve the patient’s enrollment in writing.  Once the 
site has received approval, the patient may undergo the Baseline Day 1 visit.  The site will 
randomize the patient to treatment by using the IWRS during the patient’s Baseline Day 1 visit.  
The IWRS will assign the patient identification (ID) number.  This number will identify the 
patient for the duration of the study.  A study treatment kit number will be available at the site 
according to the randomization code. 
4.7. 
Removal of Patients from Therapy 
Patients may withdraw consent to participate in the study and discontinue treatment at any time 
for any reason.  Investigators or the medical monitor may remove patients from therapy under 
this protocol for reasons of safety and/or lack of compliance as discussed below.  Patients 
removed from therapy for any reason will undergo the assessments for the Week 49 visit on the 
Schedule of Activities.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
Follow-up visits to assess safety will be performed in all study patients.  If the patient plans to 
start alternative androgen deprivation therapy less than 30 days after the End of Treatment visit, 
the Safety Follow-up visit may occur earlier, before the start of the alternative androgen 
deprivation therapy.  Testosterone recovery will be evaluated in approximately 100 patients 
randomized to relugolix and approximately 50 patients to leuprolide acetate who complete 48 
weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy and will not be offered alternative androgen 
deprivation therapy upon completion of study therapy.  These patients will return for the 60- and 
90-day follow-up Testosterone Recovery visits. 
The safety and/or compliance events shown in Table 4-1 will result in the removal of patients 
from therapy either permanently or until the etiology of the problem has been identified and 
resolved. 
Table 4-1 
Removal of Patients from Treatment 
Reason 
Comment 
Adverse event or intercurrent illness 
Any intolerable adverse event to the patient that cannot be 
ameliorated by the use of adequate medical intervention, or that 
in the opinion of the investigator or medical monitor would lead 
to undue risk to the patient if dosing continued 
Failed to meet eligibility criteria 
post randomization 
If it is discovered after randomization that a patient failed to 
meet protocol entry criteria and continued participation poses 
an unacceptable risk to the patient’s health 
Dose hold 
Relugolix dose hold that exceeds 10 consecutive days 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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Reason 
Comment 
Patient not meeting criteria for 
testosterone suppression to castrate 
level 
Patients with disease progression while on study drug, assuming 
adequate testosterone suppression (testosterone level 
≤ 50 ng/dL [1.7 nmol/L]), may receive radiotherapy as 
prescribed by the investigator. In the setting of rising PSA 
patients may also receive enzalutamide. For patients requiring 
other systemic antineoplastic therapy during the treatment 
period, the investigator should contact the medical monitor.  
Laboratory abnormality defined by 
protocol: 
ALT or AST > 8 x ULN; or 
ALT or AST > 5 x ULN and persists 
for more than 2 weeks; or 
ALT or AST > 3 x ULN in 
conjunction with elevated total 
bilirubin > 2 x ULN or INR > 1.5; or 
ALT or AST > 3 x ULN with 
appearance of fatigue, nausea, 
vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or 
eosinophilia (> 5%) 
If any of these liver test abnormalities develop, study drug 
should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a patient’s 
laboratory profile has returned to normal/baseline status). 
Confirmed QTc prolongation of 
more than 500 msec, in the absence 
of a pacemaker, as read by a 
cardiologist 
If QTc prolongation of > 500 msec in the absence of a 
pacemaker occurs, the ECG must be repeated.  Confirmed QTc 
prolongation, measured by Fridericia's formula [QTcF = 
QT/(RR^0.33)], will result in removal of the patient from 
treatment.  
Patients who have a clinically 
significant decrease in visual acuity 
as evaluated by an ophthalmologist 
that may be related to study drug 
treatment 
 
Gross noncompliance with protocol 
Patients who are, in the opinion of the investigator or the 
medical monitor, non-compliant with the protocol’s 
requirements 
Patient decision 
Patients may permanently discontinue study treatment at any 
time for any reason.  Following study drug discontinuation, 
patients should attend the protocol-required safety follow-up 
visit. 
Sponsor discontinuation of study 
The sponsor reserves the right to terminate the study anytime as 
described in Section 10.3.3.  The sponsor will terminate this 
study following completion of study objectives, or earlier if 
deemed necessary. 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; INR, 
international normalized ratio; QTc, QT interval corrected for heart rate; QTcF, QT interval corrected for heart rate 
using the Fridericia formula; ULN, upper limit of normal 
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Once study drug has been discontinued, all study procedures outlined for the Week 49 visit will 
be completed as specified in the Schedule of Activities (Section 1.1).  The primary reason for 
study drug discontinuation will be recorded on the eCRF. 
Patients who withdraw from treatment will not be replaced. 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  Patients randomized to relugolix should be counseled to notify the 
investigator in the event of intercurrent illness to determine if the study drug treatment can be 
continued.  Every effort should be made to ensure the patient’s compliance with study drug 
treatment, including calling patients to reschedule missed visits. 
In cases where the patient does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the patient.  
The site should attempt at least 3 documented telephone calls and, if necessary, a certified letter 
to the patient’s last known mailing address so that they can appropriately be withdrawn from the 
study with a primary reason of “Lost to Follow-up.” 
4.8. 
Contraception/Pregnancy Avoidance 
It is not known what effects relugolix has on human pregnancy or development of the embryo or 
fetus.  Therefore, male patients should avoid impregnating a female partner. 
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 4 months after the last dose of study drug. 
Nonsterilized male patients should use a male condom, either alone or in addition to effective 
methods of contraception used by a female partner of childbearing potential, through defined 
periods during and after study treatment as specified below.  Examples of effective contraceptive 
methods include condoms, hormonal contraceptives, and intrauterine devices. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following: 
• Use a male condom if having sex with a woman of childbearing age or a pregnant 
woman, during the entire study Treatment Period and through 4 months after the last dose 
of study drug; or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods for the female partner, and withdrawal are not acceptable methods 
of contraception.  
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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CONFIDENTIAL 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg following 
a loading dose of 360 mg on Day 1, or leuprolide acetate 22.5 mg (or 11.25 mg in Japan, Taiwan, 
and China) 3-M depot injection (plus antiandrogen for the first 4 weeks or longer if indicated in 
the opinion of the investigator).  Randomization will be stratified by geographic region, presence 
of metastatic disease, and age. 
Approximately 915 patients will be enrolled in the study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region. 
Study treatment is defined as either oral relugolix or leuprolide acetate injection (see Table 5-1). 
Table 5-1 
Description of MVT-601-3201 Study Drugs 
 
Study Treatment 
Product name: 
Relugolix 
Leuprolide Acetate 3-M Depot 
Formulation description: 
Round film coated pink tablet 
 
Dosage form: 
Tablet 
 
Unit dose strength and dosage 
level: 
120 mg, following a single-
loading dose of 360 mg 
22.5 mg (11.25 mg in Japan, 
Taiwan, and China) 
Route of Administration / 
Duration 
Oral / 48 weeksa 
Subcutaneous or intramuscular / 
48 weeksa 
a. 
Duration of treatment is 48 weeks during the Treatment Period; the last leuprolide acetate injection occurs 
12 weeks before the end of the Treatment Period. 
 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-
methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using the US 
Pharmacopeia and the National Formulary excipients. 
5.3. 
Randomization and Stratification 
Patients are assigned to one of 2 treatment arms in accordance with the randomization schedule 
using an integrated randomization system (IWRS). 
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Clinical Study Protocol:  HERO (MVT-601-3201) 
 
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At Baseline Day 1, patients will be randomized in a 2:1 ratio to one of the following treatment 
arms: 
Treatment Arm 
Randomized Treatment 
Approximate 
Number of Patients 
Arm A 
Relugolix 360 mg (three 120 mg tablets) single oral 
loading dose on Day 1 followed by 120 mg orally once 
daily 
610 
Arm B 
Leuprolide acetate, 22.5 mg 3-M depota injection 
(or 11.25 mg in Japan, Taiwan, and China) 
305 
a. 
Antiandrogen is administered for the first 4 weeks or longer if indicated, in the opinion of the investigator. 
Randomization will be stratified by geographic region, presence of metastatic disease, and age as 
follows: 
• Geographic Region 
o Europe; 
o North and South America; or 
o Asia and Rest of World. 
• Presence of Metastatic Disease 
o Metastatic disease diagnosed on locally-read imaging by abdominopelvic 
computed tomography (CT) or magnetic resonance imaging (MRI) or bone scan 
at the time of the Baseline Day 1 visit; or 
o No evidence of metastatic disease by locally-read imaging. 
• Baseline Age 
o ≤ 75 years old; or 
o > 75 years old. 
5.4. 
Directions for Administration 
Relugolix 
Relugolix 120-mg tablet strength will be available as immediate-release film-coated tablets.  
These tablets will be presented in 45-tablet bottle packaging and dispensed to patients every 
4 weeks at scheduled study visits. 
All protocol-specific criteria for administration of study drug must be met and documented prior 
to study drug administration.  Study drug will be dispensed by study personnel only to eligible 
patients who are under the supervision of the investigator or identified subinvestigator(s).  If a 
blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence, followed by the blood draw, and then the meal. 
At the Baseline Day 1 visit, the site will administer a single loading dose of oral relugolix 
360 mg (3 tablets). 
Patients randomized to relugolix will be instructed to take one tablet on an empty stomach at 
least 1 hour before breakfast once daily.  If the dose is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
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Patients may consume water ad libitum.  Patients should swallow the study medication whole 
and not chew it or manipulate it in any way before swallowing. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
Leuprolide Acetate 
Leuprolide acetate 3-M depot injection, 22.5 mg (or 11.25 in Japan, Taiwan, and China), will be 
administered every 12 weeks.  Leuprolide acetate 3-M depot will be administered on Day 1 at 
the clinic, then at 12-week intervals (see Schedule of Activities, Section 1.1) and investigators 
should follow product instructions provided by the manufacturer.  An antiandrogen may be 
administered for the first 4 weeks or longer if indicated, as determined by the investigator, and/or 
as indicated by disease status (eg, in patients with extensive localized symptomatic disease or 
with metastatic disease). 
Possible antiandrogen options include, but are not limited to, bicalutamide, flutamide, and 
nilutamide. 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that is related to study drug and cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted if the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing until the toxicity improves to a 
grade 2 or lower severity.  Study drug can be held for a period of up to 10 consecutive days for 
evaluation and treatment of an adverse event.  Patients may subsequently be re-started on study 
drug, with the written approval of the sponsor (or designee). 
5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption 
Neither dose escalations nor dose reductions are allowed in the study. 
Every effort should be made to continue relugolix administration through treatment-emergent 
adverse events unless they are grade 3 or 4 and related to study drug, or the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing.  Of note, patients on leuprolide 
acetate 3-M depot injection continue to receive GnRH agonist therapy because it is impossible to 
discontinue treatment. 
If the grade 3 or 4 adverse event improves to grade 0, 1, or 2 after holding the dose, or if the 
adverse event is no longer believed to be related to study drug, the patient may be rechallenged at 
the same dose at the discretion of the investigator and medical monitor.  If the adverse event 
remains grade 3 or grade 4 after treatment discontinuation and the investigator continues to 
believe the adverse event is related to study drug, study drug treatment should be discontinued 
permanently. 
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5.7. 
Storage, Packaging, and Labeling 
Relugolix will be packaged in bottles containing 45 120-mg tablets of relugolix.  Additional 
details regarding the packaging of relugolix are provided in the Investigator Brochure and 
investigator site file. 
Leuprolide acetate 11.25 mg or 22.5 mg 3-M depot injection will be packaged and labeled for 
clinical trial use. 
Relugolix medication should be stored in an appropriate, limited-access, secure location, 
protected from light, in the original bottles and within a temperature range at 15°C to 25°C 
(59°F to 77°F) with excursions permitted up to 30°C (86°F). 
A daily temperature log of the drug storage area must be maintained every working day. 
Study drug must be stored under the conditions specified, and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Patients will be instructed to store study drug at 
room temperature out of the reach of children. 
Further guidance and information for final disposition of unused study drug are provided in the 
investigator site file.  The investigator is responsible for study drug accountability, 
reconciliation, and record maintenance, including receipt, reconciliation, and final disposition 
records and their secure storage. 
Refer to the leuprolide acetate product labeling for information regarding the proper storage and 
handling of leuprolide acetate. 
5.8. 
Blinding 
Blinding is not applicable; this is a randomized open-label study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused study drug to each study visit.  Study drug accountability will be 
conducted and results will be recorded as the primary source of study drug accountability.  If a 
patient is persistently noncompliant with the study treatment, it may be appropriate to withdraw 
the patient from the study. 
All patients should be reinstructed regarding dosing compliance during study contacts.  The 
authorized study personnel conducting the re-education must document the process in the 
patient’s source records. 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible. The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  
 
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Patients randomized to relugolix should be counseled to notify the investigator in the event of 
intercurrent illness to determine if the study drug treatment can be continued. Should a patient 
need a surgery of any kind, please contact the medical monitor. Every effort should be made to 
ensure the patient’s compliance with study drug treatment, including calling patients to 
reschedule missed visits.  
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-2 provides examples of systemic medications that are prohibited prior to the first dose of 
study medication until the End of Treatment visit and the Follow-up Period is complete.  This list 
is not a comprehensive list of all restricted medications.  Consult the medical monitor if there is 
any uncertainty regarding patient use of a particular drug or drug class.  Patients may “wash out” 
of these prohibited medications prior to dosing based on the periods provided in Table 5-2. 
Any investigational agent for the treatment of prostate cancer where the mechanism of action is 
testosterone lowering, including agents that are commercially available for indications other than 
prostate cancer that are under investigation for the treatment of prostate cancer, are also 
prohibited for at least 12 months prior to the first dose of study medication. 
Table 5-2 
Prohibited Medications and Washout Periods 
Drug Class 
Examples 
Minimum Washout Periodc 
GnRH analogues 
Leuprolide acetate 
injectiona 
Goserelin acetate 
injection 
 
At least one dosing interval of 
the depot preparation; minimum 
of 3 monthsd 
GnRH antagonists 
Degarelix 
 
At least one dosing interval of 
the depot preparation; minimum 
of 3 monthsd 
Antiandrogensa 
Bicalutamide 
Flutamide 
Nilutamide 
Enzalutamideb 
3 months 
CYP17 inhibitors 
Abiraterone acetate + 
prednisone 
 
3 months 
Other androgen 
suppressing agents 
or androgens 
Estrogens 
Ketoconazole 
Testosterones 
Megestrol acetate 
Progestogens 
3 months 
5-alpha reductase 
inhibitors 
Finasteride 
Dutasteride 
 
4 weeks 
6 months 
Class IA an III 
antiarrhythmics 
Amiodarone 
Procainamide 
Quinidine 
Sotalol 
2 weeks  
(3 months for amiodarone) 
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Drug Class 
Examples 
Minimum Washout Periodc 
Moderate and strong 
CYP3A and 
P-glycoprotein 
inducers 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifampin 
St John’s Wort 
Primidone 
Rifabutin 
Rifapentine 
1 week 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
Moderate/strong 
P-glycoprotein 
inhibitors 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporin 
Diltiazem 
Dronedarone 
Eliglustat 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lapatinib 
Lopinavir/Ritonavir 
Quercetin 
Quinidine 
Ranolazine 
Ticagrelor 
Verapamil 
1 week 
(3 months for amiodarone) 
(3 months for ketoconazole) 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
Herbal therapies 
Chinese herbs 
Ginkgo biloba 
Kava kava 
Ginseng  
2 weeks or 5 half-lives 
(whichever is shorter) 
Abbreviation:  CYP, cytochrome P450 
a. 
Unless randomized to leuprolide acetate control arm of this study.  After randomization, antiandrogen therapy is 
permitted for the first 4 weeks or longer of leuprolide acetate treatment. 
b. Enzalutamide is allowed for the treatment of castration-resistant disease that occurs on study (rising prostate-
specific antigen in the setting of testosterone suppressed to castrate levels (≤ 50 ng/dL [1.7 nmol/L]). 
c. 
Minimum washout period is calculated from the date of last dose of prohibited medication to the first day of 
study drug. 
d. Patients with cumulative previous androgen deprivation therapy > 18 months are excluded, regardless of 
washout period. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded.  At a minimum, the drug 
generic name, dose amount, route of administration, start date, and stop date will be recorded in 
the source documents and the eCRF. 
If alternative androgen deprivation therapy is initiated prior to 30 days after the last relugolix 
dose, record the alternative androgen deprivation therapy as a concomitant medication. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive radiotherapy as prescribed by the investigator. In the setting 
of rising PSA patients may also receive enzalutamide. For patients requiring other systemic 
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antineoplastic therapy during the treatment period, the investigator should contact the medical 
monitor. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities 
(see Section 1.1).  Study procedures are briefly described within Section 6.6.  Further details of 
the procedures are provided in the investigator site file. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 3 periods:  Screening Period, Treatment 
Period, and Follow-up Period.  Unscheduled visits may also occur as needed to evaluate patients. 
6.2. 
Screening Period (Day -28 to Day -1) 
The Screening Period will be from Day -28 through Day -1.  At the Screening visit, study site 
personnel must explain to potential study participants all aspects of the study, including all 
scheduled visits and activities.  Study site personnel must obtain signed informed consent before 
any study-specific procedures are conducted, unless the procedures are part of routine standard 
of care.  The informed consent process must be documented in the patient’s clinical record. 
The investigator will assess and confirm the eligibility of each patient and determine that each 
patient will maintain study drug compliance during the treatment period.  All screening 
procedures results and relevant medical history must be available before eligibility can be 
determined.  All inclusion criteria must be met and none of the exclusion criteria may apply.  No 
eligibility waivers will be granted. 
The following assessments will be performed: 
• Complete medical history, including detailed prostate cancer history; 
• Vital signs, weight, and height; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
• An abdominopelvic CT or MRI and a bone scan should be performed and read locally to 
determine the presence of metastatic disease within 60 days prior to randomization. 
However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not 
required. If metastatic disease is not present on CT or MRI, then a bone scan is also 
required.  
• Demographics; 
• Laboratory data collection (see Section 1.1); 
• Verify inclusion/exclusion criteria; and 
• Concomitant medications and adverse events. 
A Randomization Authorization Form must be submitted to the sponsor for approval prior to 
conducting the Baseline Day 1 visit. 
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6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) 
Baseline Day 1 Visit 
Study site personnel should ensure that an approved Randomization Authorization Form is in the 
patient’s file before proceeding with the randomization and Day 1 visit procedures.  Patients will 
be randomized to either relugolix or leuprolide acetate 3-M depot injection 22.5 mg (or 11.25 mg 
in Japan, Taiwan, and China) (see Section 5.3). 
The following assessments will be performed: 
• Patient-reported outcome questionnaires (EQ-5D-5L, EORTC-QLQ-PR25, and EORTC-
QLQ-C30) 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Medical history; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Verify inclusion/exclusion criteria; 
• Concomitant medications and adverse events; 
• Randomize the patient;  
• Laboratory collection (see Section 1.1); and 
• Study drug management: 
o If study drug administration is not logistically feasible on the same day as 
randomization, Day 1 will be defined as the day of the first dose. 
o If the patient is randomized to relugolix, site personnel will administer a single 
loading dose of oral relugolix 360 mg (3 tablets) and then dispense study drug to 
the patient and instruct on daily dosing of 120 mg (1 tablet) and the importance of 
medication compliance (see Section 5.4); 
o If the patient is randomized to leuprolide acetate, site personnel will administer 
the injection in the clinic. 
Day 4 and Weeks 2 and 3 Visits (Visit Window ± 2 days) 
The following assessments will be performed: 
• Vitals signs; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
 
Note: The Week 2 visit will only occur for patients who are part of the Japan or China subset for 
PK analysis. 
 
 
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Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 Visits (Visit Window ± 7 Days) 
Importantly, patients randomized to relugolix should be called 7 days before each visit to ensure 
the patient is compliant with study drug medication. 
The following assessments will be performed: 
• Patient-reported questionnaires will be completed on the electronic tablet provided 
(Weeks 5, 13, 25, and 37 only) 
o Patients will complete the questionnaires before other study procedures, such as 
blood draws and physical examinations, are performed; 
• Vital signs, weight 
o Weight will be collected only on Weeks 13 and 25; 
• 12-lead ECG (Weeks 5, 13, and 25 only); 
• ECOG performance assessment (Week 25 only); 
• Symptom-based physical examination (except Week 25); 
• Complete physical exam and visual acuity assessment (Week 25 only); 
• Laboratory collection (see Section 1.1) 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 24 
hours after the previous dose. Patients may be dosed in the clinic at these visits, 
provided the dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability; 
 Dispense study drug. Patients may be dosed in the clinic, provided the 
dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing; 
 Remind patients on importance of medication compliance. 
o For patients randomized to leuprolide acetate, 
 Site will administer leuprolide acetate in clinic every 12 weeks (Weeks 13, 
25, and 37). 
Week 49 or (Early Termination of Study Drug) (Visit Window ± 7 Days) 
• For patients receiving relugolix, a member of the site team will call the patient 7 days 
before the Week 49 visit to remind the patient of the need for compliance with their study 
medication; 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs, weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
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• Laboratory collection (see Section 1.1); 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 24 
hours after the previous dose.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability. 
6.4. 
Follow-up Period 
The study day in which the Follow-up visit occurs is relative to when the patient takes his last 
dose of study drug.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
30-Day Safety Follow-up Visit (Visit Window ± 7 Days) 
A Safety Follow-up visit should occur 30 days after the End of Treatment and may occur earlier 
for patients who are starting alternative androgen deprivation therapy or do not complete 
12 weeks of study treatment.  Adverse events should continue to be collected and recorded 
through 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events and concomitant medications will be collected from the signing of the 
informed consent form until the Safety Follow-up visit approximately 30 days after the last dose 
of study drug. 
All other study procedures should be completed before the start of alternative androgen 
deprivation therapy. 
The following assessments will be performed: 
• Patient-reported questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
Testosterone Recovery Visit (Visit Window ± 7 Days) 
Patients who have started alternative androgen deprivation therapy will not participate in the 
60- and 90-day follow-up visits.  Approximately 100 patients randomized to receive relugolix 
and approximately 50 patients randomized to receive leuprolide acetate who complete the 
48 weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy will be included in the Testosterone Recovery 60- and 
90-day Follow-up visits.  These patients will discontinue relugolix after 48 weeks of treatment 
and will be offered a period off androgen deprivation therapy. 
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The following assessments will be performed: 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications. 
Health Status Survey 
During the final weeks prior to database lock, sites will be asked to contact all study participants 
or their immediate family regarding the current health status of previously enrolled/completed 
study patients.  If the site is unsuccessful in contacting the patient and/or immediate family, the 
site may access hospital records or publicly available sources such as national registries, 
newspaper obituaries, and social networking websites. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
investigator.  The following activities should be completed at an Unscheduled visit: recording of 
the date and reason for the visit in the patient’s source documents, concomitant medication 
review and evaluation of adverse events.  In addition, procedures such as vital signs, weight, 
symptom-directed brief physical examination, central safety laboratory assessment and collection 
of a PK sample if indicated, 12-lead ECG, study drug compliance and dispensation, etc. may be 
conducted as needed.  See Schedule of Events (see Section 1.1) for tests that may be performed 
if indicated at an unscheduled visit.  Consult with the medical monitor, if needed, to discuss 
Unscheduled visit testing. 
6.6. 
Study Procedures 
6.6.1. 
Efficacy-Related Procedures 
6.6.1.1. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, testosterone, 
dihydrotestosterone, sex hormone binding globulin, and PSA will be collected predose at the 
visits indicated in the Schedule of Activities in the protocol synopsis (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory.  Testosterone samples may 
be analyzed at a second laboratory to confirm non-castrate levels (Section 1.1). 
Serum LH, FSH, dihydrotestosterone, sex hormone binding globulin, and PSA samples will be 
analyzed at a central laboratory. 
PSA will also be used to evaluate biochemical progression per Prostate Cancer Clinical Trials 
Working Group 3 guidelines [Scher, 2016]. 
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Analysis of serum samples for testosterone is detailed below:  
Testosterone Assessment 
Serum concentrations of testosterone will be obtained as indicated in the Schedule of Activities 
(see Section 1.1). 
Testosterone will be assayed using a liquid chromatography-tandem mass spectrometry method 
sensitive at least as low as 5 ng/dL (0.17 nmol/L) for all measurements.  
Between Week 5 and Week 49 visits (inclusive), testosterone samples that are above castrate 
level (> 50 ng/dL) will be reported to the investigator at the respective study site.  Testosterone 
samples may be subject to reanalysis by liquid chromatography/mass spectrometry and/or 
immunoassay sensitive to at least as low as 10 ng/dL. 
Instructions for collection and processing of blood specimens are provided in the investigator site 
file. 
6.6.1.2. 
Pharmacokinetic Sample Collection 
Relugolix  
Pharmacokinetic samples will only be collected in patients randomized to relugolix study drug. 
Blood samples for pharmacokinetic analysis of relugolix will be collected at the visits indicated 
in the study Schedule of Activities in the protocol synopsis (see Section 1.1).  The actual date 
and time of each blood sample collection will be recorded. 
Patients may take their dose of study drug in the clinic at these visits.  Study drug will be 
administered on an empty stomach or at least 2 hours before food, and food will be withheld for 
1 hour after dosing.  The date and time of their previous dose of study drug (ie, the dose the day 
before the clinic visit) will be accurately recorded.   
Ideally, predose samples should be collected approximately 24 hours (±6 hours) after the 
previous dose of relugolix, although samples collected outside of this window would not be 
considered a protocol deviation. 
If the study patient inadvertently took the study drug at home on the morning of the clinic visit, 
the date and time of that dose should also be accurately recorded and the pharmacokinetic 
sample collected, which may be used for population PK modeling. 
Plasma from the Week 5 and Week 13 visits in all patients will be analyzed for relugolix plasma 
concentration.  Analysis of other individual patient plasma samples will be performed on a case-
by-case basis (such as those patients with non-castrate testosterone levels). 
Collection, processing, storage, and shipping instructions will be provided in the investigator site 
file.  Plasma analysis of relugolix will be performed by the sponsor (or designee). 
Leuprolide Acetate  
For patients on leuprolide acetate, in the event of non-castrate testosterone levels, a blood sample 
may be taken for potential analysis of leuprolide acetate plasma concentration, following 
discussion with the medical monitor 
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China and Japan Pharmacokinetic Subset 
In a subset of patients from China (if enrolled) and approximately 20 patients from Japan that are 
randomized to relugolix, additional relugolix PK samples will be collected on Day 1, Day 4, and 
Week 2 visits (see Schedule of Activities in the protocol synopsis, Section 1.1).  The actual date 
and time of study drug administration and the date and time of each PK sample will be 
accurately recorded. 
All samples from the China and Japan subset will be analyzed for plasma relugolix 
concentrations.  Collection, processing, storage, and shipping instructions will be provided in the 
investigator site file.  Plasma analysis of relugolix will be performed by the sponsor (or 
designee). 
6.6.1.3. 
Pharmacogenomics Sample Collection 
Whole Blood Sample for Germline Deoxyribonucleic Acid 
Pharmacogenomic analysis may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety.  Participation of study patients in 
pharmacogenomic sample collection is optional.  A pharmacogenomics sample will be collected 
from patients at all participating study centers, with individual patient consent and per local 
ethics and regulatory standards.  The sample will be retained for germline deoxyribonucleic acid 
(DNA) analysis of potential genetic determinants of drug safety, drug efficacy or disease 
response, and drug metabolism. 
Every patient must sign informed consent/be consented in order to participate in the sampling of 
whole blood for DNA analysis.  This research may be used to develop a better understanding of 
the safety and efficacy of relugolix and other study drugs, to increase understanding of the 
disease/condition being studied, and for improving the efficiency, design and study methods of 
future research studies. 
Two venous whole blood sample (4 mL per sample) for the analysis of germline DNA will be 
collected at Day 1 from all patients who have provided informed consent.  The DNA samples are 
expected to be collected at the Day 1 visit, but if necessary, may be collected at any visit after 
randomization.  If necessary and feasible, a second aliquot of blood may be taken if isolation of 
DNA from the first sample was not successful or possible.  Germline DNA analysis may be 
conducted to investigate the contribution of genetic variance on drug response, for example, its 
efficacy and safety.  As pharmacogenomics is an evolving science, currently many genes and 
their function are not yet fully understood.  Future data may suggest a role of some of these 
genes in drug response or diseases, which may lead to additional hypothesis-generating 
exploratory research on stored samples. 
Individual blood samples for germline DNA analysis, including the result of any analyses and 
corresponding information will be identified only by a code in a computer database. 
The whole blood samples for DNA analysis will be stored securely at the sponsor’s location or 
its designated central laboratory vendor until 10 years after completion of this study (HERO, 
MVT-601-3201) and/or until the drug development of relugolix is no longer actively pursued by 
Myovant or its collaborators.  The storage period for these samples may be adjusted by country 
in accordance with local regulatory and/or legal requirements for the storage of research samples.  
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Such changes will be reflected in the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) country-specific informed consent form.  After that time, the samples will be 
properly destroyed by the central laboratory or designee following approval by the sponsor.  The 
investigator will keep records linking the patient identity with the samples for the time required 
by applicable law.  Patients who consent and provide a pharmacogenomic sample for DNA 
analysis can withdraw their consent and request disposal of a stored sample at any time. 
Directions for sample collection and handling can be found in the investigator site file. 
6.6.1.4. 
Quality of Life 
European Quality of Life 5-Dimension 5-Level Assessment 
The EuroQol EQ-5D-5L comprises 5 scales and an overall assessment of health status on a 
visual analogue scale (Appendix 2).  The 5 scales include:  mobility, self-care, usual activities, 
pain and discomfort, and anxiety and depression.  The original version, the EQ-5D-3L, includes 
3 response options for each scale.  However, a new 5-level response-option version, the 
EQ-5D-5L, has been developed with the following response options:  no problems, slight 
problems, moderate problems, severe problems, and unable to/extreme problems.  It is believed 
that the EQ-5D-5L is superior to the EQ-5D-3L in terms of feasibility, ceiling effects, 
discriminatory power, and convergent validity.  The EQ-5D-5L index values will be calculated 
from the EQ-5D-5L descriptive system scores based on the Crosswalk value sets [EuroQol 
Group, 1990; Brooks, 1996; Herdman, 2011; Janssen, 2013]. 
European Organisation for Research and Treatment of Cancer Assessments 
The EORTC-QLQ-C30 [Fayers, 2001; Fayers, 2002] (Appendix 3) and the 25-item prostate 
cancer module EORTC-QLQ-PR25 [Spry, 2006] (Appendix 4) will be administered as specified 
in the Schedule of Activities (see Section 1.1). 
The EORTC QLQ-C30 core measurement will be used to capture distal outcomes, including 
physical, social functioning, and overall health-related quality of life.  The QLQ-C30 core 
questionnaire incorporates 30 questions comprising 9 multi-item scales:  5 functional scales 
(physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea 
and vomiting); and a global health and quality of life scale.  Several single-item symptom 
measures are also included.  It is a reliable and valid measure of health-related quality of life in 
patients with cancer and takes about 11 minutes to administer.  The instrument has been 
validated and used in many countries [Aaronson, 1993]. 
The EORTC-QLQ-PR25 is the 25-item Prostate Cancer module (P25) of the EORTC.  The 
EORTC-QLQ-PR25 contains 3 additional symptom scales (urinary, bowel, sexual) and 
5 treatment-related items. 
6.6.2. 
Safety-Related Procedures 
6.6.2.1. 
Weight, Height, and Body Mass Index 
Height and weight will be measured during screening (within 28 days before the first dose of 
study drug).  Weight will be obtained at additional time points as specified in the Schedule of 
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Table 6-1 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Metabolic Panel 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Neutrophils and absolute 
neutrophil count 
Platelet (count) 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Creatinine 
Chloride 
Serum gamma-glutamyl 
transferase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Total cholesterol 
High density lipoprotein 
cholesterol 
Low density lipoprotein 
cholesterol 
Triglycerides 
Hemoglobin A1c 
Endocrine Panel 
Diagnostic Screening 
(investigator’s discretion) 
 
Serum testosterone 
Serum LH 
Serum FSH 
Serum sex hormone binding 
globulin 
Hepatitis panel, according to 
CDC criteria 
 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; LH, luteinizing hormone 
 
A separate sample will be collected at the Day 1 visit and will be banked and tested for presence 
of hepatitis A, B, and C (hepatitis A antibody, IgM, hepatitis B core antibody, IgM, hepatitis B 
surface antigen, and hepatitis C antibody) if requested by the medical monitor for evaluation of 
abnormal liver function tests. 
The central laboratory will perform laboratory tests for chemistry, hematology, and plasma and 
serum hormone levels. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal and clinically 
significant results should be reported as adverse events. 
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6.6.2.5. 
12-Lead Electrocardiograms 
A 12-lead ECG will be administered at the time points specified in the Schedule of Activities 
(Section 1.1).  When an ECG is scheduled at the same time as vital signs and a blood draw, the 
ECG, when possible, will be obtained after the vital signs and prior to the blood draw; the blood 
draw will be collected at the scheduled time.  ECGs will be read locally by a qualified physician. 
If patients have a prolonged QTc (> 500 msec) in the absence of a pacemaker, the ECG should 
be repeated and confirmed.  Patients with a confirmed QTc > 500 msec, measured by Fridericia's 
formula [QTcF = QT/(RR^0.33)], should be withdrawn.  All abnormal ECG findings must be 
documented by the investigator as clinically significant or not. 
6.6.2.6. 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient 30 days 
prior to the first dose of study drug until 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection will recorded in the eCRF (Exception: 
amiodarone will be reported if taken within 3 months prior to the first day of study drug).  See 
Section 5.10.1 for a list of medications and therapies that are prohibited and/or allowed during 
the study. 
 
6.6.2.7. 
Radiologic Assessment 
CT imaging or MRI of the abdominopelvic region with contrast and a bone scan must be 
obtained prior to randomization for each patient to determine the presence or absence of 
metastatic disease.  The scans should be read locally and do not need to be repeated if a scan 
exists within 60 days prior to the Baseline Day 1 visit. However, if CT or MRI demonstrates 
presence of metastatic disease, a bone scan is not required. If metastatic disease is not present on 
CT or MRI, then a bone scan is also required.  
Radiologic assessment is not included as part of the Schedule of Activities after randomization. 
6.7. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of 8 mL of whole blood 
for pharmacogenomics testing (see Section 6.6.1.3) will be collected. 
The need to conduct pharmacogenomic analysis may be identified after this study (or 
additional studies) has been completed.  For this reason, the collected samples will be retained 
for up to 10 years after the last patient completes the study.  A patient may request the 
destruction of his sample at any time.  The sponsor may destroy the samples sooner than 
10 years after the study completes. 
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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations including visual 
acuity assessment, vital signs, weight, ECGs, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or duration 
of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate medical 
events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least one 
of the following criteria: 
o Induces clinical signs or symptoms; 
o Requires active intervention; or 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
o Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event; 
o The disease/disorder being studied, or expected progression; 
o Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; and 
o Situations where an untoward medical event has not occurred (eg, planned hospitalization 
for an elective procedure, with elective defined as known or planned at the time of 
signing of the informed consent). 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to CTCAE (Appendix 5).  Episodic adverse events, such as vomiting, or those that 
occur repeatedly over a period of consecutive days are “intermittent”.  All other events are 
“continuous”.  Additional information on detecting, documenting, and reporting adverse events 
and serious adverse events are provided below.  No toxicity-related dose reductions of study 
drug are permitted; however, study drug can be held for a period of up to 10 days for evaluation 
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and treatment of an adverse event.  The study drug may be restarted if deemed safe for the 
patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study patient was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.  For example, drug-
induced hepatitis that resolved without evidence of hepatic failure would not be considered 
life-threatening even though drug-induced hepatitis can be fatal. 
c. 
Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local IRB/IEC. 
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Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the patient is the preferred method to 
inquire about adverse event occurrence.  Appropriate questions include: 
• “How are you feeling?”  
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact? 
The patient’s answers to the EQ-5D-5L will not be used as a primary means to collect adverse 
events, however they should be reviewed by the study site personnel and the study monitors.  
Should the investigator or site staff become aware of a potential adverse event 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 adverse 
event not previously reported has been identified, normal reporting requirements should be 
applied. 
All patients who experience an adverse event will be evaluated at appropriate time intervals until 
the event resolves or has stabilized or become chronic.  At the conclusion of the study, the 
investigator and medical monitor will assess unresolved adverse events and determine if 
additional follow-up is warranted. 
All adverse events, whether or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
each sign and symptom as an individual adverse event. 
Overdose and pregnancy in a partner will be reported as described in Section 7.7 and Section 7.8, 
respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events will be collected from the time the first dose of study drug is administered until 
the Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
Serious adverse events will be collected from the signing of the informed consent form until the 
Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events reported to the investigator after the safety reporting period should be 
reported to the sponsor if the investigator assesses the event as related to the study drug 
treatment. 
Any event occurring between signing of the informed consent form and the first dose of study 
drug will be recorded as medical history and in the patient’s clinical record for any patient who 
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continues to meet eligibility criteria and proceeds to dosing with study drug; the exception to this 
includes procedure-related pretreatment-emergent events which should be recorded as adverse 
events in the electronic data capture (EDC) system for those patients who remain eligible for 
study participation. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
definitions in Table 7-1 are to be used for the relationship of the adverse event to study drug. 
Table 7-1 
Causal Relationship to Study Drug 
Relationship 
Criteria 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely attributed to concurrent disease 
or other drugs or chemicals, and that follows a clinically reasonable response on 
re-administration (re-challenge) or withdrawal (de-challenge). 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but that could also be explained by 
concurrent disease or other drugs or chemicals.  Information on drug withdrawal 
may be lacking or unclear. 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable 
and/or in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE (see Appendix 5).  For terms not specified with the CTCAE, the criteria 
in Table 7-2 should be used to determine the grade severity. 
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Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
7.5. 
Adverse Events of Clinical Interest Reporting 
Adverse events of clinical interest in this study are defined as any increase in ALT or AST 
≥ 3 x ULN. 
Any ALT or AST elevation of this degree or greater occurring during the randomized Treatment 
Period or the Follow-up visit should be reported to the sponsor using the serious adverse event 
form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), even 
if the event does not meet serious adverse event criteria.  Additional instructions for evaluating 
patients with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized ratio 
(INR) >1.5 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
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Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1) AST or ALT increases to ≥ 3 x ULN; AND 
2) Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3) Alkaline phosphatase value does not reach 2 x ULN; AND 
4) No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease; 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus); 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms; 
• Alcoholic hepatitis; 
• Nonalcoholic steatohepatitis; or 
• Autoimmune hepatitis. 
If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
7.6. 
Serious Adverse Event Reporting 
Using a serious adverse event report form, all serious adverse events must be reported within 
24 hours of the study site personnel’s knowledge of the event, regardless of the investigator 
assessment of the relationship of the event to study drug.  Serious adverse events reported to the 
investigator after the safety reporting period should be reported to the sponsor if the investigator 
assesses the event as related to the study drug treatment. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose or pregnancy of partner is available on the serious adverse event 
report form and is as follows:   
Send completed Safety Report Forms to IQVIA (previously named QuintilesIMS; contact 
information as below and on the SAE Form): 
Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary 
reporting method) 
All Regions 
 
  
 
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For questions on Serious Adverse Event (SAE)/Adverse Event of Clinical Interest or 
events of overdose reporting, please call: 
• 
North/South America: 
  
• 
Regional toll-free phone and fax lines distributed separately.  Please refer to the 
investigator site file. 
The initial report should include: 
• Study number (MVT-601-3201); 
• Site address and number; 
• Investigator name; 
• Patient ID number, sex, and age; 
• Details of study drug administration; 
• The date of the report; 
• A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); and 
• Causal relationship to the study drug. 
If the patient died, the report should include the cause of death and whether or not the cause of 
death was related to study drug, as well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 240 mg within a 24-hour window is an overdose, except 
for the 360-mg loading dose.  The sponsor does not recommend specific treatment for an 
overdose; supportive treatment should be provided as clinically applicable. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form, whether or not the overdose is associated with an 
adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); and 
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• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If the partner of any patient becomes pregnant during the study or through 4 months after the last 
dose of study drug, the investigator must inform the sponsor of the pregnancy. 
The patient should remain on study drug treatment, unless otherwise indicated. 
If the patient agrees, the patient’s pregnant partner should be notified and requested to sign a 
Release of Information form, permitting transfer of information regarding the pregnancy and 
outcome to the sponsor. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the partner pregnancy report forms.  The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated conception date, pregnancy result, 
and neonatal data, etc, should be included in this information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
Benefit/Risk Assessment 
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategies for this protocol are outlined in Table 7-3. 
Table 7-3 
Relugolix Potential Risks and Mitigation 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Hepatic Enzyme Increases 
Isolated increases in hepatic enzymes have been 
observed in prior clinical studies.  Hepatic enzyme 
increases, considered an important potential risk of 
treatment with relugolix, are closely monitored in 
accordance with FDA guidelines for assessing drug-
induced liver injury [FDA, 2009] in all relugolix 
studies. 
Exclusion criteria for 
AST and ALT > ULN; 
total bilirubin values > 
ULN unless consistent 
with Gilbert’s 
syndrome. 
Liver chemistry will be 
monitored during the 
study.  Appropriate 
liver stopping criteria 
and follow-up 
procedures are detailed 
in Section 7.5.2. 
Phospholipidosis 
Data from nonclinical studies in rats and monkeys 
showed histopathological changes consistent with 
PLD.  PLD by itself is not adverse.  No clinical 
Patients with 
significant underlying 
medical conditions are 
excluded. 
Routine safety 
monitoring including 
laboratory assessments, 
ECGs, and assessment 
of adverse events; visual 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
evidence of relugolix-related PLD-associated toxicity 
has been observed nor was there a clinically 
meaningful increase in a biomarker of PLD assessed 
in phase 2 clinical studies. 
acuity will be evaluated 
during the study. 
Risks Associated with Medical Castration 
Acute and subsequent chronic symptoms of medical 
castration (reduction of testosterone to ≤ 50 ng/dL 
[1.7 nmol/L]) include vasomotor symptoms or hot 
flushes, disturbed sleep related to vasomotor 
symptoms, decreased libido, and fatigue or loss of 
energy.  These side effects are usually not severe and 
can be managed with anticipatory guidance. 
Long-term suppression of testosterone is associated 
with well-characterized risks including bone loss, 
decreased muscle mass, possible changes in insulin 
sensitivity with increased risk of diabetes, altered 
lipid metabolism, and possible increased risk of 
cardiovascular disease [Oefelein, 2002; Lopez, 
2005; Diamond,1998; Keating, 2006; Braga-
Basaria, 2006; Saigal, 2007; Tsai, 2007; D'Amico, 
2007; Efstathiou, 2009]. 
- 
Effects can usually be 
managed with 
appropriate 
anticipatory guidance 
(eg, diet and exercise 
programs) or 
supportive therapy 
when required (eg, 
lipid-lowering or bone-
sparing agents). 
Metabolic Changes 
Metabolic changes (insulin resistance, dyslipidemia, 
and increased weight) with increased risk of diabetes 
are a potential risk of the hypoestrogenic state 
induced by relugolix. 
- 
Fasting lipids and 
glucose will be 
monitored during the 
study. 
Loss of Bone Mineral Density 
Loss of bone mineral density is considered a potential 
risk of treatment with relugolix in the prostate cancer 
indication. 
- 
Fractures will be 
assessed through 
adverse event 
monitoring.  Use of 
anti-resorptive bone 
therapy, such as 
bisphosphonates or 
denosumab, may be 
considered by the 
treating physician.  
Abbreviations:  ALT; alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; FDA, 
Food and Drug Administration; PLD, phospholipidoses; ULN, upper limit of normal 
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8. 
DATA QUALITY ASSURANCE 
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the 
investigator site file with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice regulations.  By signing this protocol, the investigator grants permission to 
Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-site 
monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and Good Clinical Practices.  The study monitor 
should have access to laboratory test results and any other source records and data needed to 
verify the entries on the eCRF.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved.  For this 
study, patient data will be entered into a sponsor-approved electronic database and combined 
with data provided from other sources in validated datasets then transmitted electronically to the 
sponsor (or designee). 
Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
8.3. 
Independent Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board will review available safety data, as 
appropriate, on a periodic basis throughout the conduct of the study.  Details of the Data and 
Safety Monitoring Board will be captured in a charter prior to the start of the study. 
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8.4. 
Steering Committee 
A Steering Committee consisting of experts in the field of prostate cancer and staff members of 
Myovant Sciences GmbH will be established to provide oversight for the clinical trial, study 
design, study conduct, data analysis, and presentation and publication of the study data.  Details 
of the Steering Committee responsibilities will be captured in a separate charter. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan will describe the detailed statistical methods and analyses for this 
study.  The statistical analysis plan will be prepared and finalized prior to database lock and 
analysis of the primary and secondary endpoints. 
All confidence intervals will be 2-sided at an alpha level of 0.05 unless otherwise specified.  The 
methodology to be used to maintain a study-wide type I error rate of 0.05 across primary and 
secondary endpoint testing will be described in the statistical analysis plan. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 2:1, relugolix to leuprolide 
acetate 3-M depot.  Randomization will be stratified by the following factors: 
• Geographic Region:  North and South America versus Europe versus Asia and Rest of 
World; 
• Presence of Metastatic Disease:  yes versus no; 
• Baseline Age:  ≤ 75 years old versus > 75 years old. 
Stratified efficacy analyses will incorporate these 3 stratification factors unless otherwise 
specified. 
9.2. 
Analysis Populations 
The Intent-To-Treat (ITT) population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis.  Patients will be analyzed according to their randomized treatment assignment. 
The Per-Protocol population will consist of those members of the ITT population who have no 
major protocol deviations as defined in the statistical analysis plan, considering the following 
protocol deviations but not limited to: 
• Those who entered the study even though they did not satisfy the entry criteria; 
• Those who developed withdrawal criteria during the study but were not withdrawn; 
• Those who received the wrong treatment or incorrect dose; 
• Those who received an excluded concomitant treatment. 
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The Per-Protocol population will not be analyzed if this population comprises more than 95% or 
less than 50% of the ITT population.  The Per-Protocol population will be used as a sensitivity 
analysis of the ITT population for the primary efficacy endpoint and secondary endpoints.  The 
Per-Protocol population will be identified prior to the database lock. 
The primary population for safety analyses will be the Safety population, defined as all patients 
who receive at least one dose of any study treatment.  Patients will be analyzed according to the 
treatment actually received, regardless of their randomized treatment assignment. 
9.3. 
Efficacy Analyses 
9.3.1. 
Primary Endpoint Analyses 
The primary efficacy endpoint is the sustained castration rate, defined as the cumulative 
probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 (Study Day 337).  This probability will be 
estimated for each treatment group using the Kaplan-Meier method with the confidence interval 
calculated using the exponential Greenwood formula via log-log transformation of the survival 
function.  Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL 
(1.7 nmol/L) will be censored at the last testosterone assessment prior to discontinuation.  
Detailed censoring rules will be described in the statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix is 
greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion. 
• Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression.  The lower bound of the 95% confidence interval for the 
difference in the cumulative probability of sustained testosterone suppression between the 
2 treatment groups will be calculated and must be greater than or equal to the non-
inferiority margin of -10% to meet this criterion.  The confidence interval of the 
treatment difference will be calculated using the formula 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡) −𝑆𝑆2෡(𝑡𝑡)൧= 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡)൧+
𝑉𝑉෠ൣ𝑆𝑆2෡(𝑡𝑡)൧ , where each of the variance of the Kaplan-Meier estimate will be calculated 
using the Greenwood's formula 𝑉𝑉෠ൣ𝑆𝑆̂(𝑡𝑡)൧= 𝑆𝑆̂(𝑡𝑡)2 ൤∑
𝑑𝑑𝑗𝑗
𝑛𝑛𝑗𝑗൫𝑛𝑛𝑗𝑗−𝑑𝑑𝑗𝑗൯
𝑗𝑗:𝑡𝑡(𝑗𝑗)≤𝑡𝑡
൨ ; nj denote the 
number of patients at risk at time t(j) and dj denote the number of events observed at time 
t(j)) [Lachin, 2000]. 
The evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans.  The 2-sided type I error rates for the final analyses will be controlled at 0.05 separately 
for each regional analysis. 
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9.3.2. 
Secondary Endpoint Analyses 
If the result of the primary endpoint is statistically significant, the secondary endpoints will be 
analyzed.  The methods and procedures necessary to maintain a study-wide 2-sided type I error 
rate of 0.05 across primary and secondary endpoint testing will be described in the statistical 
analysis plan. 
• Castration rate defined as the cumulative probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing at Week 1 Day 4, and prior to dosing at Week 3 
Day 1 will be summarized by treatment group using the Kaplan-Meier method; 
• Profound castration rate defined as the cumulative probability of testosterone suppression 
of ≤ 20 ng/dL (0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 
Day 1 will be estimated for each treatment group using the Kaplan-Meier method.  The 
difference in the cumulative probabilities between the relugolix group and the leuprolide 
acetate group will be provided, along with the 95% confidence interval calculated in the 
same manner as in the primary analysis of the primary endpoint; 
• PSA response and percent change from baseline in PSA at Week 3 and Week 5 will be 
summarized and compared between the relugolix group and the leuprolide acetate group; 
• Proportions of patients who have a PSA concentration < 0.2 ng/mL (0.2 µg/L) at 
Week 25 will be summarized by treatment group.  The proportions will be compared 
between the relugolix group and the leuprolide acetate group by constructing a 
95% confidence interval for the difference in proportions; 
• Time to testosterone recovery in approximately 100 patients randomized to relugolix and 
approximately 50 patients randomized to leuprolide acetate who complete 48 weeks of 
treatment and who do not start alternative androgen deprivation therapy within the 
following 12 weeks (or within 24 weeks following the last received leuprolide acetate 
3-M depot injection) will be compared between the relugolix group and the leuprolide 
acetate group; 
• Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 global 
health domain and the EORTC-QLQ-PR25 sexual activity and hormonal-treatment-
related symptom subdomains will be summarized by treatment group.  The least square 
means at Week 49 will be compared between the relugolix group and the leuprolide 
acetate group by constructing a 95% confidence interval for the difference in the least 
square means using a mixed model for repeated measures; 
• Absolute values and changes from baseline of the remaining domains in the EORTC 
QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L will be summarized by 
treatment group.  The least square means at Week 49 will be compared between the 
relugolix group and the leuprolide acetate group by constructing a 95% confidence 
interval for the difference in the least square means using a mixed model for repeated 
measures; 
• Time to PSA progression; 
• Proportion of patients with confirmed PSA progression among those who have achieved 
sustained testosterone suppression during the 48-week treatment. 
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Further details of the secondary analyses will be described in the statistical analysis plan. 
9.4. 
Safety Analyses 
The safety analyses will be based on the Safety population.  Safety will be assessed by 
summarizing and analyzing adverse events, laboratory analytes, vital signs, ECG parameters, and 
concomitant medications. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute’s CTCAE.  All adverse events will be coded to preferred term and system organ 
class using MedDRA 19.1 or higher.  The incidence of adverse events will be presented by 
MedDRA system organ class and preferred term, relationship to study drug treatment, and 
severity.  A patient reporting the same adverse event more than once is counted once, and at the 
maximum severity or strongest relationship to study drug treatment when calculating incidence. 
Laboratory data consist of chemistry, hematology, and hormonal tests.  Only data collected by 
the central laboratory will be used for analyses.  The National Cancer Institute CTCAE will be 
used to categorize toxicity grade for the laboratory parameters.  Shift tables will be provided for 
each gradable parameter to summarize baseline toxicity grade versus post-baseline toxicity 
grade.  For laboratory parameters that are not gradable by the CTCAE, a shift table based upon 
the normal range (low, normal, and high) will be provided for each parameter to summarize the 
baseline versus post-baseline results. 
9.5. 
Pharmacokinetic Analyses 
Plasma relugolix concentrations will be listed and summarized and included in the clinical study 
report. 
PK data may be pooled with data from other studies in healthy male patients and patients with 
prostate cancer for population PK analysis, including evaluation of covariates of relugolix PK 
parameters, and for input into a population PK/pharmacodynamics models describing the 
relationship between relugolix exposure and serum testosterone [Ahsman, 2016].  These 
population PK analyses will be detailed further in a separate statistical analysis plan and report. 
For patients from China (if enrolled) and Japan in the PK subset, plasma relugolix PK parameters 
Cmax, AUC0-τ, and tmax from Day 1 and Day 14 of dosing will be determined.  Population PK or 
PK/pharmacodynamic analyses may be conducted to explore the factors that affect relugolix 
exposure or to contribute to the assessment of the relationships between exposure and 
testosterone. 
9.6. 
Endocrine Marker Analyses 
Endocrine markers will be analyzed to see effects of relugolix and leuprolide acetate as measured 
as absolute value and change from baseline for: 
• LH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
• FSH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
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• Dihydrotestosterone at Week 5, Week 25, and Week 49 visits and/or follow-up visit(s);  
• Sex hormone binding globulin at Week 5, Week 25, and Week 49 visits and/or follow-up 
visit(s). 
9.7. 
Exploratory Analyses 
Overall survival:  Overall survival defined as time from randomization to date of death prior to 
data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions for each 
treatment arm. 
Pharmacogenomic analyses may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety, pending availability of samples.  
Polymorphisms in germline genes related to the hypothalamic-pituitary-androgen pathway, 
prostate cancer risk, or to drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix.  These analyses will be 
detailed in a separate statistical analysis plan and associated reports. 
9.8. 
Interim Analyses 
There will be no planned interim efficacy analysis for the study. 
9.9. 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• True probabilities of sustained testosterone suppression are 94% and 96% for relugolix 
and leuprolide acetate, respectively; 
• 2:1 randomization ratio (relugolix:leuprolide acetate); and 
• Dropout rate of 15%. 
The assumed probability of sustained testosterone suppression for relugolix arm is 94%.  It was 
estimated based on the predicted dose-response relationship for the effect of relugolix on 
testosterone suppression in patients with prostate cancer (data from phase 2 studies C27002 and 
C27003).  The assumed castration rate of 96% for leuprolide acetate was based on the results 
from degarelix phase 3 registration program [Shore, 2013]. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of < 90% at a 2-sided 
type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and an overall 2-sided type I 
error rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) 
will yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate.   
The final analysis will be performed separately for individual evaluation criterion using data 
collected through 48 weeks after enrollment of approximately 915 patients. 
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Approximately 915 patients will be randomized in order to fulfill the regulatory requirements of 
all participating countries. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR) Part 312, subpart D, “Responsibilities of 
sponsors and investigators,” 21 CFR Part 50, and 21 CFR Part 56, are adhered to.  These 
standards are consistent with the requirements of the European Community Directive 
2001/20/EC. 
Since this is a “covered” clinical study, the investigator will ensure that 21 CFR Part 54, is 
adhered to; a “covered” clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied.  This 
documentation must be provided before participation of the investigator and any sub-
investigator.  The investigator and sub-investigator agree to notify the sponsor of any change in 
reportable interests during the study and for one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
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10.1.3. 
Informed Consent 
A properly executed, written informed consent, in compliance with the Declaration of Helsinki, 
ICH Good Clinical Practice, US CFR for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27), and local regulations, will be obtained from each patient before entering the patient 
in the trial.  The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
The investigator will provide copies of the signed informed consent form to each patient (or to 
the patient’s legal representatives) and will maintain the signed original document within the 
patient’s record file per local requirements.  The investigator will also fully document the 
informed consent process in the patient’s source records. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator Brochure, protocol, eCRFs and other study forms, the investigational drug, 
and any other study information, remain the sole and exclusive property of the sponsor during 
the conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: 
1) Investigator’s study file:  The investigator’s study file will contain the Investigator Brochure, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents:  The required source data should include the following for 
each patient: 
• Patient identification (name, date of birth, gender); 
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• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and causality 
and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, US, Europe, or Japan) and until 
there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the sponsor.  The investigator must notify the sponsor 
before destroying any clinical study records. 
Clinical study documentation includes the Investigator Brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, curriculum vitae and all training records of study 
site personnel, and all correspondence pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
10.1.5. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on the 1572 form and/or other appropriate local health 
authority documents within a reasonable time period after data collection.  This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
Screening Period if an eCRF was initiated).  If a patient withdraws from the study, the reason 
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must be noted on the eCRF.  If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.6. 
Investigational Product Accountability 
The investigator or investigator’s designee (ie, pharmacist) is responsible for ensuring adequate 
accountability including dates and lot numbers of all study drug.  This includes acknowledgment 
of receipt of each shipment of study product (quantity and condition), patient dispensing records, 
and returned or destroyed study product.  Dispensing records will document quantities received 
from the sponsor and quantities dispensed to patients, including lot number, date dispensed, 
patient ID number, and the initials of the person dispensing the medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements.  Drug may be returned or destroyed on an ongoing basis during the study 
if appropriate.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet the sponsor’s 
requirements for disposal, arrangements will be made between the site and the sponsor (or 
designee) for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
All records must be made available to the sponsor, authorized representatives, and appropriate 
regulatory agencies, upon request. 
Current ICH Good Clinical Practice guidelines require the investigator to ensure that study drug 
deliveries from the sponsor are received by a responsible person (eg, pharmacist), and the 
following: 
• That such deliveries are recorded, for example, on the sponsor-approved drug 
accountability log, or other sponsor-approved pharmacy log; 
• That study drug is handled and stored safely and properly in accordance with the study 
protocol; 
• That study drug is only dispensed to study patients in accordance with the protocol; 
• That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be documented.  
The following guidelines are therefore pertinent: 
• The investigator agrees not to supply study drug to any persons except the patients in this 
study; 
• The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs; 
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• The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which patient; 
• The investigator/pharmacist agrees to conduct a final drug supply inventory on the drug 
accountability record at the conclusion or termination of the study.  It must be possible to 
reconcile delivery records with those of used and returned study drug.  Any discrepancies 
must be accounted for.  Appropriate forms of deliveries must be signed by the person 
responsible; 
• Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative.  Unused study drug 
not destroyed at the site must be returned to the sponsor-designated facility at the end of 
the study or upon expiration. 
10.1.7. 
Inspections 
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of the 
audit is to ensure that the study is (or was) conducted and monitored in compliance with the 
protocol as well as recognized Good Clinical Practice guidelines and regulations.  These audits 
will also increase the likelihood that the study data and all other study documentation can 
withstand a regulatory authority inspection.  If such audits are to occur, they will be arranged for 
a reasonable and agreed time.  By signing this protocol, the investigator grants permission to the 
sponsor or designee to conduct onsite audits of all appropriate facilities and study 
documentation. 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the sponsor or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 
10.1.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
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emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
(eg, http://www.clinicaltrials.gov) before enrollment of patients begins.  Results will be posted as 
required. 
10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct 
access to the investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
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10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  When the sponsor is aware of 
information on matters concerning the quality, efficacy, and safety of the study drugs, as well as 
other important information that may affect proper conduct of the clinical study, the sponsor may 
terminate the study and send a written notice of the termination along with the reasons to the 
investigator.  Should this be necessary, the sponsor will arrange discontinuation procedures and 
notify the appropriate regulatory authority(ies) and IRBs/IECs.  In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the protection of 
the study participants’ interests. 
If the investigator intends to terminate participation in the study, the investigator must 
immediately inform the sponsor and provide the reason to it. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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APPENDICES 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
Note:  Adapted from Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
 
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Appendix 2. EuroQol EQ-5D-5L Questionnaire 
 
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Appendix 3. Quality of Life Questionnaire:  EORTC QLQ-C30 
 
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Appendix 4. Quality of Life Questionnaire:  EORTC QLQ-PR25 
 
 
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Appendix 5. 
Adverse Event Severity Grading 
When assessing adverse events, refer to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03, June 14, 2010 (available at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).  A 
copy of the National Cancer Institute CTCAE table will be provided in the investigator site file. 
The National Cancer Institute CTCAE is a descriptive terminology that can be utilized for 
adverse event reporting.  A grading (severity) scale is provided for each adverse event term. 
Components and Organization of the National Cancer Institute CTCAE 
• System Organ Class (SOC).  SOC, the highest level of the Medical Dictionary for 
Regulatory Activities (MedDRA) hierarchy, is identified by anatomical or physiological 
system, etiology, or purpose (eg, SOC Investigations for laboratory test results).  CTCAE 
terms are grouped by MedDRA Primary SOCs.  Within each SOC, adverse events are 
listed and accompanied by descriptions of severity (grade). 
• CTAE Terms.  Each CTCAE term is a MedDRA LLT (Lowest Level Term). 
• Definitions.  A brief definition is provided to clarify the meaning of each adverse event 
term. 
• Grades.  Grade refers to the severity of the adverse event.  The CTCAE displays grades 1 
through 5 with unique clinical descriptions of severity for each adverse event based on 
this general guideline: 
o Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
o Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living; 
o Grade 4 Life-threatening consequences; urgent intervention indicated; and 
o Grade 5 Death related to adverse event. 
A semi-colon indicates “or” within the description of the grade.  A single dash (-) 
indicates a grade is not available.  Not all grades are appropriate for all adverse 
events.  Therefore, some adverse events are listed with fewer than 5 options for 
grade selection. 
• Grade 5.  Grade 5 (Death) is not appropriate for some adverse events and therefore is not 
an option. 
 
 
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Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes 
Study drug treatment should be withheld for any liver test abnormality listed in Section 7.5.1, 
pending investigation of alternative causes of liver injury.  Follow-up should continue until the 
liver test abnormalities resolve to baseline. For this purpose, local labs can be used. However, 
duplicate samples should be taken for central analysis. 
 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations 
in Appendix Table 2.  If close monitoring is not possible, study drug should be withheld, even if 
the results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, 
ALT, Bilirubin [Total and Direct]), 
Alkaline Phosphatase, and INR Testsa,b 
If AST or ALT ≥ 3 x ULN and total bilirubin 
> 2 x ULN or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
If ALT or AST ≥ 3 x ULN and total bilirubin 
and INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized 
ratio; ULN, upper limit of normal 
a. 
Review frequency of monitoring with medical monitor for an individual patient, in case of questions 
b. Local labs can be used. However, duplicate samples should be taken for central analysis. 
 
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Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
• 
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or 
coworkers, etc) and/or industrial chemical agents; 
• 
Prior and concurrent use of alcohol, recreational drugs, and special diets; 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants and mushrooms; 
• 
Physical examination. 
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
• 
Repeat liver tests as per Appendix Table 1a; 
• 
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat 
liver tests; 
• 
Complete blood count with differential to assess for eosinophilia; 
• 
Serum acetaminophen (paracetamol) concentration; 
• 
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus; 
• 
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune 
hepatitis, etc; 
• 
Serology for celiac disease; 
• 
Appropriate liver imaging; and 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
Abbreviations:  INR, international normalized ratio 
a. 
If the first follow-up testing does not confirm the initial abnormal liver test results, review any additional 
follow-up monitoring with the medical monitor. 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
HERO:  A Multinational Phase 3 Randomized, Open-label, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
Relugolix in Men with Advanced Prostate Cancer 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3201 
Indication: 
Advanced Prostate Cancer 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
IND Number: 
118736 
EudraCT Number: 
2017-000160-15 
Version/Effective Date: 
Original:  13 January 2017 
Amendment 1:  02 January 2018 
Amendment 2:  18 January 2018 
Amendment 3:  23 October 2018 
Study Medical Monitor: 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
Principal Investigator Name (Printed)  
Signature 
 
 
 
 
 
Date 
 
Site 
 
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TABLE OF CONTENTS 
Sponsor Signature Page .............................................................................................................................. 2 
Investigator Statement ................................................................................................................................ 3 
List of Tables ............................................................................................................................................... 8 
List of Figures .............................................................................................................................................. 8 
List of Abbreviations .................................................................................................................................. 9 
1. 
Protocol Synopsis ......................................................................................................................... 11 
1.1. 
Schedule of Activities ................................................................................................................ 24 
2. 
Introduction .................................................................................................................................. 28 
2.1. 
Prostate Cancer .......................................................................................................................... 28 
2.2. 
Relugolix ................................................................................................................................... 29 
2.2.1. 
Indication .......................................................................................................................... 29 
2.2.2. 
Pharmacology ................................................................................................................... 29 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 30 
2.2.4. 
Previous Human Experience ............................................................................................. 30 
3. 
Study Objectives and Endpoints ................................................................................................. 37 
4. 
Investigational Plan ..................................................................................................................... 40 
4.1. 
Overall Study Design................................................................................................................. 40 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 42 
4.3. 
Selection of Study Population ................................................................................................... 43 
4.3.1. 
Inclusion Criteria .............................................................................................................. 44 
4.3.2. 
Exclusion Criteria ............................................................................................................. 45 
4.4. 
Other Eligibility Criteria Considerations ................................................................................... 48 
4.5. 
Screening ................................................................................................................................... 48 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification Number ............ 48 
4.7. 
Removal of Patients from Therapy ............................................................................................ 49 
4.8. 
Contraception/Pregnancy Avoidance ........................................................................................ 51 
5. 
Treatments .................................................................................................................................... 51 
5.1. 
Treatments Administered .......................................................................................................... 51 
5.2. 
Identity of Investigational Product ............................................................................................ 52 
5.2.1. 
Product Characteristics ..................................................................................................... 52 
5.3. 
Randomization and Stratification .............................................................................................. 52 
5.4. 
Directions for Administration .................................................................................................... 53 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 54 
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5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption ......................................................... 54 
5.7. 
Storage, Packaging, and Labeling ............................................................................................. 55 
5.8. 
Blinding ..................................................................................................................................... 55 
5.9. 
Study Drug Accountability and Treatment Compliance ........................................................... 55 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 56 
5.10.1. 
Prohibited Medications ..................................................................................................... 56 
5.10.2. 
Permitted Medications ...................................................................................................... 58 
6. 
Study Assessments and Procedures ............................................................................................ 59 
6.1. 
Schedule of Observations and Procedures ................................................................................. 59 
6.2. 
Screening Period (Day -28 to Day -1) ....................................................................................... 59 
6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) ........................................................... 60 
6.4. 
Follow-up Period ....................................................................................................................... 62 
6.5. 
Unscheduled Visits .................................................................................................................... 63 
6.6. 
Study Procedures ....................................................................................................................... 63 
6.6.1. 
Efficacy-Related Procedures ............................................................................................. 63 
6.6.2. 
Safety-Related Procedures ................................................................................................ 66 
6.7. 
Biological Sample Retention and Destruction ........................................................................... 69 
7. 
Safety Considerations .................................................................................................................. 70 
7.1. 
Adverse Event Definitions......................................................................................................... 70 
7.1.1. 
Adverse Event ................................................................................................................... 70 
7.1.2. 
Serious Adverse Event ...................................................................................................... 71 
7.2. 
Adverse Event Reporting........................................................................................................... 72 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 72 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 73 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 73 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 74 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 74 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities .................................................................................................................... 75 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 75 
7.7. 
Study Drug Overdose Management .......................................................................................... 76 
7.8. 
Pregnancy Reporting ................................................................................................................. 77 
7.9. 
Benefit/Risk Assessment ........................................................................................................... 77 
8. 
Data Quality Assurance ............................................................................................................... 79 
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8.1. 
Clinical Procedures .................................................................................................................... 79 
8.2. 
Monitoring ................................................................................................................................. 79 
8.3. 
Independent Data and Safety Monitoring Board ....................................................................... 80 
8.4. 
Steering Committee ................................................................................................................... 80 
9. 
Statistical Considerations and Data Analyses ........................................................................... 80 
9.1. 
Randomization Methods ............................................................................................................ 81 
9.2. 
Analysis Populations ................................................................................................................. 81 
9.3. 
Efficacy Analyses ...................................................................................................................... 82 
9.3.1. 
Primary Endpoint Analyses .............................................................................................. 82 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 82 
9.4. 
Safety Analyses ......................................................................................................................... 84 
9.5. 
Pharmacokinetic Analyses ......................................................................................................... 84 
9.6. 
Endocrine Marker Analyses ...................................................................................................... 85 
9.7. 
Exploratory Analyses ................................................................................................................ 85 
9.8. 
Interim Analyses ........................................................................................................................ 85 
9.9. 
Sample Size ............................................................................................................................... 85 
10. 
Responsibilities ............................................................................................................................. 86 
10.1. 
Investigator Responsibilities...................................................................................................... 86 
10.1.1. 
Good Clinical Practice ...................................................................................................... 86 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 87 
10.1.3. 
Informed Consent ............................................................................................................. 87 
10.1.4. 
Confidentiality .................................................................................................................. 87 
10.1.5. 
Electronic Case Report Forms .......................................................................................... 89 
10.1.6. 
Investigational Product Accountability ............................................................................. 89 
10.1.7. 
Inspections ........................................................................................................................ 90 
10.1.8. 
Protocol Compliance ......................................................................................................... 91 
10.2. 
Sponsor Responsibilities............................................................................................................ 91 
10.2.1. 
Protocol Modifications ..................................................................................................... 91 
10.2.2. 
Study Report ..................................................................................................................... 91 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ............................ 91 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 92 
10.3.1. 
Access to Information Monitoring .................................................................................... 92 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 92 
10.3.3. 
Study Discontinuation ....................................................................................................... 92 
10.3.4. 
Publications ....................................................................................................................... 92 
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References .................................................................................................................................................. 94 
Appendices ................................................................................................................................................. 98 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status .......................................... 98 
Appendix 2. 
EuroQol EQ-5D-5L Questionnaire ............................................................................... 99 
Appendix 3. 
Quality of Life Questionnaire:  EORTC QLQ-C30 ................................................... 101 
Appendix 4. 
Quality of Life Questionnaire:  EORTC QLQ-PR25 ................................................. 103 
Appendix 5. 
Adverse Event Severity Grading ................................................................................ 105 
Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes .......................................................... 106 
 
 
 
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LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-3201............................................................. 24 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks ...................... 32 
Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) ........................................... 34 
Table 4-1 
Removal of Patients from Treatment ................................................................................ 49 
Table 5-1 
Description of MVT-601-3201 Study Drugs .................................................................... 52 
Table 5-2 
Prohibited Medications and Washout Periods .................................................................. 56 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 68 
Table 7-1 
Causal Relationship to Study Drug ................................................................................... 73 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 74 
Table 7-3 
Relugolix Potential Risks and Mitigation ......................................................................... 78 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury ...................... 106 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............................ 107 
 
LIST OF FIGURES 
Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of Relugolix 
and Degarelix at Week 25 ................................................................................................. 33 
Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent Reduction 
by Dose of Relugolix at Week 25 Day 1 .......................................................................... 35 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent Reduction 
by Leuprolide Acetate at Week 25 Day 1 ......................................................................... 35 
Figure 4-1 
Schematic of Study Design ............................................................................................... 42 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
3-M 
3-month 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
AUC0-τ 
area under the concentration-time curve from time 0 to the end of the dosing 
interval 
AV 
atrioventricular 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DHT 
dihydrotestosterone 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organisation of Research and Treatment of Cancer 
EOT 
end of treatment 
EuroQol EQ-5D-5L 
European Quality of Life 5-Dimension 5-Level Questionnaire 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
ICH 
International Conference on Harmonization 
ID 
identification 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat (population) 
IWRS 
interactive voice/web recognition system 
LH 
luteinizing hormone 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
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Term 
Explanation 
NOAEL 
no-observed-adverse-effect-level 
NYHA 
New York Heart Association 
Obs 
observed 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
PSA 
prostate-specific antigen 
Q12W 
once every 12 weeks 
Q4W 
once every 4 weeks 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QTc corrected using Fridericia’s formula 
SHBG 
sex hormone binding globulin 
TCR 
time to castration-resistance 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
US 
United States 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
HERO:  A Multinational Phase 3, Randomized, Open-label, Parallel-group Study 
to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate 
Cancer 
Protocol Number 
MVT-601-3201 
Location 
Multinational, including North and South America, Europe, and Asia-Pacific 
Study Centers 
Approximately 200 sites 
Study phase 
Phase 3 
Target Population 
Men aged 18 or older diagnosed with androgen-sensitive advanced prostate cancer 
who are candidates for at least 1 year of continuous androgen deprivation therapy 
for the management of androgen-sensitive advanced prostate cancer and who are 
not candidates for surgical therapy.  Patients previously treated with taxanes or 
expected to receive taxanes after initiation of androgen deprivation therapy are 
excluded, as are patients receiving androgen deprivation therapy adjuvant or 
neoadjuvant to radiotherapy as primary definitive therapy. 
Number of 
Patients Planned 
A total of approximately 1100 patients will be enrolled, including approximately 
390 patients with metastatic advanced prostate cancer to support the analysis of the 
secondary endpoint of time to castration-resistance (TCR), and 138 Chinese 
patients (enrolled in China and Taiwan) to support registration in China. 
• 
After the first 915 patients are enrolled, enrollment in China will continue for 
metastatic and non-metastatic patients until the target number of Chinese 
patients is reached (138).  In the rest of the world, only metastatic patients will 
continue to be enrolled until approximately 390 metastatic patients are accrued. 
• 
The primary analysis of efficacy and safety will be conducted after the first 
915 patients, enrolled in all regions, have completed study treatment and will 
include metastatic and non-metastatic patients with advanced prostate cancer. 
• 
Analysis of the secondary endpoint of TCR will be conducted when all 
metastatic patients have completed study treatment. 
• 
An analysis will be conducted when all Chinese patients have completed study 
treatment. 
Study Objectives 
Primary: 
• 
To evaluate the ability of relugolix to achieve and maintain serum testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) in men with 
androgen-sensitive advanced prostate cancer. 
 
Secondary: 
• 
To evaluate the time course and change in serum testosterone during treatment 
with relugolix; 
• 
To evaluate the time course and magnitude of prostate-specific antigen (PSA) 
reduction during treatment with relugolix; 
• 
To evaluate testosterone recovery following discontinuation of relugolix; 
• 
To evaluate quality of life using validated patient-reported outcome 
instruments; 
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• 
To evaluate the safety of relugolix 120 mg once daily in men with androgen-
sensitive advanced prostate cancer; 
• 
To evaluate the effect of relugolix and leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
To collect relugolix plasma concentration data to further evaluate relugolix 
population pharmacokinetics (PK) and the relationship between relugolix 
exposure and serum testosterone; 
• 
To characterize the relugolix plasma PK parameters in a subset of patients 
from China and Japan. 
 
• 
For patients with metastatic advanced prostate cancer (approximately 
390 patients): 
To evaluate the time course and magnitude of PSA progression and 
development of castration-resistant prostate cancer during treatment with 
relugolix. 
• 
For all enrolled patients (approximately 1100 patients): 
To evaluate the time course and magnitude of PSA progression and 
development of castration-resistant prostate cancer during treatment with 
relugolix. 
Exploratory: 
• 
To explore the overall survival of patients treated with relugolix; and 
• 
To explore the contribution of genetic variance on drug response. 
Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to evaluate the 
safety and efficacy of relugolix in patients with androgen-sensitive advanced prostate cancer who require 
at least 1 year of continuous androgen deprivation therapy.  Relugolix is an oral gonadotropin-releasing 
hormone (GnRH) receptor antagonist that lowers testosterone by inhibiting pituitary release of follicle-
stimulating hormone (FSH) and luteinizing hormone (LH).  Relugolix 120 mg orally once daily or 
leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3-months 
(3-M) will be administered to patients with prostate cancer who require androgen deprivation therapy.  
This study will evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive advanced 
prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for at least 
1 year of continuous androgen deprivation therapy for the management of androgen-sensitive advanced 
prostate cancer and must not be a candidate for surgical therapy.  Eligible patients include those with 
evidence of biochemical relapse (rising PSA) following local primary intervention with curative intent, 
newly diagnosed metastatic disease (excluding metastases to the brain), and/or advanced localized 
disease.  Patients may receive radiotherapy, cryotherapy or high frequency ultrasound no sooner than 
2 months after initiation of androgen deprivation therapy.  Patients may be included if they have not 
previously received androgen deprivation therapy for more than 18 months, and if the androgen 
deprivation therapy was completed at least 3 months prior to the baseline visit.  If the dosing interval of 
the depot is longer than 3 months, then the prior androgen deprivation therapy must have been completed 
at least as long as the dosing interval of the depot.  Patients previously treated with taxanes or expected to 
receive taxanes after initiation of androgen deprivation therapy, are excluded, as are patients receiving 
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androgen deprivation therapy adjuvant or neoadjuvant to radiotherapy as primary definitive therapy.  
Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once daily 
following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg (or 11.25 mg in 
Japan, Taiwan, and China).  After randomization, patients in the leuprolide acetate arm may receive an 
antiandrogen for the first 4 weeks, or longer if indicated, in the opinion of the investigator.  
Randomization will be stratified by geographic region, presence of metastatic disease (metastases in 
regional lymph node[s] are considered N1 and will, therefore, be stratified as non-metastatic), and age for 
the initial 915 enrolled from all regions or among the approximately 138 Chinese patients. 
A total of approximately 1100 patients from approximately 200 study centers in North and South 
America, Europe, and the Asia-Pacific region are planned to be enrolled in this study.  Included in the 
1100 enrolled patients will be approximately 390 patients with metastatic advanced prostate cancer to 
support the analysis of the secondary endpoint of TCR (these patients will be stratified by geographic 
region and age only), and 138 Chinese patients (enrolled in China and Taiwan) to support registration in 
China. 
Approximately 138 Chinese patients will be enrolled (in China and Taiwan).  Similar to the initial 
915 patients enrolled in the HERO study, these Chinese patients will include patients with metastatic and 
non-metastatic advanced prostate cancer. 
The study includes a Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a Follow-up 
Period of up to 90 days.  Additionally, unscheduled follow-up visit(s) may be arranged for patients with 
study-related safety concerns as needed.  Eligible patients will receive study treatment for 48 weeks.  
During that time, testosterone and PSA will be assessed monthly and patient-reported outcomes 
(European Organisation of Research and Treatment of Cancer [EORTC] QLQ-C30, European Quality of 
Life 5-Dimesion 5-Level questionnaire [EuroQol EQ-5D-5L]) will be assessed approximately every 
3 months during the Treatment Period and more frequently during the Follow-up Period.  Additional 
serum endocrine evaluations will include:  LH, FSH, dihydrotestosterone, and sex hormone binding 
globulin.  Relugolix PK samples will be collected throughout the study.  Full PK profiles will be 
determined in a subset of patients in China and Japan.  Safety assessments will include treatment-
emergent adverse events, vital signs, physical examinations, clinical laboratory tests, 12-lead 
electrocardiograms (ECG), and visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on study and, if indicated, may 
receive radiotherapy as prescribed by the investigator.  In the setting of rising PSA patients may also 
receive enzalutamide after the confirmation of PSA progression.  For patients requiring other systemic 
antineoplastic therapy during the treatment period, the investigator should contact the medical monitor. 
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Inclusion/Exclusion Criteria 
Inclusion Criteria 
All of the following inclusion criteria must have been met prior to randomization unless otherwise 
specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or 
study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer with one of 
the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention with 
curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency ultrasound and 
not a candidate for salvage treatment by surgery; or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease unlikely to be cured by local primary intervention with either surgery 
or radiation with curative intent; 
Note:  Radiotherapy, cryotherapy, or high frequency ultrasound are allowed after 2 months of 
androgen deprivation therapy.  Prior palliative radiation to sites other than the prostate bed is 
permitted. 
Note:  Once 915 patients are enrolled worldwide, only patients with metastatic advanced prostate 
cancer will be eligible for the study in all regions except China, where both metastatic and 
non-metastatic patients will continue to be enrolled. 
5. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L); 
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6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 µg/L), or, when applicable, 
post radical prostatectomy of > 0.2 ng/mL (0.2 µg/L) or post radiotherapy, cryotherapy, or high 
frequency ultrasound > 2.0 ng/mL (2.0 µg/L) above the post interventional nadir; 
Note:  If patient has had a radical prostatectomy then PSA must be > 0.2 ng/mL (0.2 μg/L) 
irrespective of any other treatment the patient has had. 
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial 
screening and at baseline (refer to Appendix 1); 
8. Is a male patient who, even if surgically sterilized (ie, status post vasectomy): 
a. Agrees to use a male condom if having sex with a woman of childbearing potential or a pregnant 
woman, during the entire study Treatment Period and through 4 months after the last dose of 
study drug; or 
b. Agrees to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods for 
the female partner) and withdrawal are not acceptable methods of contraception; 
9. Must agree not to donate sperm from first dose of study drug through 4 months after the last dose of 
study drug; 
10. A randomization authorization form has been signed by a study medical monitor approving the 
patient for randomization into the trial. 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. In the investigator’s opinion, is likely to require chemotherapy or surgical therapy for symptomatic 
disease management within 2 months of initiating androgen deprivation therapy; 
2. Previously received GnRH analog or other form of androgen deprivation therapy (estrogen or 
antiandrogen) for > 18 months total duration.  If androgen deprivation therapy was received for ≤ 18 
months total duration, then that therapy must have been completed at least 3 months prior to baseline. 
If the dosing interval of the depot is longer than 3 months, then the prior androgen deprivation 
therapy must have been completed at least as long as the dosing interval of the depot; 
3. Previous systemic cytotoxic treatment for prostate cancer (eg, taxane-based regimen); 
4. Metastases to brain per prior clinical evaluation; 
5. Removed; 
6. Scheduled for major surgery after baseline; 
7. History of surgical castration; 
8. Active malignancy beyond prostate cancer with the exception of any of the following:  
• 
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
carcinoma of any type; 
• 
Adequately treated Stage I cancer from which the subject is currently in remission and has been 
in remission for ≥ 2 years; 
• 
Any other cancer from which the subject has been disease-free for ≥ 5 years; 
The medical monitor should be contacted for any questions regarding this exclusion criterion;  
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable underlying 
disease, or the following laboratory values: 
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a. Serum gamma-glutamyl transferase > 2.0 x upper limit of normal (ULN); 
b. Serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > ULN; 
c. Total bilirubin > ULN (unless secondary to Gilbert’s syndrome or the pattern is consistent with a 
diagnosis of Gilbert’s syndrome); 
d. Serum creatinine > 2.0 mg/dL (176.8 µmol/L); 
e. Platelets < 100 x 103/μL or history of bleeding disorder; 
f. Hemoglobin < 10.0 g.dL (100 g/L); 
g. Leukocytes (WBC) < 3 x 103/μL (3 GI/L); or 
h. Absolute neutrophil count < 1.5 x 103/μL (1.5 GI/L); 
10. Hemoglobin A1c (HbA1c) > 10% in patients previously diagnosed with diabetes mellitus. HbA1c > 
8% in patients whose diabetes mellitus is previously undiagnosed. (Excluded patients may be 
rescreened after referral and evidence of improved control of their condition); 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A (hepatitis A 
virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus surface antigen [HBsAg] 
positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic 
acid); 
12. Known human immunodeficiency virus infection; 
13. Any of the following within 6 months before Baseline Day 1: 
a. Myocardial infarction; 
b. Unstable angina; 
c. Unstable symptomatic ischemic heart disease; 
d. New York Heart Association (NYHA) class III or IV heart failure; 
e. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic 
cerebrovascular events); 
f. Any other significant cardiac condition (eg, pericardial effusion, restrictive cardiomyopathy, 
severe untreated valvular stenosis, or severe congenital heart disease); 
14. The following ECG abnormalities are excluded: 
a. ECG evidence of acute ischemia; 
b. Q-wave infarction, unless identified 6 or more months before the Screening visit; 
c. QT interval corrected for heart rate (QTc) > 470 msec, measured by Fridericia's formula 
[QTcF = QT/(RR^0.33)].  If the QTc is prolonged in a patient with a pacemaker, the patient may 
be enrolled in the study if confirmed by the medical monitor; or 
d. Congenital long QT syndrome; 
e. Active conduction system abnormalities.  Examples of active conduction system abnormalities 
include the following: 
• 
Mobitz II second degree heart block without a permanent pacemaker in place; 
• 
Third degree heart block without permanent pacemaker in place; 
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• 
Untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute); 
• 
Clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular 
fibrillation, or torsades de pointes; 
• 
Uncontrolled atrial fibrillation (patients with chronic stable atrial fibrillation on stable 
anticoagulant therapy or patients with stable cardiac rhythm controlled by a pacemaker are 
allowed); 
The following exceptions are allowed: First degree atrioventricular (AV) block, second degree 
AV block Type 1 (Mobitz Type 1/Wenckebach type), or right bundle branch block. 
15. Uncontrolled hypertension despite appropriate medical therapy (sitting blood pressure of greater than 
160 mmHg systolic and/or 100 mmHg diastolic at 2 separate measurements no more than 45 minutes 
apart during the Screening visit).  Patients may be re-screened after referral and further management 
of hypertension; 
16. Hypotension, as indicated by systolic blood pressure < 84 mmHg on 2 repeat measures at least 
15 minutes apart, or treated ongoing symptomatic orthostatic hypotension with > 20 mmHg decrease 
in systolic blood pressure one minute or more after assuming upright position; 
17. Bradycardia as indicated by a heart rate of < 45 beats per minute on the ECG at the Screening or 
Baseline Day 1 visit; 
18. Treatment with any investigational product within 28 days or 5 half-lives (whichever is longer);  
Exception: treatment for prostate cancer with any investigational products where the mechanism of 
action is testosterone lowering.  In this circumstance, there must be a minimum 12-month treatment 
free interval; 
19. Removed; 
20. Previous treatment with relugolix in a clinical study; 
21. Patient is a study site employee or is a primary family member (spouse, parent, child, or sibling) of a 
site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance 
of relugolix, including inability to swallow whole tablets or conditions that may interfere with 
absorption at the level of the small intestine. Examples of such conditions include but are not limited 
to Crohn's disease, gastric bypass, active peptic ulcer disease, and gastrectomy.  The medical monitor 
should be contacted for any questions regarding this exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see Section 5.10.1) 
without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components thereof; 
or has a history of drug or other allergy that, in the opinion of the investigator or medical monitor, 
contraindicates study participation; 
25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse disorder 
according to Diagnostic and Statistical Manual of Mental Disorders V (all patients must be 
questioned about their drug and alcohol use and this should be documented in the electronic case 
report form [eCRF]); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would interfere 
with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
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Dose and Route of 
Administration 
Test Product 
Relugolix 120 mg tablet strength will be available as immediate-release film-
coated tablets, and 1 tablet (120 mg) will be administered once daily following an 
oral loading dose of 360 mg (three 120-mg tablets) on Day 1.  These tablets will be 
presented in 45-tablet bottles and dispensed to patients every 4 weeks at scheduled 
study visits. 
All protocol-specific inclusion criteria and none of the exclusion criteria must be 
met and documented prior to study drug administration.  Study drug will be 
dispensed only to eligible patients who are under the supervision of the investigator 
or identified subinvestigator(s). 
Reference Product 
Leuprolide acetate, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), 3-M depot 
will be administered per the approved dose and method of dosing in the region 
where the patient is enrolled.  Leuprolide acetate 3-M depot injection will be 
administered on Day 1 (with an antiandrogen of choice, if indicated according to 
the investigator, for the first 4 weeks or longer), then at 12-week intervals 
thereafter for 48 weeks.  Preparation of the depot injection and administration 
should follow the instructions provided by the manufacturer. 
Duration of 
Treatment 
The duration of treatment will be 48 weeks.  The last dose of leuprolide acetate 
3-M depot will be administered at the Week 37 visit. 
Criteria for 
Evaluation 
The following treatment arms will be evaluated after 48 weeks of study treatment: 
• 
Arm A:  Oral relugolix 120 mg once daily following a loading dose of 360 mg 
(three 120-mg tablets) on Day 1. 
• 
Arm B:  Leuprolide acetate 3-M depot injection, 22.5 mg (or 11.25 mg in 
Japan, Taiwan, and China). 
 
Primary Endpoint 
For the first 915 patients randomized: 
• 
Sustained castration rate defined as the cumulative probability of testosterone 
suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 
Day 1 (Study Day 29) through Week 49 Day 1 (Study Day 337). 
 
Secondary Endpoints 
For the first 915 patients randomized: 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative probability of testosterone 
suppression to ≤ 50 ng/dL (1.7 nmol/L) prior to dosing on Week 1 Day 4, 
prior to dosing on Week 3 Day 1; 
o Profound castration rate, defined as the cumulative probability of 
testosterone suppression to ≤ 20 ng/dL (0.7 nmol/L) while on study 
treatment from Week 25 Day 1 through Week 49 Day 1; 
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o Time to testosterone recovery in approximately 100 patients randomized to 
relugolix and approximately 50 patients randomized to leuprolide acetate 
who complete 48 weeks of treatment and who do not plan to start 
alternative androgen deprivation therapy within the following 12 weeks (or 
within 24 weeks following the last injection of leuprolide acetate 3-M 
depot); 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed PSA response by Prostate Cancer 
Clinical Trials Working Group 3 guidelines at the Week 3 and Week 5 
visits [Scher, 2016]; 
o Proportion of patients with PSA concentration < 0.2 ng/mL (0.2 µg/L) at 
the Week 3 and Week 5 visits; 
• 
Absolute values and changes from baseline in the scores of the 
EORTC-QLQ-C30 global health domain, and the EORTC-QLQ-PR25 sexual 
activity and hormonal-treatment-related symptom subdomains, at regular 
intervals during treatment, and as applicable during the Follow-up and/or at 
End of Treatment visits; 
• 
Absolute values and changes from baseline of the remaining domains in the 
EORTC QLQ-C30 and EORTC QLQ-PR25, as well as the EuroQol EQ-5D-5L 
questionnaire, at regular intervals during treatment, and as applicable during 
the Follow-up visits; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical laboratory data; 
• 
Endocrine marker effects of relugolix and leuprolide acetate as measured as 
absolute value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 25, and Week 49 visits; and 
o Sex hormone binding globulin at the Week 5, Week 25, and Week 49 
visits; 
• 
Predose relugolix plasma concentrations; 
• 
Single and repeat-dose plasma relugolix PK parameters such as maximum 
plasma concentration (Cmax), area under the concentration-time curve from 
time 0 to the end of the dosing interval (AUC0-τ), and time to maximum plasma 
concentration (tmax) in a subset of patients from China and Japan during the 
Day 1 visit; 
• Time to PSA progression. 
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For patients with metastatic advanced prostate cancer (approximately 
390 patients): 
• Time to castration-resistant (TCR) during the 48-week of treatment; 
For all enrolled patients (approximately 1100 patients): 
• 
TCR during the 48-week treatment 
 
Exploratory Endpoints 
• 
Overall survival defined as time from randomization to date of death prior to 
data cutoff date; and 
• 
The presence of polymorphisms in germline genes related to the hypothalamic-
pituitary-androgen pathway, prostate cancer risk, or to drug metabolizing 
enzymes and transporter proteins that might be implicated in the drug 
disposition, safety, or efficacy of relugolix.  These will be evaluated in a subset 
of patients. 
Statistical Methods 
A statistical analysis plan will describe the detailed statistical methods and analyses for this study.  The 
statistical analysis plan will be prepared and finalized before database lock for the primary analysis. 
There will be two analyses for the study, a primary analysis and a final analysis.  The primary analysis of 
efficacy and safety will occur after approximately the first 915 patients have been randomized to the 
study (ITT population) and have had the opportunity to be evaluated for 48 weeks and complete the 
30-day safety follow-up visit. 
The final analysis will occur after approximately 390 metastatic patients have been randomized to the 
study and have had the opportunity to be evaluated for 48 weeks of study treatment and complete the 30-
day safety follow-up visit or discontinued early. 
TCR in the subgroup of metastatic patients and the extended ITT population (approximately 
1100 patients) will be analyzed only at the time of the final analysis. 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) population defined as all 
randomized patients who have taken at least one dose of study treatment.  Randomization will be 
stratified by geographic region (North and South America versus Europe versus Asia and Rest of World), 
presence of metastatic disease (metastases in regional lymph node[s] are considered N1 and will, 
therefore, be stratified as non-metastatic) on baseline imaging (yes versus no), and age (≤ 75 years old 
versus > 75 years old).  The 2-sided type I error rate for this study is 0.05. 
After the initial 915 patients have been enrolled, only patients with metastatic advanced prostate cancer 
from other regions will continue to be enrolled (these patients will be stratified by geographic region and 
age only), except for China, where both metastatic and non-metastatic patients will continue to be 
enrolled (these patients will continue to be stratified using all of the stratification factors). 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the sustained castration rate defined as the cumulative probability of 
achieving testosterone suppression to castrate levels of ≤ 50 ng/dL (1.7 nmol/L) while on study treatment 
from Week 5 Day 1 (Study Day 29) through Week 49 Day 1 (Study Day 337).  This probability will be 
estimated for each treatment group using the Kaplan-Meier method with the confidence interval 
calculated using the exponential Greenwood formula via log-log transformation of the survival function.  
Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL (1.7 nmol/L) will be 
censored at the last testosterone assessment prior to discontinuation.  Detailed censoring rules will be 
prespecified in the statistical analysis plan. 
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There are 2 separate evaluation criteria for the primary efficacy endpoint to support different regulatory 
requirements for assessing benefit: 
• 
Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix is greater 
than or equal to 90%.  The lower bound of the 95% confidence interval for the cumulative 
probability of sustained testosterone suppression to castrate levels in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion. 
• 
Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to leuprolide 
acetate 3-M depot as assessed by the cumulative probability of sustained testosterone suppression 
to castrate levels.  The lower bound of the 95% confidence interval for the difference in the 
cumulative probability of sustained testosterone suppression to castrate levels between the 
2 treatment groups will be calculated and must be greater than or equal to the non-inferiority 
margin of -10% to meet this criterion. 
The 2-sided type I error rate will be 0.05 for each individual evaluation criterion. 
Secondary Efficacy Endpoints: 
1. Castration rate:  the cumulative probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) 
prior to dosing on Week 1 Day 4, and prior to dosing on Week 3 Day 1; 
2. Profound castration rate:  the cumulative probability of testosterone suppression to ≤ 20 ng/dL 
(0.7 nmol/L) from Week 25 through Week 49; 
3. PSA response rate:  proportion of patients with a ≥ 50% decrease in PSA from baseline at Week 3 
and confirmed at Week 5; 
4. Undetectable PSA rate:  proportion of patients with PSA concentration < 0.2 ng/mL (0.2 µg/L) at the 
Week 3 and Week 5 visits; 
5. Time to testosterone recovery in approximately 100 relugolix-treated and approximately 
50 leuprolide acetate-treated patients who complete 48 weeks of treatment and do not start alternative 
androgen deprivation therapy within 12 weeks after the last dose of relugolix or within 24 weeks 
following the last received injection of leuprolide acetate.  Kaplan-Meier methods will be used to 
describe survival distributions; 
6. Quality of Life:  absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 
global health domain, and the EORTC-QLQ-PR25 sexual activity and hormonal-treatment-related 
symptom subdomains, at regular intervals during treatment, and as applicable at the Follow-up and/or 
End-of-Study visits will be presented.  Additionally, absolute values and changes from baseline of the 
remaining domains in the EORTC QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L, at 
regular intervals during treatment, and as applicable during the Follow-up visits will be presented.  
Change from baseline will be analyzed using mixed-model repeated measures methodology; 
7. Time to PSA progression: defined per Prostate Cancer Clinical Trials Working Group 3 guidelines as 
the first increase in PSA of 25% or greater and 2 ng/mL or greater above the nadir with confirmation 
by a second PSA measurement at least 3 weeks later.  For patients without declining PSA from 
baseline, PSA increase of 25% or greater and 2 ng/mL from baseline beyond 12 weeks will be 
considered PSA progression. 
8. TCR in the subgroup of metastatic patients and the extended ITT population will only be evaluated at 
the time of final analysis, when approximately 1100 patients (reaching at least 390 metastatic 
patients) have been randomized to the study and have had the opportunity to be evaluated for 
48 weeks of study treatment and complete the 30-day safety follow-up or discontinued early.  TCR is 
defined as the time from the date of first dose to the date of PSA progression while castrated or death 
due to any reason, whichever occurs earlier.  TCR will be analyzed using the Kaplan-Meier method.  
Treatment comparison with hazard ratios will be performed using Cox proportional hazards model. 
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Exploratory Endpoints: 
1. Overall survival:  Overall survival defined as time from randomization to date of death prior to data 
cutoff date.  Kaplan-Meier methods will be used to describe survival distributions; 
2. The effect of polymorphisms in germline genes related to the hypothalamic-pituitary-androgen 
pathway, prostate cancer risk, or drug metabolizing enzymes and transporter proteins on the efficacy 
and safety of relugolix will be described in a separate statistical analysis plan. 
The methods and procedures needed to maintain a study-wide 2-sided type I error rate of 0.05 across 
primary and secondary endpoint testing will be described in the statistical analysis plan. 
Pharmacokinetics 
Relugolix plasma concentrations will be summarized and described using population PK methods.  
Plasma PK parameters in a subset of patients from China and Japan will be determined using 
noncompartmental methods. 
Safety 
Safety assessments, including adverse events, vital signs, clinical laboratory tests, and ECGs, will be 
summarized for the treatment-emergent period.  The treatment-emergent period is defined as the time 
from first dose of study drug through 30 days after the last dose of relugolix or 12 weeks plus 30 days 
after the last dose of leuprolide acetate.  Safety analyses will be based on all randomized patients who 
receive any amount of study drug (Safety population).  Drug exposure will be summarized by descriptive 
statistics.  Severity of all treatment-emergent adverse events will be evaluated by the investigator based 
on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and will 
be coded to preferred term, higher-level term, and system organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of patients with adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to study drug, and severity.  
Descriptive rather than inferential statistics will be used.  Laboratory values also will be classified by 
toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory shift tables of baseline 
versus post baseline results will be produced. 
An independent Data and Safety Monitoring Board will monitor all available safety data on a periodic 
basis.  The roles and responsibilities of the Data and Safety Monitoring Board will be described in detail 
in a separate charter. 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the following 
assumptions have been made: 
• 
True probabilities of sustained castration rates are 94% and 96% for relugolix and leuprolide 
acetate, respectively; 
• 
2:1 randomization ratio (relugolix:leuprolide acetate); 
• 
Dropout rate of 15%. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% power to 
rule out a fixed probability of sustained testosterone suppression of ≤ 90% at a 2-sided type I error rate of 
0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and a 2-sided type I error rate of 
0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) will yield at least 99% 
power in declaring the non-inferiority of relugolix compared to leuprolide acetate. 
The primary analysis will be performed separately for individual evaluation criterion using data collected 
through 48 weeks after enrollment of approximately 915 patients. 
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Approximately 915 patients will be randomized in order to fulfill the regulatory requirements of all 
participating countries included in the primary efficacy endpoint of this study.   
The study is also powered for the secondary endpoint of TCR in the high-risk subgroup of metastatic 
patients.  Approximately 107 confirmed castration-resistance events (PSA progressions while castrated or 
deaths due to any cause) will need to be observed (or approximately 390 metastatic patients will need to 
be enrolled) to detect a hazard ratio of 0.55 (relugolix versus leuprolide acetate) with 85% power with a 
two-sided type I error of 5%, assuming a castration-resistant event-free rate of 60% at 48 weeks for the 
control arm, 18-month enrollment period, 12 months of additional follow-up, and a 15% dropout rate. 
With a total of approximately 1100 patients (metastatic or non-metastatic) randomized into the study 
including approximately 138 Chinese patients, it is anticipated to observe approximately 149 confirmed 
castration-resistant events (PSA progression while castrated or deaths due to any cause).  Assuming an 
18-month enrollment period, 12 months of additional follow-up, and a 10% dropout rate, the study will 
provide approximately 85% power to detect a hazard ratio of 0.6 (relugolix versus leuprolide acetate) 
with a two-sided type I error of 5%. 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3201 
Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 17 
and 21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not 
applicable 
±2 days 
± 7 days 
 
± 7 days 
Informed Consentf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Dispensation: 
Relugolix 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xr 
 
 
 
Study Drug 
Administration: 
Relugolix Once 
Daily 
 
X 
X 
Patients will receive a single loading dose of oral relugolix 360 mg on Day 1 in the clinic; 
Starting on Day 2, patients will take oral relugolix 120 mg once daily 
Xr 
 
 
 
Study Drug 
Administration: 
Leuprolide Acetate 
3-M Depot 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Xr 
 
 
 
Phone call prior to 
visit and study drug 
accountabilityd 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(including detailed 
prostate cancer 
history) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Weight, BMI 
X 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
12-lead ECGg 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Xr 
X 
 
 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 17 
and 21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not 
applicable 
±2 days 
± 7 days 
 
± 7 days 
ECOG 
Performance 
Assessment 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
Complete Physical 
Exam and Visual 
Acuityh 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
 
 
 
Symptom Based 
Physical Exam 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xr 
X 
X 
X 
Abdominopelvic CT 
or MRI and Bone 
Scani 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
EuroQol EQ-5D-5L 
Health 
Questionnaire 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
EORTC-QLQ-
PR25 and EORTC-
QLQ-C30 Quality 
of Life 
Questionnaires 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
X 
X 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Hematology 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
Chemistry 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Xr 
X 
 
 
Lipid & HbA1ck 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Xr 
X 
 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
X 
X 
Serum Testosterone 
X 
X 
X 
X 
X 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl 
Xr 
X 
X 
X 
LH/FSH 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
X 
X 
SHBG/DHT 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
 
 
X 
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Period 
Screening 
Visit 
Treatment Period Visits 
Follow-upa,c 
Safetyb 
Testosterone 
Recovery 
Visit Name 
Screening Baseline 
Day 1 
Day 
4 
Wk 
2q 
Wk 
3 
Wk 
5 
Wk 
9 
Wk 
13 
Wk 17 
and 21 
Wk 
25 
Wk 29 
and 33 
Wk 
37 
Wk 41 
and 45 
Wk 
49e 
Un-
scheduled 
30-Day 
60-Day 
90-Day 
Study Day 
-28 to -1 
1 
4 
8 
15 
29 
57 
85 
113 
and 
141 
169 
197 and 
225 
253 
281 and 
309 
337 
 
EOT + 
30 days 
EOT + 
60 days 
EOT + 
90 days 
Visit Window 
Not 
applicable 
±2 days 
± 7 days 
 
± 7 days 
Blood Sample for 
Relugolix PKm,n 
 
Xm,n 
Xn 
Xn 
 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xr 
 
 
 
Blood Sample for 
DNAo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xr 
 
 
 
Health Status 
Surveyp 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xr 
 
 
 
Abbreviations:  3-M, 3-month; BMI, body mass index; CT, computed tomography; DHT, dihydrotestosterone; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of 
treatment; EuroQol EQ-5D-5L, European Quality of Life 5-Dimension 5-Level; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; LH, luteinizing 
hormone; MRI, magnetic resonance imaging; PK, pharmacokinetics; PSA, prostate-specific antigen; SHBG, sex hormone binding globulin 
a. 
The study day in which the Follow-up visit occurs is not specified in the table because these visits occur relative to when the patient takes his last dose of 
study drug.  The End of Treatment (EOT) is defined as the last dose of relugolix or 12 weeks after the last leuprolide acetate injection. 
b. May occur earlier for patients who are starting alternative androgen deprivation therapy, or do not complete 12 weeks of study treatment.  Adverse events, 
serious adverse events, and concomitant medications should continue to be collected and recorded through 30 days after the End of Treatment.  All other 
study procedures should be completed before the start of alternative androgen deprivation therapy. 
c. 
Patients who have started alternative androgen deprivation therapy will not participate in the 60- and 90-day Follow-up visits.  For approximately 
100 patients receiving relugolix and approximately 50 patients receiving leuprolide acetate who complete 48 weeks of study drug treatment and, in the 
opinion of the investigator, can remain off androgen deprivation therapy for 90 days will be included in the testosterone recovery 60- and 90-day Follow-up 
visits. 
d. For patients assigned to the relugolix treatment arm, the patient should be called 7 days before their next visit to check on compliance with their study 
medication.  Study drug accountability will be conducted at visits and results will be recorded as the primary source of study drug accountability. 
e. 
If patient terminates early from study treatment, the patient should be asked to come in as soon as possible and complete this visit. 
f. 
The informed consent form must be signed before any study-mandated procedures are performed. 
g. 12-lead ECGs should be read locally by a qualified physician. 
h. A complete physical examination should be performed.  Visual acuity will be evaluated by a standard visual eye chart.  The patient should wear any 
prescribed glasses or contacts during the visual acuity assessment.  Patients whose presenting visual acuity score is 90 or lower at the screening visit should 
be encouraged to obtain a diagnostic evaluation from an eye care provider (ie, an ophthalmologist or an optometrist).  Any findings (ie, diagnoses) from the 
eye examination should be recorded as medical history.  Patients whose presenting visual acuity score at Week 25, Week 49, or Early Termination has 
decreased by 10 or more points from the screening visit should be referred to an ophthalmologist for a diagnostic evaluation.  A copy of the ophthalmology 
consultation must be submitted to the sponsor. 
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i. 
An abdominopelvic CT or MRI and a bone scan should be performed and read locally to determine the presence of metastatic disease within 60 days prior to 
randomization.  However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not required.  If metastatic disease is not present on CT 
or MRI, then a bone scan is also required.  With the exception of China, which will enroll patients with metastatic and non-metastatic advanced prostate 
cancer, once 915 patients are enrolled, only patients with metastatic advanced prostate cancer will be eligible for the study, and metastatic disease must be 
confirmed on either abdominopelvic CT/MRI or bone scan. 
j. 
Collect serious adverse event information from the time of signed informed consent through the Safety Follow-up Visit, which is through 30 days after the 
last dose of relugolix or 12 weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or 
hormonal therapy or surgical intervention, whichever occurs first.  Collect nonserious adverse event information from the Baseline Day 1 visit (or from the 
time of signed informed consent if event was related to a screening study procedure through approximately 30 days after the last dose of relugolix or 
12 weeks and 30 days after the last injection of leuprolide acetate, or the date of initiation of another investigational agent or hormonal therapy or surgical 
intervention, whichever occurs first. 
k. Blood samples must be obtained fasting; nothing to eat or drink (other than water) for at least 9 hours prior to obtaining the sample. 
l. 
All testosterone samples obtained from Week 5 and beyond are to be collected during a ± 7-day window. 
m. Blood samples for PK analysis will be collected for all patients assigned to the relugolix treatment arm.  Samples will be collected predose, approximately 
24 hours after the previous dose.  Patients may be dosed in the clinic at these visits, provided the dose can be administered at least 2 hours after food; food 
should be withheld for 1 hour after dosing. 
n. A subset of patients from China and Japan will have additional samples collected predose, and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose on Day 1 and 
Week 2 visits. Patients will be dosed in the clinic at these visits.  The dose will be administered at least 2 hours after food; food should be withheld for 
1 hour after dosing.  A predose sample (approximately 24 hours after the previous dose) also will be collected at the Day 4 visit.  Patients may be dosed in 
the clinic at the Day 4 visit, provided the dose can be administered at least 2 hours after food; food should be withheld for 1 hour after dosing. 
o. The blood sample for DNA should be collected at the Baseline Day 1 visit but may be collected at any visit if it is missed at that visit. 
p. During the final weeks prior to database lock, sites will be asked to contact all study participants or their immediate family regarding the current health status 
of previously enrolled/completed study patients. 
q. Week 2 visit will only occur for patients who are part of the Japan or China subset for PK analysis. 
r. 
For an Unscheduled visit, these procedures will be performed as needed, based on the reason(s) for the Unscheduled visit. 
 
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2. 
INTRODUCTION 
2.1. 
Prostate Cancer 
Prostate cancer is the most prevalent form of cancer in men and the second leading cause of 
death due to cancer in men in the US [Greenlee, 2001] and Europe [Ferlay, 2012].  The median 
age of diagnosis is 70 years, and diagnosis before the age of 40 years is rare [Cersosimo, 1996].  
In Japanese men, prostate cancer was the fourth leading cancer diagnosis in 2007 [Foundation 
for Promotion of Cancer Research, 2012].  The incidence of invasive prostate cancer increases 
with age; a clear increase is seen among men aged 60 years or older [Siegel, 2014]. 
If prostate cancer is diagnosed at a stage where it is confined to the prostate gland and immediate 
surroundings, it is generally treated by surgical removal of the prostate gland, or prostatectomy, 
or with radiation.  Often, these procedures are successful in curing men of their disease.  Men 
whose disease progresses after prostatectomy or radiation are said to have advanced prostate 
cancer.  Advanced prostate cancer is defined as either:  PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; newly diagnosed metastatic prostate 
cancer; or advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  The cure rate following surgery, depending on the stage of the cancer, is about 70% 
overall and, following radiation, about 50% to 60%. 
Approximately 25% to 30% of men will, therefore, progress to advanced disease, excluding 
those with metastatic disease at the time of diagnosis.  Androgens, such as testosterone and its 
more potent metabolite dihydrotestosterone, are strong tumor promoters for prostate cancer 
[Bosland, 2014].  Through the androgen receptor, they synergistically augment the effect of other 
tumor promoters or carcinogens.  Although prostate cancer is driven by presumed mutations in 
other tumor promoting pathways and/or by translocations leading to aberrant activation of the 
androgen receptor pathway, most early-stage prostate cancer cells remain either sensitive to or 
dependent upon circulating androgens.  Thus, for more than 60 years, androgen deprivation 
therapy with surgical or medical castration has been the foundational therapy for either advanced 
inoperable or metastatic cancer.  Increasingly, androgen deprivation therapy is used earlier as a 
neoadjuvant/adjuvant treatment to radiation therapy or for biochemical or clinical relapse after 
local therapies of curative or palliative intent.  More than 80% of men with progressive or 
advanced disease initially respond to androgen deprivation therapy with varying degrees of 
tumor regression or stabilization [Kreis, 1995].  The duration and depth of response to androgen 
deprivation therapy is presumably dependent on the underlying tumor biology and burden.  Thus, 
patients with metastases respond for an average of 2 years before any biochemical evidence of 
castration-resistance occurs.  By contrast, patients with biochemical-only evidence of progressive 
disease may respond to androgen deprivation therapy for 5 years or more [Klotz, 2015]. 
Currently, most patients in developed countries receive medical rather than surgical castration.  
GnRH (or LH-releasing hormone) agonists (ie, long-acting leuprolide acetate depot injections) 
are the current mainstay of medical castration, causing long-term desensitization and down 
regulation of the hypothalamic-pituitary gonadal axis.  One disadvantage of the agonist form of 
GnRH is the initial stimulation of the axis lasting 1 to 3 weeks that occurs prior to 
desensitization.  This results in a rise in LH and testosterone levels and an increase in clinical 
symptoms.  In addition, at the time of repeat injection of GnRH agonist depot, microsurges of 
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LH and testosterone may occur, although the apparent incidence is low [Klotz, 2008].  The initial 
flare response may be managed with simultaneous antiandrogen administration, such as with 
bicalutamide. 
Recently, GnRH antagonists, in particular degarelix, [Firmagon, 2016], have become available as 
an alternative form of medical castration.  Degarelix, an injectable peptide, has been approved in 
some countries for the treatment of patients with advanced prostate cancer.  As a GnRH 
antagonist, degarelix achieves medical castration and PSA response with no initial agonist 
activity within the first 1 to 2 weeks of administration, and effectively can obviate the need for 
concomitant antiandrogen treatment.  Post-hoc analyses of degarelix trials [Tombal, 2010] 
suggest that it may have additional advantages regarding disease response or secondary relapse; 
however, such differences require confirmation in prospective studies.  Because of the need for 
monthly depot injections, with large volumes and accompanying local reactions, the use of 
degarelix in clinical practice has remained low. 
Relugolix, previously known as TAK-385, is a potent and highly selective oral small molecule 
antagonist for the human GnRH receptor.  For patients, relugolix may offer the advantages 
conferred by a direct receptor antagonist, including a more rapid onset of action and the absence 
of clinical flare or worsening of symptoms from the initial rise in androgens caused by GnRH 
agonists, as well as having the added convenience and relative comfort of oral dosing. 
2.2. 
Relugolix 
2.2.1. 
Indication 
Relugolix is being developed as a once daily oral medication for the treatment of advanced 
prostate cancer.  The proposed dose of relugolix is 120 mg administered orally once daily 
following a loading dose of 360 mg (three 120-mg tablets) on Day 1. 
2.2.2. 
Pharmacology 
Relugolix is an orally-active, potent, highly-selective, high-affinity small molecule GnRH 
receptor antagonist with a novel structure.  Relugolix was discovered and initially studied by 
Takeda Pharmaceutical Company, Limited, before development rights outside of Japan and 
certain East Asian countries were licensed to Myovant Sciences GmbH. 
Relugolix antagonizes the human GnRH receptors present on the gonadotrophin-secreting cells 
of the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
LH and FSH fall rapidly, followed by a decline over a few days in testosterone in men and 
estradiol and progesterone levels in women.  Relugolix acts as a potent and highly selective 
antagonist for the human GnRH receptor.  The affinity of relugolix for the human GnRH 
receptor in vitro was approximately 50-fold higher than that of GnRH in the presence of protein 
(40% fetal bovine serum).  Transgenic knock-in mice expressing the human GnRH receptor 
treated with relugolix had substantial reductions in reproductive organ weights of both female 
and male mice, suggesting that relugolix may suppress blood estrogen and testosterone levels, 
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respectively.  Orally administered relugolix suppressed the hypothalamic-pituitary axis in 
castrated cynomolgus monkeys at doses of 1 mg/kg and higher. 
2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level for liver findings in the 39-week monkey 
toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (area under the 
concentration-time curve [AUC]) in men receiving 120 mg once daily (0.469 μg⋅hr/mL), the 
dose of relugolix to be administered in this study.  Both the liver and PLD findings demonstrated 
evidence of reversibility following a 13-week recovery period in monkeys.  No evidence of PLD 
has been observed in clinical studies.  The relugolix toxicology program supports the conduct of 
clinical studies up to the NOAEL (15 mg/kg/day) exposure (5.2 μg·hr/mL) for liver toxicity in 
monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human Thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies have been completed.  In 
addition, 6 clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 
2 studies in men with prostate cancer (US and Europe), and 2 phase 3 studies in women with 
uterine fibroids in Japan.  More than 1380 patients and healthy volunteers have received at least 
one dose of relugolix, including 158 women receiving relugolix 40 mg once daily for at least 
28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg once daily for at 
least 24 weeks and for as long as 48 weeks. 
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2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of testosterone in male subjects and estradiol in female subjects.  After oral 
administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The PK and pharmacodynamics of relugolix have been evaluated and 
appear to be similar in Western and Asian volunteers, despite the lower mean body mass index 
observed in Asian volunteers. 
A relative bioavailability and food effect study was conducted using the global phase 3 prostate 
cancer formulation of 120 mg relugolix.  After administration with a high-fat, high-calorie 
breakfast, the Cmax and AUC of relugolix were reduced, on average, by 21.4% and 18.8%, 
respectively. 
In the phase 1 study C27001, serum LH, FSH, dihydrotestosterone, and testosterone 
concentrations were determined in healthy men following single and multiple oral doses of 
relugolix or placebo for up to 28 days.  Loading doses of ≥ 160 mg on Day 1 were used to 
shorten the time to testosterone suppression.  Relugolix caused an immediate and effective 
suppression of LH, FSH, and testosterone.  After 14 days of once daily dosing, mean LH and 
serum testosterone concentration profiles were similar for the 40, 80, and 180 mg relugolix dose 
cohorts.  LH, FSH, and testosterone concentrations began decreasing 2 to 6 hours postdose on 
Day 1 and remained suppressed through Day 14.  However, the relugolix once daily maintenance 
dose was a major determinant of sustained testosterone suppression.  Profound castration 
(defined as average testosterone levels < 20 ng/dL or 0.7 nmol/L) was achieved with 40, 80, or 
180 mg once daily for 14 days; however, 20 mg once daily was insufficient in maintaining 
adequate suppression of serum LH and testosterone concentration levels during the second week. 
In healthy, older men receiving 14 or 28 days of dosing, effective castration was consistently 
achieved over 14 and 28 days dosing at daily doses of 40 to 180 mg (14 days) and 80 to 160 mg 
(28 days).  Use of a loading dose for up to 3 days (or once daily doses of ≥ 160 mg) resulted in 
castration levels of testosterone (< 50 ng/dL or 1.7 nmol/L) within 24 to 48 hours.  Results 
obtained after 28 days of dosing suggested that the likely minimal, fully effective maintenance 
dose for sustained castration would be relugolix ≥ 80 mg once daily.  Doses of 80 mg and 
120 mg were moved forward into phase 2 development. 
Relugolix is to be administered in the fasted state (at least 1 hour before or 2 hours after a meal), 
as food decreases the extent of relugolix absorption by approximately 20%.  The exposure of 
relugolix is increased by inhibitors of P-glycoprotein up to 6-fold, but relugolix does not 
significantly impact the exposure of cytochrome P450 (CYP) 1A2, 2C9, 2D6, or 3A4 substrates.  
In a dedicated study, relugolix did not prolong QTc at single doses of 60 or 360 mg. 
2.2.4.2. 
Clinical Studies in Men with Prostate Cancer 
One phase 1 study and 2 phase 2 studies have been conducted evaluating relugolix in men with 
prostate cancer. 
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Study TB-AK160108 is an ongoing multicenter phase 1, open-label, dose range-finding study 
conducted in hormone treatment-naïve Asian patients with non-metastatic prostate cancer.  The 
study consists of a dose-rising phase (Part A) and an expansion phase (Part B).  In Part A, a 
loading dose of relugolix (320 or 360 mg) was administered on Day 1 followed by once daily 
dosing on Days 2 through 28, with the dosage dependent on the individual cohort of 3 to 
4 patients each.  In Part B, 30 patients receive a maximum of 96 weeks treatment at doses of 
80 and 120 mg once daily (N = 15 each arm, loading dose of 320 mg on Day 1).  Testosterone 
reduction by both doses of relugolix was rapid and sustained through 48 weeks.  Both the 
80- and 120-mg once daily doses were evaluated in phase 2 clinical studies. 
Study C27003 is a phase 2 study that enrolled men in North America or the United Kingdom 
requiring 6 months of androgen deprivation therapy as neoadjuvant and adjuvant therapy to 
external beam radiation therapy.  Patients were randomized to relugolix 120 mg once daily 
following a single oral loading dose of 320 mg (N = 65) or to degarelix 80 mg subcutaneously 
every 4 weeks following a single loading dose of 240 mg (N = 38) for 24 weeks.  External beam 
radiation therapy was initiated for most patients between Week 13 and Week 15. 
Relugolix 120 mg administered orally once daily rapidly suppressed testosterone levels below 
the castration threshold (50 ng/dL [1.7 nmol/L]) within the first week of therapy and maintained 
those levels from the end of Week 4 through at least 24 weeks.  The levels of testosterone 
suppression achieved by relugolix were similar to those achieved by monthly injections of 
degarelix.  Profound castration rates below the lower testosterone threshold of < 20 ng/dL 
(0.7 nmol/L) were also similar in the relugolix and degarelix groups (Table 2-1). 
Table 2-1 
Study C27003:  Sustained Castration Rates (Percentage of Men Achieving 
Testosterone Suppression to < 50 ng/dL [1.7 nmol/L]) through 24 Weeks 
 
Relugolix 
120 mg QDa 
N = 65 
Degarelix 
80 mg Q4Wb 
N = 38 
Castration rate over 24 weeks, % 
(95% CI) 
95% 
(87.1, 99.0) 
89% 
(75.2, 97.1) 
Note:  Castration rate is defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5, Day 1 to specific time point (Week 25, Day 1). 
Abbreviations:  CI, confidence interval; Q4W, once every 4 weeks; QD, once daily 
a. 
Loading dose of 320 mg on Day 1 
b. Loading dose of 240 mg on Day 1, then dosed every month 
 
The percentage PSA reductions and absolute PSA values over time were consistent with the 
rapid testosterone reductions observed with both therapies and were similar between the 
relugolix and degarelix treatment arms.  Prostate gland size was measured during screening and 
following 8 to12 weeks of study drug treatment.  In both treatment groups, the average reduction 
in estimated prostate volumes was similar, approximately 30%.  Following discontinuation of 
therapy at the end of 24 weeks, patients were followed for an additional 12 weeks to evaluate 
testosterone recovery and associated changes in PSA and quality of life.  At the end of the 
follow-up period, approximately half of the patients receiving relugolix had recovered either to 
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the baseline testosterone value or to > 280 ng/dL, whichever was less, compared to only 6% of 
patients receiving degarelix (Figure 2-1). 
Figure 2-1 
Study C27003:  Testosterone Recovery Following Discontinuation of 
Relugolix and Degarelix at Week 25 
 
Note:  Y-axis shows testosterone value (ng/dL); x-axis shows study week. 
 
Study C27002 is a phase 2 study of relugolix and leuprolide acetate in patients with prostate 
cancer who require first-line androgen deprivation therapy, which is ongoing in North America.  
This study was designed to help plan the population, dosing, and assessment schedules for 
phase 3 studies in patients with advanced prostate cancer.  Eligible patients in C27002 have 
evidence of advanced prostate cancer including either:  1) PSA biochemical relapse following 
primary surgical or radiation therapy of curative intent; 2) newly diagnosed metastatic prostate 
cancer; or 3) advanced localized disease for which immediate radiation or surgical therapy is not 
indicated.  In this open-label, parallel group study, patients were randomized to receive 1 of 
2 dose levels of oral relugolix (80 or 120 mg [patients randomized to relugolix received a loading 
dose of 320 mg on Day 1], N = 50 per group) or to an observation cohort to receive standard 
GnRH therapy with leuprolide acetate 22.5 mg administered by intramuscular injection every 
12 weeks (N = 25).  Relugolix or leuprolide acetate was administered for up to 48 weeks with 
patients randomized to leuprolide acetate receiving their last on-study 12-week depot injection at 
Week 37. 
The primary objective of this phase 2 study was to evaluate the ability of relugolix to achieve 
and maintain testosterone suppression (< 50 ng/dL [1.7 nmol/L]) through Week 25.  Results 
from the completed study C27002 demonstrate that both doses of relugolix, 80 mg and 120 mg 
once daily, rapidly reduced testosterone levels below the castration threshold within the first 
week of therapy and maintained those levels in 91% of patients through 24 weeks of treatment 
(Table 2-2). 
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Table 2-2 
Study C27002:  Castration Rates (Percentage of Men Achieving Testosterone 
Suppression to < 50 ng/dL [1.7 nmol/L] through 24 Weeks) 
 
Relugolix 
Leuprolide 
Acetate 
22.5 mg Q12W 
N = 24 
 
80 mg QD 
N = 56 
120 mg QD 
N = 54 
Total 
N = 110 
Patients with at least 1 dose of 
treatment, n 
56 
54 
110 
24 
Castration ratea over 24 weeks 
 
 
 
 
n (%) 
51 (91) 
49 (91) 
100 (91) 
23 (96) 
95% CIb 
80.4-97.0 
79.7-96.9 
83.9-95.6 
78.9-99.9 
Profound castration ratec over 24 weeks 
 
 
 
 
n (%) 
39 (70) 
41 (76) 
80 (73) 
18 (75) 
95% CIb 
55.9-81.2 
62.4-86.5 
63.4-80.8 
53.3-90.2 
Abbreviations:  CI, confidence interval; Q12W, once every 12 weeks; QD, daily 
a. 
Castration rate was defined as the estimated proportion of patients who have testosterone concentrations 
< 50 ng/dL at all scheduled visits Week 5 Day 1 to specific time point. 
b. The 2-sided 95% CI was calculated using the normal approximation method, if the number of non-castration 
patients was = 5 in any treatment arm, the exact CI was presented. 
c. 
Profound castration rate was defined as the estimated proportion of patients who had testosterone concentrations 
< 20 ng/dL at all scheduled visits Week 13 Day 1 through specific time point. 
 
Castration to below the lower testosterone threshold of < 20 ng/dL was also similar in the 
2 relugolix arms and to that observed in the leuprolide acetate arm.  On average, in patients 
receiving relugolix, testosterone decreased to below the castration threshold of 50 ng/dL 
(1.7 nmol/L) by the Day 4 visit, and to below the profound castration threshold of 20 ng/dL 
(0.7 nmol/L) by the Week 5 visit.  In contrast, in patients receiving leuprolide acetate, 
testosterone levels rose during the first 1 to 2 weeks of therapy and then declined to castrate 
levels by Week 5.  PSA responses between the 2 relugolix arms and leuprolide acetate were 
similar as demonstrated by PSA waterfall plots showing the reduction in PSA from baseline for 
individual patients (Figure 2-2 [relugolix] and Figure 2-3 [leuprolide acetate]). 
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Figure 2-2 
Study C27002:  Waterfall Plots of Prostate-Specific Antigen Percent 
Reduction by Dose of Relugolix at Week 25 Day 1 
 
 
Note:  Last observation carried forward method was used to impute percent prostate-specific antigen reductions for 
patients without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen; QD, once 
daily; TAK-385, relugolix 
 
Figure 2-3 
Study C27002:  Waterfall Plot of Prostate-Specific Antigen Percent 
Reduction by Leuprolide Acetate at Week 25 Day 1 
 
Notes: 
The leuprolide acetate dose was 22.5 mg every 12 weeks. 
Last observation carried forward method was used to impute percent prostate-specific antigen reductions for patients 
without an observation at Week 25 Day 1. 
Abbreviations:  LOCF, last observation carried forward; Obs, observed; PSA, prostate-specific antigen 
 
A more detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Visit
Obs on Week 25 Day 1
LOCF by Week 25 Day 1
PSA Percent Reduction
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-20
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Investigator Brochure, Version 9.0, dated 09 November 2016, along with a full discussion of the 
safety profile of relugolix. 
2.2.4.3. 
Clinical Safety of Relugolix in Men with Prostate Cancer 
A full description of the safety data for relugolix from clinical trials is available in the 
Investigator Brochure.  Overall, approximately 632 healthy volunteers (330 women, 302 men), 
535 female patients with uterine fibroids (N = 229) or endometriosis (N = 306), and 218 male 
patients with prostate cancer received at least 1 dose of relugolix.  Data from the 175 patients 
with prostate cancer who received relugolix in randomized, open-label, parallel-group phase 2 
studies, C27002 and C27003, provide the basis for the frequency of expected adverse events 
associated with relugolix in the prostate cancer indication.  The adverse drug reactions in the 
prostate cancer indication observed in the phase 2 studies include hot flush (59%), fatigue (26%), 
arthralgia (10%), nausea (5%), and gynecomastia (3%).  No clinical evidence of PLD has 
observed in any relugolix clinical study. 
Leuprolide Acetate 3-Month Depot 
Leuprolide acetate depot is indicated for the palliative treatment of advanced prostatic cancer. 
Leuprolide acetate acts as an agonist at pituitary GnRH (gonadotropin-releasing hormone) 
receptors.  Leuprolide acetate has greater receptor affinity, reduced susceptibility to enzymatic 
degradation, and is approximately 100-fold more potent than the natural GnRH molecule.  GnRH 
agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial 
release of both LH and FSH, which causes a subsequent increase in testosterone production from 
testicular Leydig cells.  Initially, leuprolide acetate stimulates LH production, which in turn 
causes a surge of testosterone and dihydrotestosterone for 5 to 12 days before the ultimate 
inhibition of LH.  This androgen surge of male hormones can cause a flare reaction (“clinical 
flare”), which may lead to an increase in bone pain, bladder obstruction, or other symptoms due 
to prostate cancer [Tolis, 1982; Schally, 1980; Waxman, 1985; Conn, 1991; Limonata, 2001]. 
Chronic stimulation by the GnRH agonist ultimately desensitizes the GnRH receptors, 
downregulating the secretion of gonadotropins, LH, and FSH, leading to hypogonadism and thus 
a dramatic reduction in testosterone and dihydrotestosterone, on which continued growth of 
prostate cancer cells depends.  The fall in serum LH leads to a decrease in serum testosterone to 
castrate levels within 3 to 4 weeks after the start of treatment.  Continued treatment maintains 
serum testosterone at castrate levels. 
The decrease in testosterone production is generally reversible over time upon cessation of 
GnRH agonist therapy.  However, testosterone production does not always return to baseline 
levels and may be related to the duration of GnRH agonist therapy, patient age, and other factors. 
The flare phenomenon can be effectively prevented with antiandrogen therapy, which blocks the 
effect of the increased serum testosterone [Loblaw, 2004].  First generation antiandrogens such 
as flutamide, bicalutamide, and nilutamide bind to androgen receptors and competitively inhibit 
their interaction with testosterone and dihydrotestosterone.  They are often used in an attempt to 
limit the clinical sequelae produced by the hormonal surge resulting from GnRH agonist 
treatment. 
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The most common adverse reactions (> 10%) reported for marketed formulations of leuprolide 
acetate depot in common use include the following examples: 
• Leuprolide (leuprorelin) acetate 11.25 mg:  weight fluctuation, hot flash, hyperhidrosis, 
muscle weakness, bone pain, decreased libido, erectile dysfunction, testicular atrophy, 
fatigue, injection site reaction [Prostap 3 DCS, 2016] 
• Leuprolide acetate 22.5 mg:  hot flashes, ecchymoses, erythema, fatigue, injection site 
burning, injection site paraesthesia [Eligard, 2016] 
In post marketing experience, mood swings, depression, rare reports of suicidal ideation and 
attempt, rare reports of pituitary apoplexy have been reported.  Leuprolide has been associated 
with mild liver enzyme elevations (generally transient and asymptomatic) during therapy in 3-
5% of patients; values above 3 times the upper limit of normal are rare, being reported in less 
than 1% of recipients.  A risk of developing or worsening diabetes has been reported in men 
receiving this class of drug. 
The package insert (approved labeling) for the leuprolide acetate study drug provided for this 
study should be referenced for warnings, precautions, and safety information. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
This phase 3 trial has 2 separate evaluation criteria for the primary efficacy endpoint to support 
different regulatory requirements for assessing benefit as listed briefly below and described in 
detail in the statistical analysis plan.  Patients enrolled into this phase 3 trial will be randomized 
2:1 to either relugolix 120 mg once daily following an oral loading dose of 360 mg on Day 1, or 
to leuprolide acetate 22.5 mg (or 11.25 mg Japan, Taiwan, and China) 3-M depot injection.  
Patients randomized to leuprolide acetate will also receive an antiandrogen if indicated at the 
discretion of the investigator. 
The first criterion for the primary efficacy endpoint will evaluate only patients randomized to 
relugolix.  The second criterion for the primary efficacy endpoint will evaluate the 
non-inferiority of patients randomized to relugolix to those randomized to leuprolide acetate as 
described below. 
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Objectives 
Endpoints 
Primary 
• 
To evaluate the ability of relugolix to achieve 
and maintain serum testosterone suppressed to 
castrate levels of ≤ 50 ng/dL (1.7 nmol/L) in 
patients with androgen-sensitive advanced 
prostate cancer. 
The primary endpoint is the sustained castration 
rate defined as the cumulative probability of 
testosterone suppression to ≤ 50 ng/dL 
(1.7 nmol/L) while on study treatment from 
Week 5 Day 1 (Study Day 29) through Week 49 
Day 1 (Study Day 337). 
• 
Evaluation Criterion 1:  to determine whether 
the sustained castration rate (defined as the 
cumulative probability of testosterone 
suppression to ≤ 50 ng/dL [1.7 nmol/L] while 
on study treatment from Week 5 Day 1 
through Week 49 Day 7) for relugolix is 
greater than or equal to 90%.  The lower 
bound of the 95% confidence interval for the 
cumulative probability of sustained 
testosterone suppression in the relugolix 
treatment group will be calculated and must be 
at least 90% to meet this criterion. 
• 
Evaluation Criterion 2:  to establish the 
non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot injection as 
assessed by the cumulative probability of 
sustained testosterone suppression.  The lower 
bound of the 95% confidence interval for the 
difference in the cumulative probability of 
sustained testosterone suppression between 
the 2 treatment groups will be calculated and 
must be greater than or equal to the 
non-inferiority margin of -10% to meet this 
criterion. 
Secondary 
• 
To evaluate the time course and change in 
serum testosterone during treatment with 
relugolix; 
• 
Describe effects on serum testosterone: 
o Castration rate defined as the cumulative 
probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing 
on Week 1 Day 4 and prior to dosing on 
Week 3 Day 1; 
o Profound castration rate defined as the 
cumulative probability of testosterone 
suppression to ≤ 20 ng/dL (0.7 nmol/L) 
while on treatment from Week 25 Day 1 
through Week 49 Day 1); 
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Objectives 
Endpoints 
• 
To evaluate the time course and magnitude of 
PSA reduction during treatment with 
relugolix; 
• 
Describe effects on PSA: 
o Proportion of patients with confirmed 
PSA response (by Prostate Cancer 
Clinical Trials Working Group 3 
[Scher, 2016]) at the Week 3 and Week 5 
visits; 
o Proportion of patients with PSA 
concentration < 0.2 ng/mL [0.2 µg/L] at 
the Week 25 visit; 
• 
To evaluate testosterone recovery following 
discontinuation of relugolix; 
• 
Time to testosterone recovery in 
approximately 100 patients randomized to 
relugolix and approximately 50 patients 
randomized to leuprolide acetate who 
complete 48 weeks of treatment and who do 
not plan to start alternative androgen 
deprivation therapy within the following 
12 weeks (or within 24 weeks following the 
last injection of leuprolide acetate 3-M depot); 
• 
To evaluate quality of life using validated 
patient-reported outcome instruments; 
• 
Absolute values and changes from baseline in 
the scores of the EORTC-QLQ-C30 global 
health domain, and the EORTC-QLQ-PR25 
sexual activity and hormonal-treatment-related 
symptom subdomains, at regular intervals 
during treatment, and as applicable during the 
Follow-up and/or End of Treatment visits; 
• 
Absolute values and changes from baseline of 
the remaining domains in the 
EORTC QLQ-C30 and EORTC QLQ-PR25, 
as well as the EuroQol EQ-5D-5L 
questionnaire, at regular intervals during 
treatment, and as applicable during the 
Follow-up visits; 
• 
To evaluate the safety of relugolix 120 mg 
once daily in men with androgen-sensitive 
advanced prostate cancer; 
• 
Incidence of adverse events; 
• 
Incidence of abnormalities in clinical 
laboratory data; 
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Objectives 
Endpoints 
• 
To evaluate the effect of relugolix and 
leuprolide acetate on endocrine 
pharmacodynamic parameters; 
• 
Endocrine marker effects of relugolix and 
leuprolide acetate as measured as absolute 
value and change from baseline for: 
o LH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o FSH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
o Dihydrotestosterone at the Week 5, Week 
25, and Week 49 visits; 
o Sex hormone binding globulin at the 
Week 5, Week 25, and Week 49 visits; 
• 
To collect relugolix plasma concentration data 
to further evaluate relugolix population PK 
and the relationship between relugolix 
exposure and serum testosterone; and 
• 
Predose relugolix plasma concentrations; 
• 
To characterize the relugolix plasma PK 
parameters in a subset of patients from China 
and Japan; 
• 
Single and repeat-dose plasma relugolix PK 
parameters such as Cmax, AUC0-τ, and tmax. 
• 
To describe the time course and magnitude of 
PSA progression and development of 
castration-resistant prostate cancer during 
treatment with relugolix; 
• 
Time to castration-resistance during the 48-
week treatment 
• 
Time to PSA progression 
Exploratory 
• 
To explore the overall survival of patients 
treated with relugolix; and 
• 
Overall survival defined as time from 
randomization to date of death prior to data 
cutoff date; 
• 
To explore the contribution of genetic 
variance on drug response. 
• 
The presence of polymorphisms in germline 
genes related to the hypothalamic-pituitary-
androgen pathway, prostate cancer risk, or to 
drug metabolizing enzymes and transporter 
proteins that might be implicated in the drug 
disposition, safety, or efficacy of relugolix. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The HERO study is a phase 3 multinational randomized, open-label, parallel-group study to 
evaluate the safety and efficacy of relugolix in patients with androgen-sensitive advanced 
prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist that lowers 
testosterone by inhibiting pituitary release of follicle-stimulating hormone (FSH) and luteinizing 
hormone (LH).  Relugolix 120 mg orally once daily or leuprolide acetate depot suspension 
22.5 mg (or 11.25 mg in Japan, Taiwan, and China) every 3-months (3-M) will be administered 
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to patients with prostate cancer who require androgen deprivation therapy.  This study will 
evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to 
castrate levels (≤ 50 ng/dL [1.7 nmol/L]) for 48 weeks in patients with androgen-sensitive 
advanced prostate cancer. 
To be eligible for the study, a patient must be, in the opinion of the investigator, a candidate for 
at least 1 year of continuous androgen deprivation therapy for the management of androgen-
sensitive advanced prostate cancer and must not be a candidate for surgical therapy.  Eligible 
patients include those with evidence of biochemical relapse (rising PSA) following local primary 
intervention with curative intent, newly diagnosed metastatic disease (excluding metastases to 
the brain), and/or advanced localized disease.  Patients may receive radiotherapy, cryotherapy or 
high frequency ultrasound no sooner than 2 months after initiation of androgen deprivation 
therapy.  Patients may be included if they have not previously received androgen deprivation 
therapy for more than 18 months, and if the androgen deprivation therapy was completed at least 
3 months prior to baseline.  If the dosing interval of the depot is longer than 3 months, then the 
prior androgen deprivation therapy must have been completed at least as long as the dosing 
interval of the depot.  Patients previously treated with taxanes or expected to receive taxanes 
after initiation of androgen deprivation therapy are excluded, as are patients receiving androgen 
deprivation therapy adjuvant or neoadjuvant to radiotherapy as primary definitive therapy.  
Baseline serum testosterone must be ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L) to be enrolled. 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg once daily 
following a loading dose of 360 mg on Day 1 or 3-M depot of leuprolide acetate 22.5 mg (or 
11.25 mg in Japan, Taiwan, and China).  After randomization, patients in the leuprolide acetate 
arm may receive an antiandrogen for the first 4 weeks or longer if indicated in the opinion of the 
investigator.  Randomization will be stratified by geographic region, presence of metastatic 
disease (metastases in regional lymph node[s] are considered N1 and will, therefore, be stratified 
as non-metastatic), and age. 
A total of approximately 1100 patients from approximately 200 study centers in North and South 
America, Europe, and the Asia-Pacific region are planned to be enrolled in this study, including 
approximately 390 patients with metastatic advanced prostate cancer and approximately 
138 Chinese patients (enrolled in China and Taiwan). 
The study includes a Screening Period of up to 28 days, a Treatment Period of 48 weeks, and a 
Follow-up Period of up to 90 days.  Additionally, unscheduled follow-up visit(s) may be 
arranged for patients with study-related safety concerns as needed.  Eligible patients will receive 
study treatment for 48 weeks.  During that time, testosterone and PSA will be assessed monthly 
and patient-reported outcomes (EORTC-QLQ-C30, EORTC-QLQ-PR25, EuroQol EQ-5D-5L) 
will be assessed approximately every 3 months during the Treatment Period and more frequently 
during the Follow-up Period.  Additional serum endocrine evaluations will include:  LH, FSH, 
dihydrotestosterone, and sex hormone binding globulin.  Relugolix PK samples will be collected 
throughout the study.  Full PK profiles will be determined in a subset of patients in China and 
Japan.  Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, 12-lead ECG, and visual acuity tests. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive radiotherapy as prescribed by the investigator.  In the setting 
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of rising PSA patients may also receive enzalutamide after the confirmation of PSA progression.  
For patients requiring other systemic antineoplastic therapy during the treatment period, the 
investigator should contact the medical monitor. 
A schematic of the overall study design is provided in Figure 4-1. 
Figure 4-1 Schematic of Study Design 
 
 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is designed to establish the safety and efficacy of relugolix 120 mg orally 
once daily in men with advanced prostate cancer who require at least 1 year of continuous 
androgen deprivation therapy for androgen-sensitive disease.  This study will focus on the 
primary objective of evaluating the ability of relugolix to achieve and maintain suppression of 
serum testosterone to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) in patients with advanced prostate 
cancer.  During the Treatment Period of the study (Day 1 to Week 49 [Study Day 337]), patients 
will be randomized to one of the study treatment arms:  oral loading dose of relugolix (360 mg) 
followed by 120 mg once daily of relugolix or leuprolide acetate 3-M depot injection of 22.5 mg 
(or 11.25 mg Japan, Taiwan, and China) at 12-week intervals for 48 weeks.  Patients treated with 
leuprolide acetate will also receive an antiandrogen for 4 weeks or longer if indicated in the 
opinion of the investigator. 
The study is designed to allow for global approvals, however, different regulatory agencies 
require different criteria for the demonstration of efficacy.  The United States (US) Food and 
Drug Administration (FDA) requires, for approval, a primary efficacy criterion to determine 
whether the sustained castration rate (defined as the cumulative probability of testosterone 
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≤ 50 ng/dL [1.7 nmol/L] while on relugolix study treatment from Week 5 Day 1 through 
Week 49 Day 1) is greater than or equal to 90%.  The lower bound of the 95% confidence 
interval for the cumulative probability of sustained testosterone suppression in the relugolix 
treatment group will be calculated and must be greater than or equal to 90% to meet this 
criterion.  The study includes a leuprolide acetate arm to meet the regulatory requirement of 
other regions to establish the non-inferiority of relugolix compared to leuprolide acetate 3-M 
depot injection as assessed by the cumulative probability of sustained testosterone suppression.  
The lower bound of the 95% confidence interval for the difference in the cumulative probability 
of sustained testosterone suppression between the 2 treatment groups will be calculated and must 
be greater than or equal to the non-inferiority margin of -10% to meet this criterion. 
In amendment 3, an additional secondary endpoint of TCR is included in the final analysis.  TCR 
is defined as the time from the date of first dose to the date of PSA progression while castrated 
(PSA progression is defined by the Prostate Cancer Clinical Trials Working Group 3 guidelines 
[Scher, 2016] as the first increase in PSA of 25% or greater and 2 ng/mL or greater above the 
nadir with confirmation by a second PSA measurement at least 3 weeks later; for patients 
without declining PSA from baseline, PSA increase of 25% or greater and 2 ng/mL from 
baseline beyond 12 weeks will be considered PSA progression) or deaths due any reasons.  PSA 
progression is indicative of castration-resistance, the onset of which signals a higher risk of 
negative clinical outcomes in prostate cancer.  It has been shown that patients with low FSH 
levels have significantly longer TCR [Hoare, 2015].  Furthermore, prior GnRH receptor 
antagonist treatment has demonstrated an increased sustained suppression of FSH, compared 
with a GnRH receptor agonist, and a 45% reduction in risk of castration-resistance events at 1 
year (HR = 0.55) [Crawford, 2011].  In previous clinical trials, relugolix was associated with 
greater suppression of FSH than leuprolide.  This endpoint is regarded as clinically meaningful 
by both patients and physicians and is an independent predictor of survival [Williams, 2004; 
Hussain, 2006; Hussain, 2009; Proust Lima, 2008].  To further explore the potential for relugolix 
to delay the TCR, this protocol is being amended so that additional patients with metastatic 
advanced prostate cancer will be enrolled (to enroll approximately 390 metastatic patients).  The 
choice to enrich the study with metastatic patients is due to a higher incidence of 
castration-resistance (PSA progression) in patients with metastatic disease. 
The dose of relugolix selected is based on data from phase 1 and 2 studies demonstrating that 
oral doses of 80 mg and 120 mg once daily following an oral loading dose of 320 mg were able 
to suppress testosterone to castrate levels (see Section 2.2.4.2 and the Investigator Brochure).  A 
loading dose of 360 mg (three 120-mg tablets) was selected for phase 3 so that only one tablet 
size was required.  Leuprolide acetate 3-M depot injection was selected as the comparator as this 
is the GnRH agonist used most commonly as standard of care in the population under evaluation.  
Degarelix, an injectable GnRH antagonist, was considered, but was not used as it has limited 
market uptake attributed at least in part to a significant number of injection site reactions. 
4.3. 
Selection of Study Population 
Approximately 1100 men with advanced prostate cancer requiring androgen deprivation therapy 
will be enrolled in this study from approximately 200 study centers in North and South America, 
Europe, and the Asia-Pacific region.  Enrollment is defined as the time at which a patient is 
randomized to a treatment group and receives at least one dose of study drug. 
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Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor prior 
to randomizing the patient. 
4.3.1. 
Inclusion Criteria 
A patient will be eligible for inclusion in this study only if all of the following inclusion criteria 
are met prior to randomization, unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form; 
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate; 
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen 
deprivation therapy for the management of androgen-sensitive advanced prostate cancer with 
one of the following clinical disease state presentations: 
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention 
with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency 
ultrasound and not a candidate for salvage treatment by surgery; or 
b. Newly diagnosed androgen-sensitive metastatic disease; or 
c. Advanced localized disease unlikely to be cured by local primary intervention with either 
surgery or radiation with curative intent; 
Note:  radiotherapy, cryotherapy, or high frequency ultrasound are allowed after 2 months 
of androgen deprivation therapy.  Prior palliative radiation to sites other than the prostate 
bed is permitted. 
Note:  Once 915 patients are enrolled worldwide, only patients with metastatic advanced 
prostate cancer will be eligible for the study in all regions, except China, where both 
metastatic and non-metastatic patients will continue to be enrolled. 
5. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (1.50 ng/mL or 5.2 nmol/L); 
6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 µg/L), or, when 
applicable, post radical prostatectomy of > 0.2 ng/mL (0.2 µg/L) or post radiotherapy, 
cryotherapy, or high frequency ultrasound > 2.0 ng/mL (2.0 µg/L) above the post 
interventional nadir; 
Note:  If patient has had a radical prostatectomy then PSA must be > 0.2 ng/mL (0.2 μg/L) 
irrespective of any other treatment the patient has had. 
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial 
screening and at baseline (refer to Appendix 1); 
8. Is a male patient who, even if surgically sterilized (ie, status post vasectomy): 
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a. Agrees to use a male condom if having sex with a woman of childbearing potential or a 
pregnant woman, during the entire study Treatment Period and through 4 months after the 
last dose of study drug; or 
b. Agrees to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner) and withdrawal are not acceptable methods 
of contraception; 
9. Must agree not to donate sperm from first dose of study drug through 4 months after the last 
dose of study drug; 
10. A randomization authorization form has been signed by a study medical monitor approving 
the patient for randomization into the trial. 
4.3.2. 
Exclusion Criteria 
A patient will not be eligible for inclusion in this study if any of the following criteria apply: 
1. In the investigator’s opinion, is likely to require chemotherapy or surgical therapy for 
symptomatic disease management within 2 months of initiating androgen deprivation 
therapy; 
2. Previously received GnRH analog or other form of androgen deprivation therapy (estrogen or 
antiandrogen) for > 18 months total duration.  If androgen deprivation therapy was received 
for ≤ 18 months total duration, then that therapy must have been completed at least 3 months 
prior to baseline.  If the dosing interval of the depot is longer than 3 months, then the prior 
androgen deprivation therapy must have been completed at least as long as the dosing 
interval of the depot; 
3. Previous systemic cytotoxic treatment for prostate cancer (eg, taxane-based regimen); 
4. Metastases to brain per prior clinical evaluation; 
5. Removed; 
6. Scheduled for major surgery after baseline; 
7. History of surgical castration; 
8. Active malignancy beyond prostate cancer with the exception of any of the following:  
• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
carcinoma of any type 
• Adequately treated Stage I cancer from which the subject is currently in remission and 
has been in remission for ≥ 2 years 
• Any other cancer from which the subject has been disease-free for ≥ 5 years 
The medical monitor should be contacted for any questions regarding this exclusion criterion. 
9. Abnormal laboratory values at the Screening visit that suggest a clinically unstable 
underlying disease, or the following laboratory values: 
a. Serum gamma-glutamyl transferase > 2.0 x ULN; 
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b. Serum ALT and/or AST > ULN; 
c. Total bilirubin > ULN (unless secondary to Gilbert’s syndrome or the pattern is 
consistent with a diagnosis of Gilbert’s syndrome) or; 
d. Serum creatinine > 2.0 mg/dL (176.8 µmol/L); 
e. Platelets < 100 x 103/μL or history of bleeding disorder; 
f. Hemoglobin < 10.0 g/dL (100 g/L); 
g. Leukocytes (WBC) < 3 x 103/μL (3 GI/L); 
h. Absolute neutrophil count < 1.5 x 103/μL (1.5 GI/L); 
10. Hemoglobin A1c (HbA1c) > 10% in patients previously diagnosed with diabetes mellitus.  
HbA1c > 8% in patients whose diabetes mellitus is previously undiagnosed (excluded 
patients may be rescreened after referral and evidence of improved control of their 
condition); 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(hepatitis A virus IgM positive), hepatitis B (HBsAg positive), or hepatitis C (HCV antibody 
positive, confirmed by HCV ribonucleic acid); 
12. Known human immunodeficiency virus infection; 
13. Any of the following within 6 months before Baseline Day 1: 
a. Myocardial infarction; 
b. Unstable angina; 
c. Unstable symptomatic ischemic heart disease; 
d. New York Heart Association (NYHA) class III or IV heart failure 
e. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or 
symptomatic cerebrovascular events); 
f. Any other significant cardiac condition (eg, pericardial effusion, restrictive 
cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease); 
14. The following ECG abnormalities are excluded: 
a. ECG evidence of acute ischemia; 
b. Q-wave infarction, unless identified 6 or more months before the Screening visit; 
c. QTc > 470 msec, measured by Fridericia's formula [QTcF = QT/(RR^0.33)].  If the QTc 
is prolonged in a patient with a pacemaker, the patient may be enrolled in the study if 
confirmed by the medical monitor;  
d. Congenital long QT syndrome; 
e. Active conduction system abnormalities. Examples of active conduction system 
abnormalities include the following: 
• Mobitz II second degree heart block without a permanent pacemaker in place; 
• Third degree heart block without permanent pacemaker in place; 
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• Untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute); 
• Clinically significant ventricular arrhythmias such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes; 
• Uncontrolled atrial fibrillation (patients with chronic stable atrial fibrillation on stable 
anticoagulant therapy or patients with stable cardiac rhythm controlled by a 
pacemaker are allowed); 
The following exceptions are allowed:  First degree atrioventricular (AV) block, second 
degree AV block Type 1 (Mobitz Type 1/Wenckebach type), or right bundle branch block. 
15. Uncontrolled hypertension despite appropriate medical therapy (sitting blood pressure of 
greater than 160 mmHg systolic and/or 100 mmHg diastolic at 2 separate measurements no 
more than 45 minutes apart during the Screening visit).  Patients may be re-screened after 
referral and further management of hypertension; 
16. Hypotension, as indicated by systolic blood pressure < 84 mmHg on 2 repeat measures at 
least 15 minutes apart, or treated ongoing symptomatic orthostatic hypotension with 
> 20 mmHg decrease in systolic blood pressure one minute or more after assuming upright 
position; 
17. Bradycardia as indicated by a heart rate of < 45 beats per minute on the ECG at the Screening 
or Baseline Day 1 visit; 
18. Treatment with any investigational product within 28 days or 5 half-lives (whichever is 
longer);  
Exception: treatment for prostate cancer with any investigational products where the 
mechanism of action is testosterone lowering.  In this circumstance, there must be a 
minimum 12-month treatment free interval. 
19. Removed; 
20. Previous treatment with relugolix in a clinical study; 
21. Patient is a study site employee or is a primary family member (spouse, parent, child, or 
sibling) of a site employee involved in the conduct of the study; 
22. Known gastrointestinal disease or procedure that could interfere with the oral absorption or 
tolerance of relugolix, including inability to swallow whole tablets or conditions that may 
interfere with absorption at the level of the small intestine. Examples of such conditions 
include but are not limited to Crohn's disease, gastric bypass, active peptic ulcer disease, and 
gastrectomy. The medical monitor should be contacted for any questions regarding this 
exclusion criterion; 
23. Use or planned use of any medication listed in the prohibited medications table (see 
Section 5.10.1) without the appropriate washout period; 
24. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
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25. Has a prior (within 1 year of the Screening visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form); 
26. Any other medical or psychiatric condition that, in the opinion of the investigator, would 
interfere with completion of treatment according to this protocol. 
27. Weight ≥ 400 pounds (181 kg) or has a body mass index ≥ 50; 
4.4. 
Other Eligibility Criteria Considerations 
Patient eligibility may require additional or repeat assessments such as safety labs, vital signs, or 
ECG during the Screening Period. 
To assess any potential impact on patient eligibility with regard to safety, the investigator is 
referred to the Investigator Brochure for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the investigational 
product(s) used in this study. 
4.5. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the Screening Period.  Study site personnel will access the interactive voice/web 
recognition system (IWRS) to assign a screening identification number to a potential patient. 
For patients who provide informed consent and subsequently do not meet eligibility criteria, or 
withdraw consent are considered screen failures and are not randomized.  Study site personnel 
should ensure that the source record includes documentation for the screen failure (eg, medical 
history, eligibility criteria, procedures performed). 
Patient numbers assigned to patients who become screen failures are not to be reused.  Patient 
identification numbers will be assigned to eligible patients at randomization, as described in 
Section 4.6. 
4.6. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number 
After a patient is screened and the investigator determines that the patient is eligible for 
enrollment, the site staff will complete the Randomization Authorization Form and send it to the 
sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the investigator 
site file.  The sponsor (or designee) will approve the patient’s enrollment in writing.  Once the 
site has received approval, the patient may undergo the Baseline Day 1 visit.  The site will 
randomize the patient to treatment by using the IWRS during the patient’s Baseline Day 1 visit.  
The IWRS will assign the patient identification (ID) number.  This number will identify the 
patient for the duration of the study.  A study treatment kit number will be available at the site 
according to the randomization code. 
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4.7. 
Removal of Patients from Therapy 
Patients may withdraw consent to participate in the study and discontinue treatment at any time 
for any reason.  Investigators or the medical monitor may remove patients from therapy under 
this protocol for reasons of safety and/or lack of compliance as discussed below.  Patients 
removed from therapy for any reason will undergo the assessments for the Week 49 visit on the 
Schedule of Activities.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
Follow-up visits to assess safety will be performed in all study patients.  If the patient plans to 
start alternative androgen deprivation therapy less than 30 days after the End of Treatment visit, 
the Safety Follow-up visit may occur earlier, before the start of the alternative androgen 
deprivation therapy.  Testosterone recovery will be evaluated in approximately 100 patients 
randomized to relugolix and approximately 50 patients to leuprolide acetate who complete 
48 weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy and will not be offered alternative androgen 
deprivation therapy upon completion of study therapy.  These patients will return for the 
60- and 90-day follow-up Testosterone Recovery visits. 
The safety and/or compliance events shown in Table 4-1 will result in the removal of patients 
from therapy either permanently or until the etiology of the problem has been identified and 
resolved. 
Table 4-1 
Removal of Patients from Treatment 
Reason 
Comment 
Adverse event or intercurrent illness 
Any intolerable adverse event to the patient that cannot be 
ameliorated by the use of adequate medical intervention, or that 
in the opinion of the investigator or medical monitor would lead 
to undue risk to the patient if dosing continued 
Failed to meet eligibility criteria 
post randomization 
If it is discovered after randomization that a patient failed to 
meet protocol entry criteria and continued participation poses 
an unacceptable risk to the patient’s health 
Dose hold 
Relugolix dose hold that exceeds 10 consecutive days 
Patient not meeting criteria for 
testosterone suppression to castrate 
level 
Patients with disease progression during the treatment period, in 
the setting of testosterone suppression to castrate levels 
(≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive radiotherapy as prescribed 
by the investigator.  In the setting of rising PSA patients may 
also receive enzalutamide after the confirmation of PSA 
progression.  For patients requiring other systemic 
antineoplastic therapy during the treatment period, the 
investigator should contact the medical monitor. 
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Reason 
Comment 
Laboratory abnormality defined by 
protocol: 
ALT or AST > 8 x ULN; or 
ALT or AST > 5 x ULN and persists 
for more than 2 weeks; or 
ALT or AST > 3 x ULN in 
conjunction with elevated total 
bilirubin > 2 x ULN or INR > 1.5; or 
ALT or AST > 3 x ULN with 
appearance of fatigue, nausea, 
vomiting, right upper quadrant pain 
or tenderness, fever, rash and/or 
eosinophilia (> 5%) 
If any of these liver test abnormalities develop, study drug 
should be discontinued immediately with appropriate clinical 
follow-up (including repeat laboratory tests, until a patient’s 
laboratory profile has returned to normal/baseline status). 
Confirmed QTcF prolongation of 
more than 500 msec, in the absence 
of a pacemaker, as read by a 
cardiologist 
If QTc prolongation of > 500 msec in the absence of a 
pacemaker occurs, the ECG must be repeated.  Confirmed QTc 
prolongation, measured by Fridericia's formula 
[QTcF = QT/(RR^0.33)], will result in removal of the patient 
from treatment.  
Patients who have a clinically 
significant decrease in visual acuity 
as evaluated by an ophthalmologist 
that may be related to study drug 
treatment 
 
Gross noncompliance with protocol 
Patients who are, in the opinion of the investigator or the 
medical monitor, non-compliant with the protocol’s 
requirements 
Patient decision 
Patients may permanently discontinue study treatment at any 
time for any reason.  Following study drug discontinuation, 
patients should attend the protocol-required safety follow-up 
visit. 
Sponsor discontinuation of study 
The sponsor reserves the right to terminate the study anytime as 
described in Section 10.3.3.  The sponsor will terminate this 
study following completion of study objectives, or earlier if 
deemed necessary. 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; INR, 
international normalized ratio; QTc, QT interval corrected for heart rate; QTcF, QT interval corrected for heart rate 
using the Fridericia formula; ULN, upper limit of normal 
 
Once study drug has been discontinued, all study procedures outlined for the Week 49 visit will 
be completed as specified in the Schedule of Activities (Section 1.1).  The primary reason for 
study drug discontinuation will be recorded on the eCRF. 
Patients who withdraw from treatment will not be replaced. 
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Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance.  Patients randomized to relugolix should be counseled to notify the 
investigator in the event of intercurrent illness to determine if the study drug treatment can be 
continued.  Every effort should be made to ensure the patient’s compliance with study drug 
treatment, including calling patients to reschedule missed visits. 
In cases where the patient does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the patient.  
The site should attempt at least 3 documented telephone calls and, if necessary, a certified letter 
to the patient’s last known mailing address so that they can appropriately be withdrawn from the 
study with a primary reason of “Lost to Follow-up.” 
4.8. 
Contraception/Pregnancy Avoidance 
It is not known what effects relugolix has on human pregnancy or development of the embryo or 
fetus.  Therefore, male patients should avoid impregnating a female partner. 
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 4 months after the last dose of study drug. 
Nonsterilized male patients should use a male condom, either alone or in addition to effective 
methods of contraception used by a female partner of childbearing potential, through defined 
periods during and after study treatment as specified below.  Examples of effective contraceptive 
methods include condoms, hormonal contraceptives, and intrauterine devices. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following: 
• Use a male condom if having sex with a woman of childbearing age or a pregnant 
woman, during the entire study Treatment Period and through 4 months after the last dose 
of study drug; or 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods for the female partner, and withdrawal are not acceptable methods 
of contraception.  
5. 
TREATMENTS 
5.1. 
Treatments Administered 
Patients enrolled in this study will be randomized 2:1 to receive oral relugolix 120 mg following 
a loading dose of 360 mg on Day 1, or leuprolide acetate 22.5 mg (or 11.25 mg in Japan, Taiwan, 
and China) 3-M depot injection (plus antiandrogen for the first 4 weeks or longer if indicated in 
the opinion of the investigator).  Randomization will be stratified by geographic region, presence 
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of metastatic disease (metastases in regional lymph node[s] are considered N1 and will, 
therefore, be stratified as non-metastatic), and age. 
Approximately 1100 patients will be enrolled in the study from approximately 200 study centers 
in North and South America, Europe, and the Asia-Pacific region. 
Study treatment is defined as either oral relugolix or leuprolide acetate injection (see Table 5-1). 
Table 5-1 
Description of MVT-601-3201 Study Drugs 
 
Study Treatment 
Product name: 
Relugolix 
Leuprolide Acetate 3-M Depot 
Formulation description: 
Round film coated pink tablet 
 
Dosage form: 
Tablet 
 
Unit dose strength and dosage 
level: 
120 mg, following a single-
loading dose of 360 mg 
22.5 mg (11.25 mg in Japan, 
Taiwan, and China) 
Route of Administration / 
Duration 
Oral / 48 weeksa 
Subcutaneous or intramuscular / 
48 weeksa 
a. 
Duration of treatment is 48 weeks during the Treatment Period; the last leuprolide acetate injection occurs 
12 weeks before the end of the Treatment Period. 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-
methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N'-
methoxyurea. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using the US 
Pharmacopeia and the National Formulary excipients. 
5.3. 
Randomization and Stratification 
Patients are assigned to one of two treatment arms in accordance with the randomization 
schedule using an integrated randomization system (IWRS). 
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At Baseline Day 1, patients will be randomized in a 2:1 ratio to one of the following treatment 
arms: 
Treatment Arm 
Randomized Treatment 
Approximate 
Number of Patients 
Arm A 
Relugolix 360 mg (three 120 mg tablets) single oral 
loading dose on Day 1 followed by 120 mg orally once 
daily 
610 
Arm B 
Leuprolide acetate, 22.5 mg 3-M depota injection 
(or 11.25 mg in Japan, Taiwan, and China) 
305 
a. 
Antiandrogen is administered for the first 4 weeks or longer if indicated, in the opinion of the investigator. 
Randomization will be stratified by geographic region, presence of metastatic disease, and age as 
follows: 
• Geographic Region 
o Europe; 
o North and South America; or 
o Asia and Rest of World. 
• Presence of Metastatic Disease 
o Metastatic disease diagnosed on locally-read imaging by abdominopelvic 
computed tomography (CT) or magnetic resonance imaging (MRI) or bone scan 
at the time of the Baseline Day 1 visit; or 
o No evidence of metastatic disease by locally-read imaging (metastases in regional 
lymph node(s) are considered N1 and will, therefore, be stratified as 
non-metastatic). 
• Baseline Age 
o ≤ 75 years old; or 
o > 75 years old. 
After the first 915 patients are enrolled, enrollment in China will continue for metastatic and 
non-metastatic patients until the target number of Chinese patients is reached (138 patients).  In 
the rest of the world, only metastatic patients will continue to be enrolled until approximately 
390 metastatic patients for the overall study are accrued. 
5.4. 
Directions for Administration 
Relugolix 
Relugolix 120-mg tablet strength will be available as immediate-release film-coated tablets.  
These tablets will be presented in 45-tablet bottle packaging and dispensed to patients every 
4 weeks at scheduled study visits. 
All protocol-specific criteria for administration of study drug must be met and documented prior 
to study drug administration.  Study drug will be dispensed by study personnel only to eligible 
patients who are under the supervision of the investigator or identified subinvestigator(s).  If a 
blood draw or any study procedure coincides with a meal, the study procedure will take 
precedence, followed by the blood draw, and then the meal. 
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At the Baseline Day 1 visit, the site will administer a single loading dose of oral relugolix 
360 mg (3 tablets). 
Patients randomized to relugolix will be instructed to take one tablet on an empty stomach at 
least 1 hour before breakfast once daily.  If the dose is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
Patients may consume water ad libitum.  Patients should swallow the study medication whole 
and not chew it or manipulate it in any way before swallowing. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
Leuprolide Acetate 
Leuprolide acetate 3-M depot injection, 22.5 mg (or 11.25 mg in Japan, Taiwan, and China), will 
be administered every 12 weeks.  Leuprolide acetate 3-M depot will be administered on Day 1 at 
the clinic, then at 12-week intervals (see Schedule of Activities, Section 1.1) and investigators 
should follow product instructions provided by the manufacturer.  An antiandrogen may be 
administered for the first 4 weeks or longer if indicated, as determined by the investigator, and/or 
as indicated by disease status (eg, in patients with extensive localized symptomatic disease or 
with metastatic disease). 
Possible antiandrogen options include, but are not limited to, bicalutamide, flutamide, and 
nilutamide. 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that is related to study drug and cannot be ameliorated by the use of 
adequate medical intervention should have their treatment interrupted if the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing until the toxicity improves to a 
grade 2 or lower severity.  Study drug can be held for a period of up to 10 consecutive days for 
evaluation and treatment of an adverse event.  Patients may subsequently be re-started on study 
drug, with the written approval of the sponsor (or designee). 
5.6. 
Dose Escalation, Dose Reduction, and Dose Interruption 
Neither dose escalations nor dose reductions are allowed in the study. 
Every effort should be made to continue relugolix administration through treatment-emergent 
adverse events unless they are grade 3 or 4 and related to study drug, or the investigator believes 
it is in the best interest of the patient to interrupt relugolix dosing.  Of note, patients on leuprolide 
acetate 3-M depot injection continue to receive GnRH agonist therapy because it is impossible to 
discontinue treatment. 
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If the grade 3 or 4 adverse event improves to grade 0, 1, or 2 after holding the dose, or if the 
adverse event is no longer believed to be related to study drug, the patient may be rechallenged at 
the same dose at the discretion of the investigator and medical monitor.  If the adverse event 
remains grade 3 or grade 4 after treatment discontinuation and the investigator continues to 
believe the adverse event is related to study drug, study drug treatment should be discontinued 
permanently. 
5.7. 
Storage, Packaging, and Labeling 
Relugolix will be packaged in bottles containing forty-five 120-mg tablets of relugolix.  
Additional details regarding the packaging of relugolix are provided in the Investigator Brochure 
and investigator site file. 
Leuprolide acetate 11.25 mg or 22.5 mg 3-M depot injection will be packaged and labeled for 
clinical trial use. 
Relugolix medication should be stored in an appropriate, limited-access, secure location, 
protected from light, in the original bottles and within a temperature range at 15°C to 25°C 
(59°F to 77°F) with excursions permitted up to 30°C (86°F). 
A daily temperature log of the drug storage area must be maintained every working day. 
Study drug must be stored under the conditions specified and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Patients will be instructed to store study drug at 
room temperature out of the reach of children. 
Further guidance and information for final disposition of unused study drug are provided in the 
investigator site file.  The investigator is responsible for study drug accountability, 
reconciliation, and record maintenance, including receipt, reconciliation, and final disposition 
records and their secure storage. 
Refer to the leuprolide acetate product labeling for information regarding the proper storage and 
handling of leuprolide acetate. 
5.8. 
Blinding 
Blinding is not applicable; this is a randomized open-label study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused study drug to each study visit.  Study drug accountability will be 
conducted and results will be recorded as the primary source of study drug accountability.  If a 
patient is persistently noncompliant with the study treatment, it may be appropriate to withdraw 
the patient from the study. 
All patients should be reinstructed regarding dosing compliance during study contacts.  The 
authorized study personnel conducting the re-education must document the process in the 
patient’s source records. 
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Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous non-compliance. 
Patients randomized to relugolix should be counseled to notify the investigator in the event of 
intercurrent illness to determine if the study drug treatment can be continued. Should a patient 
need a surgery of any kind, please contact the medical monitor.  Every effort should be made to 
ensure the patient’s compliance with study drug treatment, including calling patients to 
reschedule missed visits. 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-2 provides examples of systemic medications that are prohibited prior to the first dose of 
study medication until the End of Treatment visit and the Follow-up Period is complete.  This list 
is not a comprehensive list of all restricted medications.  Consult the medical monitor if there is 
any uncertainty regarding patient use of a particular drug or drug class.  Patients may “wash out” 
of these prohibited medications prior to dosing based on the periods provided in Table 5-2. 
Any investigational agent for the treatment of prostate cancer where the mechanism of action is 
testosterone lowering, including agents that are commercially available for indications other than 
prostate cancer that are under investigation for the treatment of prostate cancer, are also 
prohibited for at least 12 months prior to the first dose of study medication. 
Table 5-2 
Prohibited Medications and Washout Periods 
Drug Class 
Examples 
Minimum Washout Periodc 
GnRH analogues 
Leuprolide acetate 
injectiona 
Goserelin acetate 
injection 
 
At least one dosing interval 
of the depot preparation; 
minimum of 3 monthsd 
GnRH antagonists 
Degarelix 
 
At least one dosing interval 
of the depot preparation; 
minimum of 3 monthsd 
Antiandrogensa 
Bicalutamide 
Flutamide 
Nilutamide 
Enzalutamideb 
3 months 
CYP17 inhibitors 
Abiraterone acetate + 
prednisone 
 
3 months 
Other androgen 
suppressing agents or 
androgens 
Estrogens 
Ketoconazole 
Testosterones 
Megestrol acetate 
Progestogens 
3 months 
5-alpha reductase 
inhibitors 
Finasteride 
Dutasteride 
 
4 weeks 
6 months 
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Drug Class 
Examples 
Minimum Washout Periodc 
Class IA an III 
antiarrhythmics 
Amiodarone 
Procainamide 
Quinidine 
Sotalol 
2 weeks  
(3 months for amiodarone) 
Moderate and strong 
CYP3A and 
Pglycoprotein- inducers 
Bosentan 
Carbamazepine 
Efavirenz 
Etravirine 
Mitotane 
Modafinil 
Nafcillin 
Phenobarbital 
Phenytoin 
Rifampin 
St John’s Wort 
Primidone 
Rifabutin 
Rifapentine 
1 week 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
Moderate/strong 
P-glycoprotein 
inhibitors 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporin 
Diltiazem 
Dronedarone 
Eliglustat 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lapatinib 
Lopinavir/Ritonavir 
Quercetin 
Quinidine 
Ranolazine 
Ticagrelor 
Verapamil 
1 week 
(3 months for amiodarone) 
(3 months for ketoconazole) 
Note: For patients requiring a 
short course of these drugs 
during the study, investigator 
must contact the medical 
monitor for approval and 
guidance on study drug 
administration during this 
period. 
High-dose biotin 
supplementse 
Vitamin B7 
Vitamin H 
 
CoEnzyme R 
 
 
Herbal therapiesf 
Ginkgo biloba 
Kava kava 
Ginseng  
2 weeks or 5 half-lives 
(whichever is shorter) 
Abbreviation:  CYP, cytochrome P450 
a. 
Unless randomized to leuprolide acetate control arm of this study.  After randomization, antiandrogen therapy is 
permitted for the first 4 weeks or longer of leuprolide acetate treatment. 
b. Enzalutamide is allowed for the treatment of castration-resistant disease that occurs on study (rising 
prostate-specific antigen in the setting of testosterone suppressed to castrate levels (≤ 50 ng/dL [1.7 nmol/L]) 
after the confirmation of PSA progression. 
c. 
Minimum washout period is calculated from the date of last dose of prohibited medication to the first day of 
study drug. 
d. Patients with cumulative previous androgen deprivation therapy > 18 months are excluded, regardless of 
washout period. 
e. 
See Section 5.10.1.1 for additional details.  For questions about which biotin supplements may be permitted, 
please consult with the study Medical Monitor. 
f. 
For patients taking herbal remedies, questions regarding appropriate wash-out period should be addressed on a 
case-by-case basis with the study Medical Monitor. 
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5.10.1.1. 
High-Dose Biotin Supplements 
In November 2017, the FDA issued a safety communication on biotin interference intended for 
healthcare professionals [FDA, 2017].  Briefly, the communication made the following 
recommendations: 
• Talk to your patients about any biotin supplements they may be taking, including 
supplements marketed for hair, skin, and nail growth. 
• Be aware that many laboratory tests, including but not limited to cardiovascular 
diagnostic tests and hormone tests, that use biotin technology are potentially affected, and 
incorrect test results may be generated if there is biotin in the patient’s specimen. 
• Communicate to the laboratory conducting the testing if your patient is taking biotin. 
• If a laboratory test result doesn’t match the clinical presentation of your patient, consider 
biotin interference as a possible source of error. 
• Know that biotin is found in multivitamins, including prenatal multivitamins, biotin 
supplements, and dietary supplements for hair, skin, and nail growth in levels that may 
interfere with laboratory tests. 
• Report to the laboratory test manufacturer and the FDA if you become aware of a patient 
experiencing an adverse event following potentially incorrect laboratory test results due 
to biotin interference. 
A threshold ‘high level’ biotin dose has not yet been defined by FDA. 
Study Investigators should discuss with study patients about any biotin supplements they may be 
taking.  For patients taking biotin supplements, the investigator should assess if it is possible to 
discontinue use of these supplements.  In cases where the investigator believes a patient is taking 
high doses of biotin and discontinuation of this supplementation is not in the best interest of the 
patient, the investigator should contact the Medical Monitor to assess the potential impact on 
study laboratory test results. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded.  At a minimum, the drug 
generic name, dose amount, route of administration, start date, and stop date will be recorded in 
the source documents and the eCRF. 
If alternative androgen deprivation therapy is initiated prior to 30 days after the last relugolix 
dose, record the alternative androgen deprivation therapy as a concomitant medication. 
Patients with disease progression during the treatment period, in the setting of testosterone 
suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L]), should be encouraged to remain on 
study and, if indicated, may receive radiotherapy as prescribed by the investigator.  In the setting 
of rising PSA patients may also receive enzalutamide after the confirmation of PSA progression.  
For patients requiring other systemic antineoplastic therapy during the treatment period, the 
investigator should contact the medical monitor. 
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6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities 
(see Section 1.1).  Study procedures are briefly described within Section 6.6.  Further details of 
the procedures are provided in the investigator site file. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 3 periods:  Screening Period, Treatment 
Period, and Follow-up Period.  Unscheduled visits may also occur as needed to evaluate patients. 
6.2. 
Screening Period (Day -28 to Day -1) 
The Screening Period will be from Day -28 through Day -1.  At the Screening visit, study site 
personnel must explain to potential study participants all aspects of the study, including all 
scheduled visits and activities.  Study site personnel must obtain signed informed consent before 
any study-specific procedures are conducted, unless the procedures are part of routine standard 
of care.  The informed consent process must be documented in the patient’s clinical record. 
The investigator will assess and confirm the eligibility of each patient and determine that each 
patient will maintain study drug compliance during the treatment period.  All screening 
procedures results and relevant medical history must be available before eligibility can be 
determined.  All inclusion criteria must be met and none of the exclusion criteria may apply.  No 
eligibility waivers will be granted. 
The following assessments will be performed: 
• Complete medical history, including detailed prostate cancer history; 
• Vital signs, weight, and height; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
• An abdominopelvic CT or MRI and a bone scan should be performed and read locally to 
determine the presence of metastatic disease within 60 days prior to randomization. 
However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is not 
required. If metastatic disease is not present on CT or MRI, then a bone scan is also 
required.  
• Demographics; 
• Laboratory data collection (see Section 1.1); 
• Verify inclusion/exclusion criteria; and 
• Concomitant medications and adverse events. 
A Randomization Authorization Form must be submitted to the sponsor for approval prior to 
conducting the Baseline Day 1 visit. 
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6.3. 
Treatment Period (Day 1 to Week 49 [Study Day 337]) 
Baseline Day 1 Visit 
Study site personnel should ensure that an approved Randomization Authorization Form is in the 
patient’s file before proceeding with the randomization and Day 1 visit procedures.  Patients will 
be randomized to either relugolix or leuprolide acetate 3-M depot injection 22.5 mg (or 11.25 mg 
in Japan, Taiwan, and China) (see Section 5.3). 
The following assessments will be performed: 
• Patient-reported outcome questionnaires (EQ-5D-5L, EORTC-QLQ-PR25, and 
EORTC-QLQ-C30) 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Medical history; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Verify inclusion/exclusion criteria; 
• Concomitant medications and adverse events; 
• Randomize the patient;  
• Laboratory collection (see Section 1.1); and 
• Study drug management: 
o If study drug administration is not logistically feasible on the same day as 
randomization, Day 1 will be defined as the day of the first dose. 
o If the patient is randomized to relugolix, site personnel will administer a single 
loading dose of oral relugolix 360 mg (3 tablets) and then dispense study drug to 
the patient and instruct on daily dosing of 120 mg (1 tablet) and the importance of 
medication compliance (see Section 5.4); 
o If the patient is randomized to leuprolide acetate, site personnel will administer 
the injection in the clinic. 
Day 4 and Weeks 2 and 3 Visits (Visit Window ± 2 days) 
The following assessments will be performed: 
• Vitals signs; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
 
Note: The Week 2 visit will only occur for patients who are part of the Japan or China subset for 
PK analysis. 
 
 
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Weeks 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, and 45 Visits (Visit Window ± 7 Days) 
Importantly, patients randomized to relugolix should be called 7 days before each visit to ensure 
the patient is compliant with study drug medication. 
The following assessments will be performed: 
• Patient-reported questionnaires will be completed on the electronic tablet provided 
(Weeks 5, 13, 25, and 37 only) 
o Patients will complete the questionnaires before other study procedures, such as 
blood draws and physical examinations, are performed; 
• Vital signs, weight 
o Weight will be collected only on Weeks 13 and 25; 
• 12-lead ECG (Weeks 5, 13, and 25 only); 
• ECOG performance assessment (Week 25 only); 
• Symptom-based physical examination (except Week 25); 
• Complete physical exam and visual acuity assessment (Week 25 only); 
• Laboratory collection (see Section 1.1) 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 24 
hours after the previous dose. Patients may be dosed in the clinic at these visits, 
provided the dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability; 
 Dispense study drug. Patients may be dosed in the clinic, provided the 
dose can be administered at least 2 hours after food; food should be 
withheld for 1 hour after dosing; 
 Remind patients on importance of medication compliance. 
o For patients randomized to leuprolide acetate, 
 Site will administer leuprolide acetate in clinic every 12 weeks (Weeks 13, 
25, and 37). 
Week 49 or (Early Termination of Study Drug) (Visit Window ± 7 Days) 
• For patients receiving relugolix, a member of the site team will call the patient 7 days 
before the Week 49 visit to remind the patient of the need for compliance with their study 
medication; 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs, weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Complete physical exam and visual acuity assessment; 
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• Laboratory collection (see Section 1.1); 
o Blood samples for PK analysis will be collected for all patients assigned to the 
relugolix treatment arm. Samples will be collected predose, approximately 
24 hours after the previous dose.  
• Concomitant medications and adverse events; and 
• Study drug management: 
o For patients randomized to relugolix, 
 Perform study drug accountability. 
6.4. 
Follow-up Period 
The study day in which the Follow-up visit occurs is relative to when the patient takes his last 
dose of study drug.  The End of Treatment is defined as the last dose of relugolix or 12 weeks 
after the last leuprolide acetate injection. 
30-Day Safety Follow-up Visit (Visit Window ± 7 Days) 
A Safety Follow-up visit should occur 30 days after the End of Treatment and may occur earlier 
for patients who are starting alternative androgen deprivation therapy or do not complete 
12 weeks of study treatment.  Adverse events should continue to be collected and recorded 
through 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events and concomitant medications will be collected from the signing of the 
informed consent form until the Safety Follow-up visit approximately 30 days after the last dose 
of study drug. 
All other study procedures should be completed before the start of alternative androgen 
deprivation therapy. 
The following assessments will be performed: 
• Patient-reported questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs and weight; 
• 12-lead ECG; 
• ECOG performance assessment; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications and adverse events. 
Testosterone Recovery Visit (Visit Window ± 7 Days) 
Patients who have started alternative androgen deprivation therapy will not participate in the 
60- and 90-day follow-up visits.  Approximately 100 patients randomized to receive relugolix 
and approximately 50 patients randomized to receive leuprolide acetate who complete the 
48 weeks of study drug treatment and, in the opinion of the investigator, are candidates for 
intermittent androgen deprivation therapy will be included in the Testosterone Recovery 
60- and 90-day Follow-up visits.  These patients will discontinue relugolix after 48 weeks of 
treatment and will be offered a period off androgen deprivation therapy. 
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The following assessments will be performed: 
• Patient-reported outcome questionnaires 
o Patients will complete the questionnaires on the tablet provided before other study 
procedures, such as blood draws and physical examinations, are performed; 
• Vital signs; 
• Symptom-based physical examination; 
• Laboratory collection (see Section 1.1); and 
• Concomitant medications. 
Health Status Survey 
During the final weeks prior to database lock, sites will be asked to contact all study participants 
or their immediate family regarding the current health status of previously enrolled/completed 
study patients.  If the site is unsuccessful in contacting the patient and/or immediate family, the 
site may access hospital records or publicly available sources such as national registries, 
newspaper obituaries, and social networking websites. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
investigator.  The following activities should be completed at an Unscheduled visit: recording of 
the date and reason for the visit in the patient’s source documents, concomitant medication 
review and evaluation of adverse events.  In addition, procedures such as vital signs, weight, 
symptom-directed brief physical examination, central safety laboratory assessment and collection 
of a PK sample if indicated, 12-lead ECG, study drug compliance and dispensation, etc. may be 
conducted as needed.  See Schedule of Events (see Section 1.1) for tests that may be performed 
if indicated at an unscheduled visit.  Consult with the medical monitor, if needed, to discuss 
Unscheduled visit testing. 
6.6. 
Study Procedures 
6.6.1. 
Efficacy-Related Procedures 
6.6.1.1. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, testosterone, 
dihydrotestosterone, sex hormone binding globulin, and PSA will be collected predose at the 
visits indicated in the Schedule of Activities in the protocol synopsis (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory.  Testosterone samples may 
be analyzed at a second laboratory to confirm non-castrate levels (Section 1.1). 
Serum LH, FSH, dihydrotestosterone, sex hormone binding globulin, and PSA samples will be 
analyzed at a central laboratory. 
PSA will also be used to evaluate biochemical progression per Prostate Cancer Clinical Trials 
Working Group 3 guidelines [Scher, 2016]. 
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Analysis of serum samples for testosterone is detailed below:  
Testosterone Assessment 
Serum concentrations of testosterone will be obtained as indicated in the Schedule of Activities 
(see Section 1.1). 
Testosterone will be assayed using a liquid chromatography-tandem mass spectrometry method 
sensitive at least as low as 5 ng/dL (0.17 nmol/L) for all measurements.  
Between Week 5 and Week 49 visits (inclusive), testosterone samples that are above castrate 
level (> 50 ng/dL) will be reported to the investigator at the respective study site.  Testosterone 
samples may be subject to reanalysis by liquid chromatography/mass spectrometry and/or 
immunoassay sensitive to at least as low as 10 ng/dL. 
Instructions for collection and processing of blood specimens are provided in the investigator site 
file. 
6.6.1.2. 
Pharmacokinetic Sample Collection 
Relugolix  
Pharmacokinetic samples will only be collected in patients randomized to relugolix study drug. 
Blood samples for pharmacokinetic analysis of relugolix will be collected at the visits indicated 
in the study Schedule of Activities in the protocol synopsis (see Section 1.1).  The actual date 
and time of each blood sample collection will be recorded. 
Patients may take their dose of study drug in the clinic at these visits.  Study drug will be 
administered on an empty stomach or at least 2 hours before food, and food will be withheld for 
1 hour after dosing.  The date and time of their previous dose of study drug (ie, the dose the day 
before the clinic visit) will be accurately recorded.   
Ideally, predose samples should be collected approximately 24 hours (±6 hours) after the 
previous dose of relugolix, although samples collected outside of this window would not be 
considered a protocol deviation. 
If the study patient inadvertently took the study drug at home on the morning of the clinic visit, 
the date and time of that dose should also be accurately recorded and the PK sample collected, 
which may be used for population PK modeling. 
Plasma from the Week 5 and Week 13 visits in all patients will be analyzed for relugolix plasma 
concentration.  Analysis of other individual patient plasma samples will be performed on a case-
by-case basis (such as those patients with non-castrate testosterone levels). 
Collection, processing, storage, and shipping instructions will be provided in the investigator site 
file.  Plasma analysis of relugolix will be performed by the sponsor (or designee). 
Leuprolide Acetate 
For patients on leuprolide acetate, in the event of non-castrate testosterone levels, a blood sample 
may be taken for potential analysis of leuprolide acetate plasma concentration, following 
discussion with the medical monitor 
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China and Japan Pharmacokinetic Subset 
In a subset of patients from China and approximately 20 patients from Japan that are randomized 
to relugolix, additional relugolix PK samples will be collected on Day 1, Day 4, and Week 2 
visits (see Schedule of Activities in the protocol synopsis, Section 1.1).  The actual date and time 
of study drug administration and the date and time of each PK sample will be accurately 
recorded. 
All samples from the China and Japan subset will be analyzed for plasma relugolix 
concentrations.  Collection, processing, storage, and shipping instructions will be provided in the 
investigator site file.  Plasma analysis of relugolix will be performed by the sponsor (or 
designee). 
6.6.1.3. 
Pharmacogenomics Sample Collection 
Whole Blood Sample for Germline Deoxyribonucleic Acid 
Pharmacogenomic analysis may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety.  Participation of study patients in 
pharmacogenomic sample collection is optional.  A pharmacogenomics sample will be collected 
from patients at all participating study centers, with individual patient consent and per local 
ethics and regulatory standards.  The sample will be retained for germline deoxyribonucleic acid 
(DNA) analysis of potential genetic determinants of drug safety, drug efficacy or disease 
response, and drug metabolism. 
Every patient must sign informed consent/be consented in order to participate in the sampling of 
whole blood for DNA analysis.  This research may be used to develop a better understanding of 
the safety and efficacy of relugolix and other study drugs, to increase understanding of the 
disease/condition being studied, and for improving the efficiency, design and study methods of 
future research studies. 
Two venous whole blood sample (4 mL per sample) for the analysis of germline DNA will be 
collected at Day 1 from all patients who have provided informed consent.  The DNA samples are 
expected to be collected at the Day 1 visit, but if necessary, may be collected at any visit after 
randomization.  If necessary and feasible, a second aliquot of blood may be taken if isolation of 
DNA from the first sample was not successful or possible.  Germline DNA analysis may be 
conducted to investigate the contribution of genetic variance on drug response, for example, its 
efficacy and safety.  As pharmacogenomics is an evolving science, currently many genes and 
their function are not yet fully understood.  Future data may suggest a role of some of these 
genes in drug response or diseases, which may lead to additional hypothesis-generating 
exploratory research on stored samples. 
Individual blood samples for germline DNA analysis, including the result of any analyses and 
corresponding information will be identified only by a code in a computer database. 
The whole blood samples for DNA analysis will be stored securely at the sponsor’s location or 
its designated central laboratory vendor until 10 years after completion of this study (HERO, 
MVT-601-3201) and/or until the drug development of relugolix is no longer actively pursued by 
Myovant or its collaborators.  The storage period for these samples may be adjusted by country 
in accordance with local regulatory and/or legal requirements for the storage of research samples.  
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Such changes will be reflected in the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) country-specific informed consent form.  After that time, the samples will be 
properly destroyed by the central laboratory or designee following approval by the sponsor.  The 
investigator will keep records linking the patient identity with the samples for the time required 
by applicable law.  Patients who consent and provide a pharmacogenomic sample for DNA 
analysis can withdraw their consent and request disposal of a stored sample at any time. 
Directions for sample collection and handling can be found in the investigator site file. 
6.6.1.4. 
Quality of Life 
European Quality of Life 5-Dimension 5-Level Assessment 
The EuroQol EQ-5D-5L comprises 5 scales and an overall assessment of health status on a 
visual analogue scale (Appendix 2).  The 5 scales include:  mobility, self-care, usual activities, 
pain and discomfort, and anxiety and depression.  The original version, the EQ-5D-3L, includes 
3 response options for each scale.  However, a new 5 level-response-option version, the 
EQ-5D-5L, has been developed with the following response options:  no problems, slight 
problems, moderate problems, severe problems, and unable to/extreme problems.  It is believed 
that the EQ-5D-5L is superior to the EQ-5D-3L in terms of feasibility, ceiling effects, 
discriminatory power, and convergent validity.  The EQ-5D-5L index values will be calculated 
from the EQ-5D-5L descriptive system scores based on the Crosswalk value sets [Eligard, 2016; 
EuroQol Group, 1990; Brooks, 1996; Herdman, 2011; Janssen, 2013]. 
European Organisation for Research and Treatment of Cancer Assessments 
The EORTC-QLQ-C30 [Fayers, 2001; Fayers, 2002] (Appendix 3) and the 25-item prostate 
cancer module EORTC-QLQ-PR25 [Spry, 2006] (Appendix 4) will be administered as specified 
in the Schedule of Activities (see Section 1.1). 
The EORTC QLQ-C30 core measurement will be used to capture distal outcomes, including 
physical, social functioning, and overall health-related quality of life.  The QLQ-C30 core 
questionnaire incorporates 30 questions comprising 9 multi-item scales:  5 functional scales 
(physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea 
and vomiting); and a global health and quality of life scale.  Several single-item symptom 
measures are also included.  It is a reliable and valid measure of health-related quality of life in 
patients with cancer and takes about 11 minutes to administer.  The instrument has been 
validated and used in many countries [Aaronson, 1993]. 
The EORTC-QLQ-PR25 is the 25-item Prostate Cancer module (P25) of the EORTC.  The 
EORTC-QLQ-PR25 contains 3 additional symptom scales (urinary, bowel, sexual) and 
5 treatment-related items. 
6.6.2. 
Safety-Related Procedures 
6.6.2.1. 
Weight, Height, and Body Mass Index 
Height and weight will be measured during screening (within 28 days before the first dose of 
study drug).  Weight will be obtained at additional time points as specified in the Schedule of 
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Activities (see Section 1.1).  Patients should have weight and height measured while wearing 
indoor clothing and with shoes removed. 
6.6.2.2. 
Vital Signs 
Vital sign measurements include temperature, pulse rate, and seated measurement of diastolic 
and systolic blood pressure.  For each patient, temperature should be recorded using the same 
modality throughout the entire study.  Patients should be sitting at rest for 5 minutes before blood 
pressure is measured.  When vital sign measurements are scheduled at the same time as an ECG 
and blood draw, the vital signs, when possible, will be obtained immediately prior to the ECG 
and blood draw, and the blood draw will be collected at the scheduled time. 
6.6.2.3. 
Physical Exams and Visual Acuity 
A complete physical examination will include head, ears, eyes, nose, mouth, thyroid, skin, heart, 
and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.  All 
subsequent physical examinations should focus on signs and symptoms reported by the patient to 
assess for clinically significant changes from the baseline assessment.   
Visual acuity will be evaluated at Screening, Week 25, and Week 49 by a standard visual eye 
chart. Presenting visual acuity must be assessed with the supplied study eye chart.  If the patient 
uses corrective lenses, he should wear his usual prescription glasses or contact lenses during the 
assessment, and the same prescription lenses should be worn at subsequent visual testing, as 
possible.  Perform the visual acuity testing using the entire eye chart. Do not stop at a visual 
acuity of 100 – continue as far as the patient can go per the testing instructions (see the 
investigator site file for additional details). 
Patients whose presenting visual acuity score is 90 or lower at the screening visit should be 
encouraged to obtain a diagnostic evaluation from an eye care provider (ie, an ophthalmologist 
or an optometrist).  Any findings (ie, diagnoses) from the eye examination should be recorded as 
medical history.  
Patients whose presenting visual acuity score at Week 25, Week 49, or Early Termination has 
decreased by 10 or more points from the screening visit must be referred to an ophthalmologist 
for a diagnostic evaluation.  A copy of the ophthalmology consultation must be submitted to the 
sponsor. 
6.6.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the 
investigator site file and the protocol Schedule of Activities (see Section 1.1).  Laboratory 
requisition forms must be completed and samples must be clearly labelled with the patient ID 
number, protocol number, site/center number, and visit date.  Details for the preparation and 
shipment of samples will be provided.  Reference ranges for all safety parameters will be 
provided to the site by the central laboratory. 
The samples collected for clinical laboratory tests are listed in Table 6-1. 
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Table 6-1 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Metabolic Panel 
Hematocrit 
Hemoglobin 
Leukocytes with differential 
Neutrophils and absolute 
neutrophil count 
Platelet (count) 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bilirubin (total) 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Creatinine 
Chloride 
Serum gamma-glutamyl 
transferase 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Urate 
Total cholesterol 
High density lipoprotein 
cholesterol 
Low density lipoprotein 
cholesterol 
Triglycerides 
Hemoglobin A1c 
Endocrine Panel 
Diagnostic Screening 
(investigator’s discretion) 
 
Serum testosterone 
Serum LH 
Serum FSH 
Serum sex hormone binding 
globulin 
Hepatitis panel, according to 
CDC criteria 
 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating 
hormone; HBsAg, hepatitis B virus surface antigen; HCV, hepatitis C virus; LH, luteinizing hormone 
A separate sample will be collected at the Day 1 visit and will be banked and tested for presence 
of hepatitis A, B, and C (hepatitis A antibody, IgM, hepatitis B core antibody, IgM, hepatitis B 
surface antigen, and hepatitis C antibody) if requested by the medical monitor for evaluation of 
abnormal liver function tests. 
The central laboratory will perform laboratory tests for chemistry, hematology, and plasma and 
serum hormone levels. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal and clinically 
significant results should be reported as adverse events. 
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6.6.2.5. 
12-Lead Electrocardiograms 
A 12-lead ECG will be administered at the time points specified in the Schedule of Activities 
(Section 1.1).  When an ECG is scheduled at the same time as vital signs and a blood draw, the 
ECG, when possible, will be obtained after the vital signs and prior to the blood draw; the blood 
draw will be collected at the scheduled time.  ECGs will be read locally by a qualified physician. 
If patients have a prolonged QTcF (> 500 msec), as measured by Fridericia's formula 
[QTcF = QT/(RR^0.33)], in the absence of a pacemaker, the ECG should be repeated and 
confirmed.  Patients with a confirmed QTcF > 500 msec, in the absence of a pacemaker, as read 
by a cardiologist should be withdrawn.  All abnormal ECG findings must be documented by the 
investigator as clinically significant or not. 
6.6.2.6. 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient 30 days 
prior to the first dose of study drug until 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection will recorded in the eCRF (Exception: 
amiodarone will be reported if taken within 3 months prior to the first day of study drug).  See 
Section 5.10.1 for a list of medications and therapies that are prohibited and/or allowed during 
the study. 
6.6.2.7. 
Radiologic Assessment 
CT imaging or MRI of the abdominopelvic region with contrast (except where contrast is 
medically contraindicated) and a bone scan must be obtained prior to randomization for each 
patient to determine the presence or absence of metastatic disease (metastases in regional lymph 
node[s] are considered N1 and will, therefore, be stratified as non-metastatic).  The scans should 
be read locally and do not need to be repeated if a scan exists within 60 days prior to the Baseline 
Day 1 visit.  However, if CT or MRI demonstrates presence of metastatic disease, a bone scan is 
not required.  If metastatic disease is not present on CT or MRI, then a bone scan is also 
required. 
Radiologic assessment is not included as part of the Schedule of Activities after randomization. 
6.7. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.   
Exploratory testing for markers of cardiovascular disease, including tests such as plasma N-
terminal pro- brain natriuretic peptide (NT-proBNP) or markers for ischemia, may be 
conducted using stored samples from patients who provided consent for this testing, to 
explore whether there are differences in measures of cardiovascular function between patients 
treated with relugolix and patients treated with leuprolide, to inform future studies.   
Samples of 8 mL of whole blood for pharmacogenomics testing (see Section 6.6.1.3) will be 
collected.  The need to conduct pharmacogenomic analysis may be identified after this study 
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(or additional studies) has been completed.  For this reason, the collected samples will be 
retained for up to 10 years after the last patient completes the study.  A patient may request 
the destruction of his sample at any time.  The sponsor may destroy the samples sooner than 
10 years after the study completes. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations including visual 
acuity assessment, vital signs, weight, ECGs, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or duration 
of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate medical 
events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least one 
of the following criteria: 
o Induces clinical signs or symptoms; 
o Requires active intervention; or 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
o Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event; 
o The disease/disorder being studied, or expected progression; 
o Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; and 
o Situations where an untoward medical event has not occurred (eg, planned hospitalization 
for an elective procedure, with elective defined as known or planned at the time of 
signing of the informed consent). 
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Adverse events that occur during the study should be evaluated by the investigator and graded 
according to CTCAE (Appendix 5).  Episodic adverse events, such as vomiting, or those that 
occur repeatedly over a period of consecutive days are “intermittent”.  All other events are 
“continuous”.  Additional information on detecting, documenting, and reporting adverse events 
and serious adverse events are provided below.  No toxicity-related dose reductions of study 
drug are permitted; however, study drug can be held for a period of up to 10 days for evaluation 
and treatment of an adverse event.  The study drug may be restarted if deemed safe for the 
patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study patient was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.  For example, 
drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
c. 
Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere or prevent everyday 
life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
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7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local IRB/IEC. 
Care will be taken not to introduce bias when detecting adverse events and/or serious adverse 
events.  Open-ended and non-leading verbal questioning of the patient is the preferred method to 
inquire about adverse event occurrence.  Appropriate questions include: 
• “How are you feeling?”  
• “Have you had any (other) medical problems since your last visit/contact?” 
• “Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact? 
The patient’s answers to the EQ-5D-5L will not be used as a primary means to collect adverse 
events, however they should be reviewed by the study site personnel and the study monitors.  
Should the investigator or site staff become aware of a potential adverse event 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 adverse 
event not previously reported has been identified, normal reporting requirements should be 
applied. 
All patients who experience an adverse event will be evaluated at appropriate time intervals until 
the event resolves or has stabilized or become chronic.  At the conclusion of the study, the 
investigator and medical monitor will assess unresolved adverse events and determine if 
additional follow-up is warranted. 
All adverse events, whether or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
each sign and symptom as an individual adverse event. 
Overdose and pregnancy in a partner will be reported as described in Section 7.7 and Section 7.8, 
respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events will be collected from the time the first dose of study drug is administered until 
the Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
Serious adverse events will be collected from the signing of the informed consent form until the 
Safety Follow-up visit approximately 30 days after the last dose of relugolix or 12 weeks plus 
30 days after the last leuprolide acetate injection, or the date of initiation of another 
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investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  
Serious adverse events reported to the investigator after the safety reporting period should be 
reported to the sponsor if the investigator assesses the event as related to the study drug 
treatment. 
Any event occurring between signing of the informed consent form and the first dose of study 
drug will be recorded as medical history and in the patient’s clinical record for any patient who 
continues to meet eligibility criteria and proceeds to dosing with study drug; the exception to this 
includes procedure-related pretreatment-emergent events which should be recorded as adverse 
events in the electronic data capture (EDC) system for those patients who remain eligible for 
study participation. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
definitions in Table 7-1 are to be used for the relationship of the adverse event to study drug. 
Table 7-1 
Causal Relationship to Study Drug 
Relationship 
Criteria 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely attributed to concurrent disease 
or other drugs or chemicals, and that follows a clinically reasonable response on 
re-administration (re-challenge) or withdrawal (de-challenge). 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but that could also be explained by 
concurrent disease or other drugs or chemicals.  Information on drug withdrawal 
may be lacking or unclear. 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable 
and/or in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
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The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE (see Appendix 5).  For terms not specified with the CTCAE, the criteria 
in Table 7-2 should be used to determine the grade severity. 
Table 7-2 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
7.5. 
Adverse Events of Clinical Interest Reporting 
Adverse events of clinical interest in this study are defined as any increase in ALT or AST 
≥ 3 x ULN. 
Any ALT or AST elevation of this degree or greater occurring during the randomized Treatment 
Period or the Follow-up visit should be reported to the sponsor using the serious adverse event 
form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), even 
if the event does not meet serious adverse event criteria.  Additional instructions for evaluating 
patients with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized ratio 
(INR) >1.5 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
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Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1) AST or ALT increases to ≥ 3 x ULN; AND 
2) Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3) Alkaline phosphatase value does not reach 2 x ULN; AND 
4) No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease; 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus); 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms; 
• Alcoholic hepatitis; 
• Nonalcoholic steatohepatitis; or 
• Autoimmune hepatitis. 
If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
7.6. 
Serious Adverse Event Reporting 
Using a serious adverse event report form, all serious adverse events must be reported within 
24 hours of the study site personnel’s knowledge of the event, regardless of the investigator 
assessment of the relationship of the event to study drug.  Serious adverse events reported to the 
investigator after the safety reporting period should be reported to the sponsor if the investigator 
assesses the event as related to the study drug treatment. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose or pregnancy of partner is available on the serious adverse event 
report form and is as follows: 
Send completed Safety Report Forms to IQVIA (previously named QuintilesIMS; contact 
information as below and on the SAE Form): 
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Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary 
reporting method) 
All Regions 
 
  
 
For questions on Serious Adverse Event (SAE)/Adverse Event of Clinical Interest or 
events of overdose reporting, please call: 
• 
North/South America: 
  
• 
Regional toll-free phone and fax lines distributed separately.  Please refer to the 
investigator site file. 
The initial report should include: 
• Study number (MVT-601-3201); 
• Site address and number; 
• Investigator name; 
• Patient ID number, sex, and age; 
• Details of study drug administration; 
• The date of the report; 
• A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); and 
• Causal relationship to the study drug. 
If the patient died, the report should include the cause of death and whether or not the cause of 
death was related to study drug, as well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 240 mg within a 24-hour window is an overdose, except 
for the 360-mg loading dose.  The sponsor does not recommend specific treatment for an 
overdose; supportive treatment should be provided as clinically applicable. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
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• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form, whether or not the overdose is associated with an 
adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); and 
• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If the partner of any patient becomes pregnant during the study or through 4 months after the last 
dose of study drug, the investigator must inform the sponsor of the pregnancy. 
The patient should remain on study drug treatment, unless otherwise indicated. 
If the patient agrees, the patient’s pregnant partner should be notified and requested to sign a 
Release of Information form, permitting transfer of information regarding the pregnancy and 
outcome to the sponsor. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the partner pregnancy report forms.  The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated conception date, pregnancy result, 
and neonatal data, etc, should be included in this information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
Benefit/Risk Assessment 
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategies for this protocol are outlined in Table 7-3. 
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Table 7-3 
Relugolix Potential Risks and Mitigation 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Hepatic Enzyme Increases 
Isolated increases in hepatic enzymes have been 
observed in prior clinical studies.  Hepatic enzyme 
increases, considered an important potential risk of 
treatment with relugolix, are closely monitored in 
accordance with FDA guidelines for assessing drug-
induced liver injury [FDA, 2009] in all relugolix 
studies. 
Exclusion criteria for 
AST and ALT > ULN; 
total bilirubin values > 
ULN unless consistent 
with Gilbert’s 
syndrome. 
Liver chemistry will be 
monitored during the 
study.  Appropriate 
liver stopping criteria 
and follow-up 
procedures are detailed 
in Section 7.5.2. 
Phospholipidosis 
Data from nonclinical studies in rats and monkeys 
showed histopathological changes consistent with 
PLD.  PLD by itself is not adverse.  No clinical 
evidence of relugolix-related PLD-associated toxicity 
has been observed nor was there a clinically 
meaningful increase in a biomarker of PLD assessed 
in phase 2 clinical studies. 
Patients with 
significant underlying 
medical conditions are 
excluded. 
Routine safety 
monitoring including 
laboratory assessments, 
ECGs, and assessment 
of adverse events; visual 
acuity will be evaluated 
during the study. 
Risks Associated with Medical Castration 
Acute and subsequent chronic symptoms of medical 
castration (reduction of testosterone to ≤ 50 ng/dL 
[1.7 nmol/L]) include vasomotor symptoms or hot 
flushes, disturbed sleep related to vasomotor 
symptoms, decreased libido, and fatigue or loss of 
energy.  These side effects are usually not severe and 
can be managed with anticipatory guidance. 
Long-term suppression of testosterone is associated 
with well-characterized risks including bone loss, 
decreased muscle mass, possible changes in insulin 
sensitivity with increased risk of diabetes, altered 
lipid metabolism, and possible increased risk of 
cardiovascular disease [Oefelein, 2002; Lopez, 
2005; Diamond,1998; Keating, 2006; Braga-
Basaria, 2006; Saigal, 2007; Tsai, 2007; D'Amico, 
2007; Efstathiou, 2009]. 
- 
Effects can usually be 
managed with 
appropriate 
anticipatory guidance 
(eg, diet and exercise 
programs) or 
supportive therapy 
when required (eg, 
lipid-lowering or bone-
sparing agents). 
Metabolic Changes 
Metabolic changes (insulin resistance, dyslipidemia, 
and increased weight) with increased risk of diabetes 
are a potential risk of the hypoestrogenic state 
induced by relugolix. 
- 
Fasting lipids and 
glucose will be 
monitored during the 
study. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Stopping Criteria 
Loss of Bone Mineral Density 
Loss of bone mineral density is considered a potential 
risk of treatment with relugolix in the prostate cancer 
indication. 
- 
Fractures will be 
assessed through 
adverse event 
monitoring.  Use of 
anti-resorptive bone 
therapy, such as 
bisphosphonates or 
denosumab, may be 
considered by the 
treating physician.  
Abbreviations:  ALT; alanine aminotransferase; AST, aspartate aminotransferase; ECG, electrocardiogram; FDA, 
Food and Drug Administration; PLD, phospholipidoses; ULN, upper limit of normal 
8. 
DATA QUALITY ASSURANCE 
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the 
investigator site file with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice regulations.  By signing this protocol, the investigator grants permission to 
Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-site 
monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and Good Clinical Practices.  The study monitor 
should have access to laboratory test results and any other source records and data needed to 
verify the entries on the eCRF.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved.  For this 
study, patient data will be entered into a sponsor-approved electronic database and combined 
with data provided from other sources in validated datasets then transmitted electronically to the 
sponsor (or designee). 
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Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
8.3. 
Independent Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board will review available safety data, as 
appropriate, on a periodic basis throughout the conduct of the study.  Details of the Data and 
Safety Monitoring Board will be captured in a charter prior to the start of the study. 
8.4. 
Steering Committee 
A Steering Committee consisting of experts in the field of prostate cancer and staff members of 
Myovant Sciences GmbH will be established to provide oversight for the clinical trial, study 
design, study conduct, data analysis, and presentation and publication of the study data.  Details 
of the Steering Committee responsibilities will be captured in a separate charter. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan will describe the detailed statistical methods and analyses for this 
study.  The statistical analysis plan will be prepared and finalized before database lock for the 
primary analysis. 
There will be two analyses for the study, a primary analysis and a final analysis.  The primary 
analysis of efficacy and safety will occur after approximately the first 915 patients have been 
randomized to the study and have had the opportunity to be evaluated for 48 weeks and complete 
the 30-day safety follow-up visit or discontinued early. 
The secondary analysis will occur after approximately 390 metastatic patients have been to the 
study and have had the opportunity to be evaluated for 48 weeks of study treatment and complete 
the 30-day safety follow-up visit. 
TCR in the subgroup of metastatic patients and the extended ITT population will be analyzed 
only at the time of the final analysis. 
All confidence intervals will be 2-sided at an alpha level of 0.05 unless otherwise specified.  The 
methodology to be used to maintain a study-wide type I error rate of 0.05 across primary and 
secondary endpoint testing will be described in the statistical analysis plan. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
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9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 2:1, relugolix to leuprolide 
acetate 3-M depot.  Randomization will be stratified by the following factors: 
• Geographic Region:  North and South America versus Europe versus Asia and Rest of 
World; 
• Presence of Metastatic Disease (metastases in regional lymph node[s] are considered N1 
and will, therefore, be stratified as non-metastatic):  yes versus no; 
• Baseline Age:  ≤ 75 years old versus > 75 years old. 
Stratified efficacy analyses will incorporate these 3 stratification factors unless otherwise 
specified. 
After the first 915 patients are enrolled, enrollment in China will continue for metastatic and 
non-metastatic patients until the target number of Chinese patients is reached (138 patients).  In 
the rest of the world, only metastatic patients will continue to be enrolled until approximately 
390 metastatic patients are accrued. 
9.2. 
Analysis Populations 
The Intent-To-Treat (ITT) population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis.  Patients will be analyzed according to their randomized treatment assignment. 
The Per-Protocol population will consist of those members of the ITT population who have no 
major protocol deviations as defined in the statistical analysis plan, considering the following 
protocol deviations but not limited to: 
• Those who entered the study even though they did not satisfy the entry criteria; 
• Those who developed withdrawal criteria during the study but were not withdrawn; 
• Those who received the wrong treatment or incorrect dose; 
• Those who received an excluded concomitant treatment. 
The Per-Protocol population will not be analyzed if this population comprises more than 95% or 
less than 50% of the ITT population.  The Per-Protocol population will be used as a sensitivity 
analysis of the ITT population for the primary efficacy endpoint and secondary endpoints.  The 
Per-Protocol population will be identified prior to the database lock. 
The primary population for safety analyses will be the Safety population, defined as all patients 
who receive at least one dose of any study treatment.  Patients will be analyzed according to the 
treatment actually received, regardless of their randomized treatment assignment. 
 
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9.3. 
Efficacy Analyses 
9.3.1. 
Primary Endpoint Analyses 
The primary endpoint will be analyzed in the initial 915 patients enrolled to the study.  The 
primary efficacy endpoint is the sustained castration rate, defined as the cumulative probability 
of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 
Day 1 (Study Day 29) through Week 49 (Study Day 337).  This probability will be estimated for 
each treatment group using the Kaplan-Meier method with the confidence interval calculated 
using the exponential Greenwood formula via log-log transformation of the survival function.  
Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL 
(1.7 nmol/L) will be censored at the last testosterone assessment prior to discontinuation.  
Detailed censoring rules will be described in the statistical analysis plan. 
There are 2 separate evaluation criteria for the primary efficacy endpoint to support different 
regulatory requirements for assessing benefit: 
• Evaluation Criterion 1:  to determine whether the sustained castration rate for relugolix is 
greater than or equal to 90%.  The lower bound of the 95% confidence interval for the 
cumulative probability of sustained testosterone suppression in the relugolix treatment 
group will be calculated and must be greater than or equal to 90% to meet this criterion. 
• Evaluation Criterion 2:  to establish the non-inferiority of relugolix compared to 
leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained 
testosterone suppression.  The lower bound of the 95% confidence interval for the 
difference in the cumulative probability of sustained testosterone suppression between the 
2 treatment groups will be calculated and must be greater than or equal to the non-
inferiority margin of -10% to meet this criterion.  The confidence interval of the 
treatment difference will be calculated using the formula 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡) −𝑆𝑆2෡(𝑡𝑡)൧= 𝑉𝑉෠ൣ𝑆𝑆1෡(𝑡𝑡)൧+
𝑉𝑉෠ൣ𝑆𝑆2෡(𝑡𝑡)൧ , where each of the variance of the Kaplan-Meier estimate will be calculated 
using the Greenwood's formula 𝑉𝑉෠ൣ𝑆𝑆̂(𝑡𝑡)൧= 𝑆𝑆̂(𝑡𝑡)2 ൤∑
𝑑𝑑𝑗𝑗
𝑛𝑛𝑗𝑗൫𝑛𝑛𝑗𝑗−𝑑𝑑𝑗𝑗൯
𝑗𝑗:𝑡𝑡(𝑗𝑗)≤𝑡𝑡
൨ ; nj denote the 
number of patients at risk at time t(j) and dj denote the number of events observed at time 
t(j)) [Lachin, 2000]. 
The evaluation criteria used for the primary efficacy endpoint assessment will be determined by 
regional regulatory requirements and will be prespecified in separate regional statistical analysis 
plans.  The 2-sided type I error rates for the final analyses will be controlled at 0.05 separately 
for each regional analysis. 
9.3.2. 
Secondary Endpoint Analyses 
If the result of the primary endpoint is statistically significant, the secondary endpoints will be 
analyzed.  The methods and procedures necessary to maintain a study-wide 2-sided type I error 
rate of 0.05 across primary and secondary endpoint testing will be described in the statistical 
analysis plan. 
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• Castration rate defined as the cumulative probability of testosterone suppression to 
≤ 50 ng/dL (1.7 nmol/L) prior to dosing at Week 1 Day 4, and prior to dosing at Week 3 
Day 1 will be summarized by treatment group using the Kaplan-Meier method; 
• Profound castration rate defined as the cumulative probability of testosterone suppression 
of ≤ 20 ng/dL (0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 
Day 1 will be estimated for each treatment group using the Kaplan-Meier method.  The 
difference in the cumulative probabilities between the relugolix group and the leuprolide 
acetate group will be provided, along with the 95% confidence interval calculated in the 
same manner as in the primary analysis of the primary endpoint; 
• PSA response and percent change from baseline in PSA at Week 3 and Week 5 will be 
summarized and compared between the relugolix group and the leuprolide acetate group; 
• Proportions of patients who have a PSA concentration < 0.2 ng/mL (0.2 µg/L) at 
Week 25 will be summarized by treatment group.  The proportions will be compared 
between the relugolix group and the leuprolide acetate group by constructing a 
95% confidence interval for the difference in proportions; 
• Time to testosterone recovery in approximately 100 patients randomized to relugolix and 
approximately 50 patients randomized to leuprolide acetate who complete 48 weeks of 
treatment and who do not start alternative androgen deprivation therapy within the 
following 12 weeks (or within 24 weeks following the last received leuprolide acetate 
3-M depot injection) will be compared between the relugolix group and the leuprolide 
acetate group; 
• Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 global 
health domain and the EORTC-QLQ-PR25 sexual activity and hormonal-treatment-
related symptom subdomains will be summarized by treatment group.  The least square 
means at Week 49 will be compared between the relugolix group and the leuprolide 
acetate group by constructing a 95% confidence interval for the difference in the least 
square means using a mixed model for repeated measures; 
• Absolute values and changes from baseline of the remaining domains in the EORTC 
QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L will be summarized by 
treatment group.  The least square means at Week 49 will be compared between the 
relugolix group and the leuprolide acetate group by constructing a 95% confidence 
interval for the difference in the least square means using a mixed model for repeated 
measures; 
• Time to PSA progression; 
o PSA progression is defined per Prostate Cancer Clinical Trials Working Group 3 
guidelines [Scher, 2016] as the first increase in PSA of 25% or greater and 
2 ng/mL or greater above the nadir with confirmation by a second PSA 
measurement at least 3 weeks later.  For patients without declining PSA from 
baseline, PSA increase of 25% or greater and 2 ng/mL from baseline beyond 
12 weeks will be considered PSA progression 
 
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• TCR in the subgroup of metastatic patients and the extended ITT population will only be 
evaluated at the time of final analysis, when approximately 390 metastatic patients have 
been randomized to the study and have had the opportunity to be evaluated for 48 weeks 
of study treatment and complete the 30-day safety follow-up visit or discontinued early.  
TCR will be evaluated first in the subgroup of metastatic patients at a two-sided 
significance level of 0.05. TCR in the extended ITT population will be tested only if the 
two-sided p-value in the subset of metastatic patients is < 0.05. 
o TCR is defined as the time from the date of first dose to the date of PSA 
progression while castrated or death due to any reason, whichever occurs earlier.  
TCR will be analyzed using the Kaplan-Meier method.  Treatment comparison 
with hazard ratios will be performed using Cox proportional hazards model. 
Additional details of the secondary analyses will be described in the statistical analysis plan. 
9.4. 
Safety Analyses 
The safety analyses will be based on the Safety population.  Safety will be assessed by 
summarizing and analyzing adverse events, laboratory analytes, vital signs, ECG parameters, and 
concomitant medications. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute’s CTCAE.  All adverse events will be coded to preferred term and system organ 
class using MedDRA 19.1 or higher.  The incidence of adverse events will be presented by 
MedDRA system organ class and preferred term, relationship to study drug treatment, and 
severity.  A patient reporting the same adverse event more than once is counted once, and at the 
maximum severity or strongest relationship to study drug treatment when calculating incidence. 
Laboratory data consist of chemistry, hematology, and hormonal tests.  Only data collected by 
the central laboratory will be used for analyses.  The National Cancer Institute CTCAE will be 
used to categorize toxicity grade for the laboratory parameters.  Shift tables will be provided for 
each gradable parameter to summarize baseline toxicity grade versus post-baseline toxicity 
grade.  For laboratory parameters that are not gradable by the CTCAE, a shift table based upon 
the normal range (low, normal, and high) will be provided for each parameter to summarize the 
baseline versus post-baseline results. 
9.5. 
Pharmacokinetic Analyses 
Plasma relugolix concentrations will be listed and summarized and included in the clinical study 
report. 
PK data may be pooled with data from other studies in healthy male patients and patients with 
prostate cancer for population PK analysis, including evaluation of covariates of relugolix PK 
parameters, and for input into a population PK/pharmacodynamics models describing the 
relationship between relugolix exposure and serum testosterone [Ahsman, 2016].  These 
population PK analyses will be detailed further in a separate statistical analysis plan and report. 
For patients from China and Japan in the PK subset, plasma relugolix PK parameters Cmax, 
AUC0-τ, and tmax from Day 1 and Day 14 of dosing will be determined.  Population PK or 
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PK/pharmacodynamic analyses may be conducted to explore the factors that affect relugolix 
exposure or to contribute to the assessment of the relationships between exposure and 
testosterone. 
9.6. 
Endocrine Marker Analyses 
Endocrine markers will be analyzed to see effects of relugolix and leuprolide acetate as measured 
as absolute value and change from baseline for: 
• LH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
• FSH at Day 4, Week 5, Week 25, and Week 49 visits and/or follow-up visit(s); 
• Dihydrotestosterone at Week 5, Week 25, and Week 49 visits and/or follow-up visit(s);  
• Sex hormone binding globulin at Week 5, Week 25, and Week 49 visits and/or follow-up 
visit(s). 
9.7. 
Exploratory Analyses 
Overall survival:  Overall survival defined as time from randomization to date of death prior to 
data cutoff date.  Kaplan-Meier methods will be used to describe survival distributions for each 
treatment arm. 
Pharmacogenomic analyses may be conducted to examine the contribution of genetic variance on 
drug response, for example, its efficacy and safety, pending availability of samples.  
Polymorphisms in germline genes related to the hypothalamic-pituitary-androgen pathway, 
prostate cancer risk, or to drug metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix.  These analyses will be 
detailed in a separate statistical analysis plan and associated reports. 
9.8. 
Interim Analyses 
There will be no planned interim efficacy analysis for the study. 
9.9. 
Sample Size 
To calculate the sample size required for the primary efficacy endpoint of this study, the 
following assumptions have been made: 
• True probabilities of sustained testosterone suppression are 94% and 96% for relugolix 
and leuprolide acetate, respectively; 
• 2:1 randomization ratio (relugolix:leuprolide acetate); and 
• Dropout rate of 15%. 
The assumed probability of sustained testosterone suppression for relugolix arm is 94%.  It was 
estimated based on the predicted dose-response relationship for the effect of relugolix on 
testosterone suppression in patients with prostate cancer (data from phase 2 studies C27002 and 
C27003).  The assumed castration rate of 96% for leuprolide acetate was based on the results 
from degarelix phase 3 registration program [Shore, 2013]. 
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For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of < 90% at a 
two-sided type I error rate of 0.05. 
For Evaluation Criterion 2, with the non-inferiority margin of -10% and an overall 2-sided type I 
error rate of 0.05, a total of approximately 915 patients (610 relugolix, 305 leuprolide acetate) 
will yield at least 99% power in declaring the non-inferiority of relugolix compared to leuprolide 
acetate. 
The primary analysis will be performed separately for individual evaluation criterion using data 
collected through 48 weeks after enrollment of approximately 915 patients. 
Approximately 915 patients will be randomized in order to fulfill the regulatory requirements of 
all participating countries included in the primary efficacy endpoint of this study. 
The study is also powered for the secondary endpoint of TCR in the high-risk subgroup of 
metastatic patients.  Approximately 107 confirmed castration-resistance events (PSA 
progressions while castrated or deaths due to any cause) will need to be observed (or 
approximately 390 metastatic patients will need to be enrolled) to detect a hazard ratio of 0.55 
(relugolix versus leuprolide acetate) with 85% power with a two-sided type I error of 5%, 
assuming a castration-resistant event-free rate of 60% at 48 weeks for the control arm, an 
18-month enrollment period, 12 months of additional follow-up, and a 15% dropout rate. 
With a total of approximately 1100 patients (metastatic or non-metastatic) randomized into the 
study including approximately 138 Chinese patients, it is anticipated to observe approximately 
149 confirmed castration-resistant events (PSA progression while castrated or deaths due to any 
cause).  Assuming an 18-month enrollment period, 12 months of additional follow-up, and a 
10% dropout rate the study will provide approximately 85% power to detect a hazard ratio of 0.6 
(relugolix versus leuprolide acetate) with a two-sided type I error of 5%. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Council on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR) Part 312, subpart D, “Responsibilities of 
sponsors and investigators,” 21 CFR Part 50, and 21 CFR Part 56, are adhered to.  These 
standards are consistent with the requirements of the European Community Directive 
2001/20/EC. 
Since this is a “covered” clinical study, the investigator will ensure that 21 CFR Part 54, is 
adhered to; a “covered” clinical study is any “study of a drug or device in humans submitted in a 
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marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied.  This 
documentation must be provided before participation of the investigator and any sub-
investigator.  The investigator and sub-investigator agree to notify the sponsor of any change in 
reportable interests during the study and for one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
A properly executed, written informed consent, in compliance with the Declaration of Helsinki, 
ICH Good Clinical Practice, US CFR for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27), and local regulations, will be obtained from each patient before entering the patient 
in the trial.  The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
The investigator will provide copies of the signed informed consent form to each patient (or to 
the patient’s legal representatives) and will maintain the signed original document within the 
patient’s record file per local requirements.  The investigator will also fully document the 
informed consent process in the patient’s source records. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
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showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the Investigator Brochure, protocol, eCRFs and other study forms, the investigational drug, 
and any other study information, remain the sole and exclusive property of the sponsor during 
the conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following 2 categories: 
1) Investigator’s study file:  The investigator’s study file will contain the Investigator Brochure, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents:  The required source data should include the following for 
each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and causality 
and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, US, Europe, or Japan) and until 
there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the sponsor.  The investigator must notify the sponsor 
before destroying any clinical study records. 
Clinical study documentation includes the Investigator Brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
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study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, curriculum vitae and all training records of study 
site personnel, and all correspondence pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
10.1.5. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on the 1572 form and/or other appropriate local health 
authority documents within a reasonable time period after data collection.  This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
Screening Period if an eCRF was initiated).  If a patient withdraws from the study, the reason 
must be noted on the eCRF.  If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.6. 
Investigational Product Accountability 
The investigator or investigator’s designee (ie, pharmacist) is responsible for ensuring adequate 
accountability including dates and lot numbers of all study drug.  This includes acknowledgment 
of receipt of each shipment of study product (quantity and condition), patient dispensing records, 
and returned or destroyed study product.  Dispensing records will document quantities received 
from the sponsor and quantities dispensed to patients, including lot number, date dispensed, 
patient ID number, and the initials of the person dispensing the medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements.  Drug may be returned or destroyed on an ongoing basis during the study 
if appropriate.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet the sponsor’s 
requirements for disposal, arrangements will be made between the site and the sponsor (or 
designee) for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
All records must be made available to the sponsor, authorized representatives, and appropriate 
regulatory agencies, upon request. 
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Current ICH Good Clinical Practice guidelines require the investigator to ensure that study drug 
deliveries from the sponsor are received by a responsible person (eg, pharmacist), and the 
following: 
• That such deliveries are recorded, for example, on the sponsor-approved drug 
accountability log, or other sponsor-approved pharmacy log; 
• That study drug is handled and stored safely and properly in accordance with the study 
protocol; 
• That study drug is only dispensed to study patients in accordance with the protocol; 
• That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be documented.  
The following guidelines are therefore pertinent: 
• The investigator agrees not to supply study drug to any persons except the patients in this 
study; 
• The investigator/pharmacist will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs; 
• The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which patient; 
• The investigator/pharmacist agrees to conduct a final drug supply inventory on the drug 
accountability record at the conclusion or termination of the study.  It must be possible to 
reconcile delivery records with those of used and returned study drug.  Any discrepancies 
must be accounted for.  Appropriate forms of deliveries must be signed by the person 
responsible; 
• Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative.  Unused study drug 
not destroyed at the site must be returned to the sponsor-designated facility at the end of 
the study or upon expiration. 
10.1.7. 
Inspections 
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of the 
audit is to ensure that the study is (or was) conducted and monitored in compliance with the 
protocol as well as recognized Good Clinical Practice guidelines and regulations.  These audits 
will also increase the likelihood that the study data and all other study documentation can 
withstand a regulatory authority inspection.  If such audits are to occur, they will be arranged for 
a reasonable and agreed time.  By signing this protocol, the investigator grants permission to the 
sponsor or designee to conduct onsite audits of all appropriate facilities and study 
documentation. 
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The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the sponsor or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 
10.1.8. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
(eg, http://www.clinicaltrials.gov) before enrollment of patients begins.  Results will be posted as 
required. 
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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct 
access to the investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  When the sponsor is aware of 
information on matters concerning the quality, efficacy, and safety of the study drugs, as well as 
other important information that may affect proper conduct of the clinical study, the sponsor may 
terminate the study and send a written notice of the termination along with the reasons to the 
investigator.  Should this be necessary, the sponsor will arrange discontinuation procedures and 
notify the appropriate regulatory authority(ies) and IRBs/IECs.  In terminating the study, the 
sponsor and the investigator will assure that adequate consideration is given to the protection of 
the study participants’ interests. 
If the investigator intends to terminate participation in the study, the investigator must 
immediately inform the sponsor and provide the reason to it. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
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The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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APPENDICES 
Appendix 1. 
Eastern Cooperative Oncology Group Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined 
to bed or chair. 
5 
Dead 
Note:  Adapted from Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. 
 
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Appendix 2. EuroQol EQ-5D-5L Questionnaire 
 
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Appendix 3. Quality of Life Questionnaire:  EORTC QLQ-C30 
 
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Appendix 4. Quality of Life Questionnaire:  EORTC QLQ-PR25 
 
 
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Appendix 5. 
Adverse Event Severity Grading 
When assessing adverse events, refer to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03, June 14, 2010 (available at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).  A 
copy of the National Cancer Institute CTCAE table will be provided in the investigator site file. 
The National Cancer Institute CTCAE is a descriptive terminology that can be utilized for 
adverse event reporting.  A grading (severity) scale is provided for each adverse event term. 
Components and Organization of the National Cancer Institute CTCAE 
• System Organ Class (SOC).  SOC, the highest level of the Medical Dictionary for 
Regulatory Activities (MedDRA) hierarchy, is identified by anatomical or physiological 
system, etiology, or purpose (eg, SOC Investigations for laboratory test results).  CTCAE 
terms are grouped by MedDRA Primary SOCs.  Within each SOC, adverse events are 
listed and accompanied by descriptions of severity (grade). 
• CTAE Terms.  Each CTCAE term is a MedDRA LLT (Lowest Level Term). 
• Definitions.  A brief definition is provided to clarify the meaning of each adverse event 
term. 
• Grades.  Grade refers to the severity of the adverse event.  The CTCAE displays grades 1 
through 5 with unique clinical descriptions of severity for each adverse event based on 
this general guideline: 
o Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
o Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living; 
o Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living; 
o Grade 4 Life-threatening consequences; urgent intervention indicated; and 
o Grade 5 Death related to adverse event. 
A semi-colon indicates “or” within the description of the grade.  A single dash (-) 
indicates a grade is not available.  Not all grades are appropriate for all adverse 
events.  Therefore, some adverse events are listed with fewer than 5 options for 
grade selection. 
• Grade 5.  Grade 5 (Death) is not appropriate for some adverse events and therefore is not 
an option. 
 
 
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Appendix 6. 
Guidelines for Elevations in Hepatic Enzymes 
Study drug treatment should be withheld for any liver test abnormality listed in Section 7.5.1, 
pending investigation of alternative causes of liver injury.  Follow-up should continue until the 
liver test abnormalities resolve to baseline. For this purpose, local labs can be used. However, 
duplicate samples should be taken for central analysis. 
 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations 
in Appendix Table 2.  If close monitoring is not possible, study drug should be withheld, even if 
the results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoring of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, 
ALT, Bilirubin [Total and Direct]), 
Alkaline Phosphatase, and INR Testsa,b 
If AST or ALT ≥ 3 x ULN and total bilirubin 
> 2 x ULN or INR > 1.5 
Every 24 hours until laboratory 
abnormalities improve 
If ALT or AST ≥ 3 x ULN and total bilirubin 
and INR are normal 
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized 
ratio; ULN, upper limit of normal 
a. 
Review frequency of monitoring with medical monitor for an individual patient, in case of questions 
b. Local labs can be used. However, duplicate samples should be taken for central analysis. 
 
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Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
• 
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or 
coworkers, etc) and/or industrial chemical agents; 
• 
Prior and concurrent use of alcohol, recreational drugs, and special diets; 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants and mushrooms; 
• 
Physical examination. 
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
• 
Repeat liver tests as per Appendix Table 1a; 
• 
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat 
liver tests; 
• 
Complete blood count with differential to assess for eosinophilia; 
• 
Serum acetaminophen (paracetamol) concentration; 
• 
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus; 
• 
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune 
hepatitis, etc; 
• 
Serology for celiac disease; 
• 
Appropriate liver imaging; and 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
Abbreviations:  INR, international normalized ratio 
a. 
If the first follow-up testing does not confirm the initial abnormal liver test results, review any additional 
follow-up monitoring with the medical monitor. 
 
Clinical Study Report
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SAP_000.pdf: 
 
 Study Title:  
HERO: A Multinational Phase 3 Randomized, Open-
Label, Parallel Group Study to Evaluate the Safety and 
Efficacy of Relugolix in Men with Advanced Prostate 
Cancer  
 
 
NCT Number:  
03085095 
 
Document Date: 
Statistical Analysis Plan V3.0 / 07 November 2019 
  
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
 
Study Title: 
HERO:  A Multinational Phase 3 Randomized, Open-Label, 
Parallel Group Study to Evaluate the Safety and Efficacy of 
Relugolix in Men with Advanced Prostate Cancer 
 
 
 
Investigational 
Product: 
 
Relugolix 
Protocol Number: 
MVT-601-3201 
 
Indication: 
Advanced Prostate Cancer 
 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel Switzerland 
 
IND No.: 
118736 
 
Version/Effective Date: 
V1.0 / 12 September 2019 
V2.0 / 29 October 2019 
V3.0 / 07 November 2019 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property or under control of Myovant Sciences 
GmbH and cannot be disclosed without written authorization from Myovant Sciences GmbH. 
 
 
 




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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL SHEET ............................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Study Objectives and Endpoints ...................................................................................8 
2. 
STUDY DESIGN .......................................................................................................14 
2.1. 
Summary .....................................................................................................................14 
2.2. 
Sample Size Justification ............................................................................................15 
3. 
PLANNED ANALYSES ............................................................................................17 
3.1. 
Interim Analysis ..........................................................................................................17 
3.2. 
Primary Analysis ........................................................................................................17 
3.3. 
Final Analysis .............................................................................................................17 
3.4. 
Other Analyses ............................................................................................................17 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA ............................................................................18 
4.1. 
Data Presentation Conventions ...................................................................................18 
4.2. 
Analysis Populations ..................................................................................................19 
4.2.1. 
Modified Intent-to-Treat Population ...........................................................................19 
4.2.2. 
Per-Protocol Population ..............................................................................................19 
4.2.3. 
Safety Population ........................................................................................................19 
4.3. 
Definitions, Computations, and Conventions .............................................................19 
4.3.1. 
Date of First Dose and Date of Last Dose of Study Drug ..........................................19 
4.3.2. 
Treatment Day ............................................................................................................20 
4.3.3. 
Treatment Period ........................................................................................................20 
4.3.4. 
Treatment Duration .....................................................................................................20 
4.3.5. 
Baseline Value and Postbaseline Value ......................................................................20 
4.3.6. 
Visit Windows ............................................................................................................20 
4.4. 
General Rules for Missing Data .................................................................................23 
4.4.1. 
By -Visit Endpoints ....................................................................................................23 
4.4.2. 
Adverse Events ...........................................................................................................23 
4.4.3. 
Concomitant Medications ...........................................................................................24 


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5. 
PATIENT POPULATION ..........................................................................................25 
5.1. 
Patient Disposition ......................................................................................................25 
5.2. 
Screen Failure .............................................................................................................25 
5.3. 
Protocol Deviations ....................................................................................................25 
5.4. 
Demographics and Baseline Characteristics ...............................................................26 
5.5. 
Medical History ..........................................................................................................26 
5.6. 
Prior and Concomitant Medications ...........................................................................26 
5.7. 
Prior and Current Procedures......................................................................................26 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................27 
7. 
EFFICACY ANALYSES ...........................................................................................29 
7.1. 
General Considerations ...............................................................................................29 
7.2. 
Multiplicity Adjustment..............................................................................................29 
7.3. 
Primary Efficacy Endpoint .........................................................................................29 
7.3.1. 
Primary Efficacy Analyses .........................................................................................30 
7.3.2. 
Sensitivity Analyses ....................................................................................................32 
7.3.3. 
Subgroup Analyses .....................................................................................................33 
7.4. 
Secondary Efficacy Endpoints ....................................................................................34 
7.4.1. 
Key Secondary Efficacy Endpoints with Alpha-Protection .......................................34 
7.4.2. 
Other Secondary Efficacy Endpoints ..........................................................................37 
7.4.3. 
Analyses of Secondary Efficacy Endpoints ................................................................37 
7.5. 
Exploratory Efficacy Endpoints and Analyses ...........................................................42 
7.5.1. 
Overall Survival ..........................................................................................................42 
7.5.2. 
Pharmacogenomics Analyses .....................................................................................42 
7.6. 
Patient Reported Outcomes ........................................................................................42 
7.6.1. 
EORTC QLQ-C30 and QLQ-PR25 ............................................................................42 
7.6.2. 
EuroQoL EQ-5D-5L ...................................................................................................44 
8. 
PHARMACODYNAMIC ANALYSES .....................................................................45 
9. 
PHARMACOKINETIC ANALYSES ........................................................................46 
10. 
SAFETY ANALYSES ...............................................................................................47 
10.1. 
Adverse Events ...........................................................................................................47 
10.2. 
Laboratory Data ..........................................................................................................49 
10.3. 
Other Safety Analyses ................................................................................................50 
10.3.1. 
Electrocardiograms .....................................................................................................50 


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10.3.2. 
Visual Acuity ..............................................................................................................50 
10.3.3. 
Vital Signs ..................................................................................................................50 
REFERENCES ..............................................................................................................................52 
REVISION HISTORY...................................................................................................................53 
APPENDIX 1:  LIST OF MEDICATIONS THAT HAVE IMPACT ON 
TESTOSTERONE OR PROSTATE-SPECIFIC ANTIGEN LEVEL .......................54 
APPENDIX 2:  LIST OF PRE-DEFINED THRESHOLD IN SELECTED CHEMISTRY 
AND HEMATOLOGY TEST RESULTS ..................................................................56 
 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints ...................................................................................9 
Table 2: 
Visit Windows ............................................................................................................22 
Table 3: 
Visit Windows for Assessments in Quality of Life ....................................................23 
Table 4: 
Testing Order and Timing of Analysis for Primary and Key Secondary 
Endpoints for Different Regulatory Agencies ............................................................36 
Table 5: 
Visit Windows in the First 4 Weeks under Original Protocol ....................................38 
Table 6:   Scoring Procedure .......................................................................................................42 
Table 7:   Constitution of Adverse Event Categories .................................................................48 
Table 8:   Categories of Liver Function Test Elevations ............................................................50 
Table 9:   Categories of Potentially Clinically Significant Abnormalities in Vital Signs ..........51 
Table 10:   Revision History .........................................................................................................53 
 
 
 
LIST OF FIGURES 
Figure 1: 
Schematic of Study Design .........................................................................................15 
Figure 2: 
Diagram of Testing Order in Primary and Key Secondary Endpoints for 
Different Regulatory Agencies ...................................................................................35 
 


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LIST OF ABBREVIATIONS 
Term 
Definition 
3-M 
3-month 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-τ 
area under the curve from time 0 to the end of the dosing interval 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CRFS 
castration resistance free survival 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
data and safety monitoring board 
ECOG 
Eastern Cooperative Oncology Group 
eDISH 
evaluation of drug induced serious hepatotoxicity  
EMA 
European Medicines Agency 
EORTC 
European Organisation of Research and Treatment of Cancer 
EOT 
end-of-treatment 
EuroQol EQ-5D-5L European Quality of Life 5-Dimension 5-Level Questionnaire 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
ICF 
informed consent form   
IWRS 
interactive web response systems  
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat (Population) 
NCI CTCAE 
National Cancer Institute’s Common Terminology Criteria for Adverse 
Events 
PD 
pharmacodynamic 
PMDA 
Japanese Pharmaceutical and Medical Device Agency 
PK 
pharmacokinetics 
PSA 
prostate-specific antigen 
Q12W 
once every 12 weeks 
QTcF 
corrected QT interval Fridericia 
SAP 
statistical analysis plan 
SD 
standard deviation 
tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
VAS 
visual analogue scale 


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Term 
Definition 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses planned for phase 3 
study MVT-601-3201 (HERO), entitled “A Multinational Phase 3 Randomized, Open-Label, 
Parallel Group Study to Evaluate the Safety and Efficacy of Relugolix in Men with Advanced 
Prostate Cancer.”  This SAP is based on protocol amendment 3, dated 23 Oct 2018.   
The study has two analyses, the primary and the final analyses.  The primary analysis of the 
study will be performed when all patients randomized under protocol amendment 2 (targeting 
approximately 915 patients), dated 18 Jan 2018, have either completed 48 weeks of study 
treatment with the 30-day safety follow-up visit or discontinued early.  The primary endpoint, 
secondary efficacy endpoints, and safety of relugolix in men with advanced prostate cancer will 
be evaluated.   
The final analysis of the study will occur after approximately 390 patients with metastatic 
disease have been randomized to the study and have either completed 48 weeks of study 
treatment with the 30-day safety follow-up visit or discontinued early.  As the enrollment in 
China is concurred with the enrollment of patients with metastatic disease under protocol 
amendment 3, Chinese patients with metastatic disease randomized prior to the completion of the 
enrollment of patients with metastatic disease will be included in the final analysis.    
This SAP describes the statistical analysis plan for the primary and final analyses of the study.  
However, the SAP will be finalized prior to the database lock of the study for the primary 
analysis.   
Any subsequent analyses conducted at later data cut-off dates (ie, analysis inclusive of all 
Chinese patients enrolled) will be described in separate SAPs.   
1.1. 
Study Objectives and Endpoints 
The study objectives and corresponding endpoints are listed in Table 1. 
The endpoints in italics either are not listed in the protocol or have been modified.  These 
endpoints are included in this SAP because they have been identified as important for assessment 
of treatment effect, on the basis of emerging literature review and clinical relevance to the study 
objectives. 
For the primary efficacy endpoint, there are two evaluation criteria in the protocol to support 
different regulatory requirements for assessing benefit.  The first criterion evaluates castration 
rate in approximately 610 patients randomized to relugolix.  The second criterion evaluates the 
noninferiority of relugolix in approximately 610 randomized patients compared with leuprolide 
acetate in approximately 305 randomized patients.   


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Table 1: 
Study Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
To evaluate the ability of relugolix to 
achieve and maintain serum 
testosterone suppression to castrate 
levels of < 50 ng/dL (1.7 nmol/L) in 
men with androgen-sensitive 
advanced prostate cancer 
 
The primary endpoint is the sustained castration rate, 
defined as the cumulative probability of testosterone 
suppression to < 50 ng/dL (1.7 nmol/L) while on study 
treatment from Week 5 Day 1 (study Day 29) through 
Week 49 Day 1 (study Day 337). 
• Evaluation Criterion 1:  to determine whether 
the sustained castration rate (defined as the 
cumulative probability of testosterone 
suppression to < 50 ng/dL [1.7 nmol/L] while 
on study treatment from Week 5 Day 1 through 
Week 49 Day 1) for relugolix is ≥ 90%.  The 
lower bound of the 95% confidence interval 
for the cumulative probability of sustained 
testosterone suppression in the relugolix 
treatment group will be calculated and must be 
at least 90% for this criterion to be met. 
• Evaluation Criterion 2:  to establish the 
noninferiority of relugolix compared to 
leuprolide acetate every 3-month (3-M) depot 
injection as assessed by the cumulative 
probability of sustained testosterone 
suppression.  The lower bound of the 95% 
confidence interval for the difference in the 
cumulative probability of sustained 
testosterone suppression between the two 
treatment groups will be calculated and must 
be greater than or equal to the noninferiority 
margin of -10% for this criterion to be met. 


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Key Secondary Efficacy 
(Alpha-Protected for Hierarchical Hypothesis Testing)  
To determine the time course and 
change in serum testosterone 
 
Cumulative probability of testosterone suppression to 
< 50 ng/dL (1.7 nmol/L) prior to dosing on Week 1 
Day 4 
Cumulative probability of testosterone suppression to 
< 50 ng/dL (1.7 nmol/L) prior to dosing on Week 3 
Day 1 
To evaluate the time course and 
magnitude of PSA reduction 
Proportion of patients with PSA response (by Prostate 
Cancer Clinical Trials Working Group 3 [Scher et 
al, 2016] at Week 3 Day 1 followed with the 
confirmation at Week 5 Day 1 
To determine the time course and 
change in serum testosterone 
Profound castration rate defined as cumulative 
probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) prior to dosing on Week 3 Day 1. 
To evaluate the effect of relugolix 
and leuprolide acetate on endocrine 
pharmacodynamic parameters. 
FSH level at Week 25 Day 1 
To describe the time course and 
magnitude of development of 
castration resistant prostate cancer a 
Castration resistance free survival during the 48-week 
treatment in patients with metastatic prostate cancer 
 
 
Castration resistance free survival during the 48-week 
treatment in patients with or without metastatic 
prostate cancer 
To evaluate testosterone recovery 
following discontinuation of study 
treatment 
Cumulative probability of testosterone recovery to 
280 ng/dL at the 90-day follow-up in approximately 
150 patients who complete 48 weeks of treatment and 
who do not plan to start alternative androgen 
deprivation therapy within the following 12 weeks (or 
within 24 weeks following the last injection of 
leuprolide acetate 3-M depot) 
 
 


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Other Secondary Efficacy 
(Not for Hierarchical Hypothesis Testing)  
To determine the time course and 
change in serum testosterone 
Sustained profound castration rate from Week 5 Day 1 
through Week 49 Day 1 defined as the cumulative 
probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) while on treatment from Week 5 Day 1 
through Week 49 Day 1; 
Sustained profound castration rate from Week 25 Day 
1 through Week 49 Day 1 defined as the cumulative 
probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) while on treatment from Week 25 Day 1 
through Week 49 Day 1. 
To evaluate the time course and 
magnitude of PSA reduction during 
treatment 
Proportion of patients with confirmed PSA response at 
Week 5 Day 1; 
Proportion of patients with PSA concentration 
< 0.02 ng/mL (0.02 µg/L) at Week 25 visit. 
To describe the time course and 
magnitude of PSA progression and 
development of castration resistant 
prostate cancer during treatment 
Time to PSA progression per Prostate Cancer Clinical 
Trials Working Group 3 
 
To evaluate testosterone recovery 
following discontinuation of study 
treatment 
Cumulative probability of testosterone recovery back 
to 50 ng/dL or back to baseline or 280 ng/dL at the 90-
day follow-up in approximately 150 patients who 
complete 48 weeks of treatment and who do not plan 
to start alternative androgen deprivation therapy 
within the following 12 weeks (or within 24 weeks 
following the last injection of leuprolide acetate 3-M 
depot) 
To evaluate the impact of treatment 
on quality of life using validated 
patient-report outcome instruments. 
• Absolute values and changes from baseline in the 
scores of the EORTC-QLQ-C30 global health 
domain, and the EORTC-QLQ-PR25 sexual 
activity and hormonal-treatment-related symptom 
subdomains, at regular intervals during treatment, 
and as applicable during the Follow-up and/or End 
of Treatment visits; 
• Absolute values and changes from baseline of the 
remaining domains in the EORTC QLQC30 and 
EORTC QLQ-PR25, as well as the EuroQol 
EQ-5D-5L questionnaire, at regular intervals 
during treatment, and as applicable during the 
Follow-up visits. 


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Safety 
To evaluate the safety of relugolix 
120 mg once daily in men with 
androgen-sensitive advanced prostate 
cancer. 
Treatment-emergent adverse events, clinical 
laboratory tests, and vital sign measurements. 
Pharmacodynamic 
To evaluate the effect of relugolix 
and leuprolide acetate on endocrine 
pharmacodynamic parameters. 
Endocrine marker effects of relugolix and leuprolide 
acetate as measured as absolute values and change 
from baseline for: 
• LH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
• FSH at the Day 4, Week 5, Week 25, and 
Week 49 visits; 
• Dihydrotestosterone at the Week 5, Week 25, 
and Week 49 visits; 
• Sex hormone-binding globulin at Week 5, 
Week 25, and Week 49 visits. 
Pharmacokinetics 
To collect relugolix plasma 
concentration data to further evaluate 
relugolix population 
pharmacokinetics and the relationship 
between relugolix exposure and 
serum testosterone. 
Predose relugolix plasma concentrations 
 
 
To characterize the relugolix plasma 
pharmacokinetic parameters in a 
subset of patients from China and 
Japan. 
Single and repeat-dose plasma relugolix 
pharmacokinetic parameters such as Cmax, AUC0-τ, and 
tmax in subsets of patients from China or Japan. 
Exploratory 
To explore the overall survival  
Overall survival defined as time from randomization 
to date of death prior to data cut-off date. 
To explore the contribution of genetic 
variance on drug response. 
 
The presence of polymorphisms in germline genes 
related to the hypothalamic-pituitary androgen 
pathway, prostate cancer risk, or to drug metabolizing 
enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy 
of relugolix. 


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Abbreviations:  3-M = every 3 months; AUC0-τ = area under the curve from time 0 to the end of the dosing 
interval; Cmax = maximum plasma concentration; EuroQol EQ-5D-5L = European Quality of Life 5-Dimension 5-
Level Questionnaire; FSH = follicle-stimulating hormone; LH = luteinizing hormone; PSA = prostate-specific 
antigen; tmax = time to maximum plasma concentration. 
a Castration resistance free survival will not be assessed in the primary analysis of the study.  It will be evaluated 
at the time of approximately 390 patients with metastatic disease enrolled and completed the 48 weeks of study 
treatment. 
 
 


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2. 
STUDY DESIGN 
2.1. 
Summary  
The MVT-601-3201 (HERO) study is a phase 3, multinational, randomized, open-label, parallel-
group study to evaluate the safety and efficacy of relugolix in patients with androgen-sensitive 
advanced prostate cancer who require at least 1 year of continuous androgen deprivation therapy.  
Oral relugolix or leuprolide acetate depot subcutaneous or intramuscular injection will be 
administered to patients with prostate cancer who require androgen deprivation therapy.  The 
primary endpoint is sustained castration rate, defined as the cumulative probability of 
testosterone suppression to < 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 
Day 1 (Study Day 29) through Week 49 Day 1 (Study Day 337).   
Approximately 915 patients will be enrolled and randomized in a 2:1 ratio to the following two 
treatment groups:   
• Oral relugolix 120 mg once daily, following a loading dose of 360 mg on Day 1;  
• Leuprolide acetate 22.5 mg (or 11.25 mg in some Asian countries) every 3 months 
(3-M) depot subcutaneous or intramuscular injection. 
Randomization will be stratified as follows:  
• Geographic region:  North and South America; Europe; Asia and Rest of World; 
• Presence of metastatic disease: yes, no; 
• Baseline age:  ≤ 75 years old, > 75 years old. 
After the initial 915 patients have been enrolled under protocol amendment 2, only patients with 
metastatic advanced prostate cancer will be enrolled under protocol amendment 3 to assess 
castration resistance free survival (ie, time to castration resistance) as a key secondary endpoint.  
A total of approximately 390 patients with metastatic disease as the high-risk subgroup for 
developing castration resistance, randomized in a 2:1 ratio to relugolix versus leuprolide acetate, 
are required to evaluate castration resistance free survival.  In parallel, for approval in China 138 
patients in China and Taiwan will be enrolled, with or without metastatic advanced prostate 
cancer, under protocol amendment 3.  To support applications across various countries and 
regions, a total of approximately 1100 patients is expected to be enrolled in the study.   
This study includes a screening period of up to 28 days, a treatment period of 48 weeks, and a 
follow-up period of up to 30 days.  Approximately 100 patients randomized to relugolix and 
approximately 50 patients randomized to leuprolide acetate who completed 48 weeks of 
treatment and who do not plan to start alternative androgen deprivation therapy within the 
following 12 weeks will be followed for testosterone recovery at the 60- and 90-day follow-up 
visits.   
Testosterone assayed using a liquid chromatography-tandem mass spectrometry method sensitive 
at least as low as 5 ng/dL (0.17 nmol/L) and prostate-specific antigen (PSA) will be assessed at 
Day 4, Week 3 Day 1 and Week 5 Day 1, then monthly afterwards.  Additional serum endocrine 
evaluations and quality of life questionnaires will be collected throughout the study.   


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An external independent Data and Safety Monitoring Board (DSMB) was established to review 
periodic safety analyses.  The roles and responsibilities of the independent DSMB are described 
in the DSMB charter.  A separate SAP was created to specify the safety data analyses performed 
by an independent data coordinating center and reviewed by the DSMB. 
A schematic of the study is presented in Figure 1. 
 
Figure 1: 
Schematic of Study Design 
 
 
2.2. 
Sample Size Justification 
The following assumptions were used to determine the sample size for this study: 
• True probabilities of sustained testosterone suppression are 94% and 96% for 
relugolix and leuprolide acetate, respectively; 
• 2:1 randomization ratio (relugolix: leuprolide acetate);  
• Dropout rate:  15%. 
For Evaluation Criterion 1, 610 patients in the relugolix group will provide approximately 90% 
power to rule out a fixed probability of sustained testosterone suppression of < 90% at a two-
sided type I error rate of 0.05. 
For Evaluation Criterion 2, with a noninferiority margin of -10% and an overall two-sided type I 
error rate of 0.05, a total of approximately 915 patients (610 receiving relugolix, 305 receiving 
leuprolide acetate) will yield at least 99% power to declare the noninferiority of relugolix to 
leuprolide acetate.  The 10% noninferiority margin for the comparison of relugolix versus 


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leuprorelin is based on regulatory precedence of pivotal assessment of gonadotropin-releasing 
hormone (GnRH) antagonist degarelix versus leuprorelin as well as studies of branded GnRH 
agonist generics.  
The primary analysis will be performed separately for each evaluation criterion using data 
collected through 48 weeks after enrollment of approximately 915 patients. 
Approximately 915 patients will be randomized in order to fulfill the regulatory requirements of 
all participating countries included in the primary efficacy endpoint of this study.   
Under amendment 3 the study is also powered for the secondary endpoint of castration resistance 
free survival in the high-risk subgroup of patients with metastatic disease, although this is not 
part of the primary analysis.  Approximately 107 confirmed castration-resistance events (ie, PSA 
progression while castrated or deaths due to any reasons) will need to be observed (or 
approximately 390 patients with metastatic disease will need to be enrolled) to detect a hazard 
ratio of 0.55 (relugolix vs. leuprolide acetate) with 85% power and a two-sided type I error of 
5%, assuming a castration-resistant event–free rate of 60% at 48 weeks for the control arm, an 
18-month enrollment period, 12 months of additional follow-up, and a 15% dropout rate. 
With a total of approximately 1100 patients with or without metastatic disease randomized into 
the study through amendment 3, including approximately 138 Chinese patients, it is anticipated 
that approximately 149 confirmed castration-resistance events (PSA progression while castrated 
or deaths due to any cause) will be observed.  Assuming an 18-month enrollment period, 
12 months of additional follow-up, and a 10% dropout rate, the study will provide approximately 
85% power to detect a hazard ratio of 0.6 (relugolix vs. leuprolide acetate) with a two-sided type 
I error of 5%.   
 


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3. 
PLANNED ANALYSES 
3.1. 
Interim Analysis 
There will be no interim efficacy analysis performed for this study.   
Periodic safety data is reviewed by the DSMB.  An independent data coordinating center will 
perform the periodic safety data analyses and provide the results of these analyses to the DSMB, 
as defined in the DSMB charter. 
3.2. 
Primary Analysis 
The primary analysis of the study will occur after approximately 915 patients have been 
randomized into the study, have had the opportunity to be evaluated for 48 weeks, and either 
have completed the 30-day safety follow-up visit or have discontinued early. 
The statistical methods for the primary analysis of the study will be specified in this SAP.   
There will be two dates of data analysis cut-off for the primary analysis.  The first data analysis 
cut-off date will be the date when the last Week 49 Day 1 visit has occurred.  The second 
analysis cut-off date will be the date of the last safety follow-up visit.  Analyses from both data 
cut-off dates will be used as the basis for the clinical study report. 
3.3. 
Final Analysis 
The final analysis of the study will occur after approximately 390 patients with metastatic 
disease have been randomized into the study, have had the opportunity to be evaluated for 
48 weeks of study treatment, and either have completed the 30-day safety follow-up visit or have 
discontinued early. The statistical methods for the final analysis of the study will be specified in 
this SAP.   
3.4. 
Other Analyses 
Other analyses, inclusive of all Chinese patients enrolled, are expected to be completed later and 
will be described separately.   
 
 


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4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA 
4.1. 
Data Presentation Conventions 
Leuprolide acetate injection with 22.5 mg or 11.25 mg (in Japan, Taiwan, and China) every 
12 weeks (Q12W) will be presented in total in one column. 
All statistical analyses will be conducted using SAS® Version 9.2 or higher. 
Unless otherwise stated, a statistical test will be assessed at two-sided α = 0.05 significance level 
and all confidence intervals (CIs) will be reported as two-sided. 
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.  For continuous variables, the number of subjects with non-missing values and 
the mean, median, standard deviation (SD), minimum, and maximum values will be tabulated. 
Unless otherwise specified, the following conventions will be applied to all analyses: 
• Mean and median values will be formatted to one more decimal place than the 
measured value.  Standard deviation values will be formatted to two more decimal 
places than the measured value, and minimum and maximum values will be presented 
to the same number of decimal places as the measured value.  If the measured value is 
large (eg, > 100), fewer decimal places may be displayed. 
• Percentages will be rounded to one decimal place;   
• p-values will be rounded to 4 decimal places.  p-values < 0.0001 will be presented as 
“< 0.0001” and p-values > 0.9999 will be presented as “> 0.9999”; 
• 1 month = 30.4375 days.  Month is calculated as (days/30.4375) rounded to 1 decimal 
place; 
• 1 year = 365.25 days.  Year is calculated as (days/365.25) rounded to 1 decimal place; 
• Age = integer part of month (date of randomization – date of birth – X)/12, where 
X = 1 if day of randomization date < day of birth date and X = 0 otherwise.  If only 
birth year is provided, 1 July of the birth year will be used to calculate age; 
• 1 pound = 0.454 kg; 
• 1 inch = 2.54 cm; 
• Missing efficacy or safety data will not be imputed, unless otherwise specified; 
• For laboratory results above or below sensitivity limits displayed as < or > a 
quantification threshold, 0.0000000001 will be subtracted or added, respectively, to 
the sensitivity limit to derive a numeric result for analyses; 
• For safety analyses, calculation of percentages will be calculated on the basis of the 
number of patients in the analysis population in each treatment group; 


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• For by-visit observed data analyses, calculation of percentages will be calculated on 
the basis of the number of patients with non-missing data as the denominator, unless 
otherwise specified; 
• For continuous endpoints, the summary statistics will include mean, standard 
deviation, median, and range (minimum and maximum); 
• For time-to-event endpoints, the summary statistics will include median time to 
event-free survival, 25th and 75th percentiles and number of patients at risk at 
specified time points; 
• For categorical endpoints, the summary statistics will include counts and percentages; 
• Confidence intervals, when presented, will generally be constructed at the 95% level.  
For binomial variables, exact methods will be employed unless otherwise specified. 
4.2. 
Analysis Populations 
Three analysis populations are defined as below.  Number and percent of patients meeting the 
definition of each analysis population will be summarized by treatment group. 
4.2.1. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population is defined as all randomized patients who have 
taken at least one dose of any study treatment.  Unless otherwise specified, all analyses use the 
mITT population by treatment group as assigned by randomization (not by actual treatment 
received).  The mITT population will be the primary population used for efficacy endpoints. 
4.2.2. 
Per-Protocol Population 
The per-protocol population will consist of those members of the mITT population who do not 
have important protocol deviations (see Section 5.3).  The per-protocol population will not be 
analyzed if this population comprises > 95% or < 50% of the mITT population.  This population 
will be used for sensitivity analysis of the mITT population for the primary efficacy endpoint. 
The per-protocol population and the associated subset of important protocol deviations will be 
identified prior to database lock.   
4.2.3. 
Safety Population 
The safety population is defined as all randomized patients who receive at least one dose of any 
study treatment.  Unless otherwise specified, all safety analyses will use the safety population 
according to the actual treatment received (not the treatment assigned).  Actual treatment 
received will be determined by the treatment received on Day 1.   
4.3. 
Definitions, Computations, and Conventions 
4.3.1. 
Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date a patient receives the first dose of 
study drug.  The date of the last dose of study drug is defined as the date a patient receives the 
last dose of study drug.   


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4.3.2. 
Treatment Day 
Treatment day will be calculated in reference to the date of the first dose of study drug.  
Treatment Day 1 corresponds to the date a patient receives the first dose of study drug.  For 
assessments conducted on or after the date of the first dose of study drug, treatment day will be 
calculated as (assessment date – date of first dose of study drug + 1).  There will be no Treatment 
Day 0.  Efficacy and safety analyses will be based on treatment day, unless otherwise specified. 
4.3.3. 
Treatment Period  
The treatment period is defined as the period of time from the date of the first dose of study drug 
through the date of last dose.  The treatment period per protocol is 48 weeks (Treatment 
Day 336).  For patients in the leuprolide acetate treatment arm, treatment period ends 12 weeks 
after the last leuprolide acetate injection.   
4.3.4. 
Treatment Duration  
Treatment duration is defined as the duration of time from the date of the first dose of study drug 
to the date of the last dose of study drug, calculated as follows:   
For relugolix treatment arm, treatment duration is:  
(Date of last dose of study drug – Date of first dose of study drug) + 1.   
For leuprolide acetate treatment arm, treatment duration is:  
(Date of last dose of study drug – Date of first dose of study drug) + 84. 
4.3.5. 
Baseline Value and Postbaseline Value  
Both date and time of study drug administration and measurement will be considered when 
calculating baseline value.  Unless otherwise specified, the baseline value is defined as the last 
measurement on or before the first administration date (if time is not available) of study drug.  Or 
the baseline value is defined as the last measurement before the first administration date and time 
of study drug.  Postbaseline value is defined as any measurement taken after the first 
administration of study drug.  Change from baseline is defined as (postbaseline value – baseline 
value).  If time is not available, then date only will be used.    
4.3.6. 
Visit Windows 
Visit windows will be used to associate assessments with a scheduled visit and will be used only 
for summarizing data by visit.  Visit windows for each assessment are defined as shown in 
Table 2. A separate set of visit windows for assessment of quality of life are defined in 
 
 


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Table 3.   For both efficacy and safety assessments, the Treatment Day will be used to determine 
the associated visit window. 
If more than one observation lies within the same visit window, the observation with the closest 
study day to the target study day will be used.  If there are two observations equidistant to the 
scheduled target day, the earlier assessment will be used.   
 
 


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Table 2: 
Visit Windows 
 
 
 
Visit 
Start Day 
Target Day 
End Day 
Week 1 Day 4a 
1 
4 
8 
Week 3 Day 1 
9 
15 
21 
Week 5 Day 1 
22 
29 
43 
Week 9 Day 1 
44 
57 
71 
Week 13 Day 1 
72 
85 
99 
Week 17 Day 1 
100 
113 
127 
Week 21 Day 1 
128 
141 
155 
Week 25 Day 1 
156 
169 
183 
Week 29 Day 1 
184 
197 
211 
Week 33 Day 1 
212 
225 
239 
Week 37 Day 1 
240 
253 
267 
Week 41 Day 1 
268 
281 
295 
Week 45 Day 1 
296 
309 
323 
Week 49 Day 1 
324 
337 
365 
Safety Follow-up b 
Date of last dose + 2 
days in relugolix arm 
Date of last dose + 8 
days in leuprolide arm 
Date of last dose + 30 
days 
Date of last dose + 45 
(59 d) days 
60-Day Testosterone 
Recovery c 
Date of last dose + 46 
days 
Date of last dose + 60 
days 
Date of last dose + 75 
days 
90-Day Testosterone 
Recovery c 
Date of last dose + 76 
days 
Date of last dose + 90 
days 
Date of last dose + 119 
days 
Date of last dose in leuprolide acetate ends 12 weeks after the last leuprolide acetate injection. 
a Start day of Week 1 Day 4 only includes postbaseline assessments on or after the first dose. 
b The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
c Approximately 100 patients receiving relugolix and 50 patients receiving leuprolide acetate who complete 
the 48 weeks of study treatment and, in the opinion of the investigator, can remain off androgen deprivation 
therapy for 90 days will be included in the testosterone recovery 60- and 90-day follow-up visits. 
d For patients not enrolled in the testosterone recovery follow-up, the end day of safety follow-up visit can be 
extended to Day 59 after the date of last dose. 


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Table 3: 
Visit Windows for Assessments in Quality of Life 
4.4. 
General Rules for Missing Data 
Handling of missing data for the efficacy endpoints is described in Section 7. 
4.4.1. 
By -Visit Endpoints 
By-visit endpoints will be analyzed using observed data, unless otherwise specified.  For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included. 
4.4.2. 
Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates.  
The imputed dates will be used to determine the treatment-emergent period.  For adverse events 
with a partial date, available date parts (year, month, and day) of the partial date will be 
compared with the corresponding date components of the start date and end date of the 
treatment-emergent period to determine if the event is treatment emergent.  When in doubt, the 
adverse event will be considered treatment emergent by default.  The following rules will be 
applied to impute partial dates for adverse events: 
 
 
Visit 
Start Day 
Target Day 
End Day 
Week 5 Day 1 
9 
29 
57 
Week 13 Day 1 
58 
85 
127 
Week 25 Day 1 
128 
169 
211 
Week 37 Day 1 
212 
253 
295 
Week 49 Day 1 
296 
337 
365 
Safety Follow-up a 
Date of last dose + 2 
days in relugolix arm 
Date of last dose + 8 
days in leuprolide arm 
Date of last dose + 30 
days 
Date of last dose + 45 
(59 c) days 
60-Day Testosterone 
Recovery b 
Date of last dose + 46 
days 
Date of last dose + 60 
days 
Date of last dose + 75 
days 
90-Day Testosterone 
Recovery b 
Date of last dose + 76 
days 
Date of last dose + 90 
days 
Date of last dose + 119 
days 
Date of last dose in leuprolide acetate ends 12 weeks after the last leuprolide acetate injection. 
a The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy or surgical intervention, whichever occurs first. 
b Approximately 100 patients receiving relugolix and 50 patients receiving leuprolide acetate who complete 
the 48 weeks of study treatment and, in the opinion of the investigator, can remain off androgen deprivation 
therapy for 90 days will be included in the testosterone recovery 60- and 90-day follow-up visits. 
c For patients not enrolled in the testosterone recovery follow-up, the end day of safety follow-up visit can be 
extended to day 59 after the date of last dose. 


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If start date of an adverse event is partially missing, impute as follows: 
• If both Month and Day are missing and Year = Year of treatment start date, then set 
to treatment start date, as long as adverse event end date is not prior to treatment start 
date; 
• If both Month and Day are missing and Year ≠ Year of treatment start date, then set 
to January 1; 
• If Day is missing and Month and Year = Month and Year of treatment start date, then 
set to treatment start date, as long as adverse event end date is not prior to treatment 
start date; 
• If Day is missing and Month and Year ≠ Month and Year of treatment start date, then 
set to first of the month; 
• If start date is completely missing, set to treatment start date, as long as adverse event 
end date is not prior to treatment start date. 
If end date of an adverse event is partially missing, impute as follows: 
• If both Month and Day are missing, then set to December 31; 
• If only Day is missing, then set to last day of the month; 
• If end date is completely missing, do not impute. 
4.4.3. 
Concomitant Medications 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant (or both).  The following rules will be 
applied to impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
• If both Month and Day are missing, then set to January 1; 
• If only Day is missing, then set to the first of the month; 
If end date of a medication is partially missing, impute as follows: 
• If both Month and Day are missing, then set to December 31; 
• If only Day is missing, then set to last day of the month; 
If start date or end date of a medication is completely missing, do not impute. 


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5. 
PATIENT POPULATION 
5.1. 
Patient Disposition 
The number of patients for each of the following categories will be summarized by treatment 
group: 
• All randomized patients; 
• Number and percentage of patients in the safety population;  
• Number and percentage of patients who did not receive study treatment;  
• Number and percentage of patients who completed 48 weeks of study treatment; 
• Number and percentage of patients who prematurely discontinued study treatment 
and reasons for treatment discontinuation; 
• Number and percentage of patients who participated in testosterone recovery 
follow-up.   
Patient disposition will be summarized for all randomized patients.   
5.2. 
Screen Failure 
Reasons for screen failure will be summarized.  Number and percentage of patients who did not 
pass screening will be based on the patients who signed the informed consent form but were not 
randomized.   
5.3. 
Protocol Deviations 
Protocol deviations will be categorized as important protocol deviation or protocol deviation 
according to the protocol deviation plan.  Important protocol deviations will include but not be 
limited to the following: 
• Patients who did not satisfy key entry criteria;  
• Patients who met withdrawal criteria during the study but were not withdrawn;  
• Patients who received the wrong treatment; 
• Patients who received a prohibited concomitant medication that met criteria for an 
important protocol deviation. 
Important protocol deviations will be summarized by deviation category for all patients in the 
mITT population.  A by-patient listing of important protocol deviations will be provided. 
Patient eligibility including inclusion criteria that are not met and exclusion criteria that are met 
at enrollment will be summarized for all patients in the mITT population.   
A selected subset of the important protocol deviations that are likely to affect analysis of efficacy 
will be identified to define the per-protocol population prior to the database lock.  This subset 
will include but will not be limited to the following import protocol deviations: 
• Did not satisfy key entry criteria; 


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• Drug compliance < 75% over more than 1 consecutive month; 
• Patient received prohibited concomitant medications that met criteria for important 
protocol deviations.   
5.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics for patients in the mITT population will be 
summarized by treatment group.   
Demographics will include age, race, ethnicity and geographic region while baseline disease 
characteristics will include clinical disease stage, baseline PSA, presence of metastatic disease, 
and Eastern Cooperative Oncology Group (ECOG) status.   
5.5. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be summarized by system organ class and preferred term.   
In addition, summaries will be provided of medical and surgical treatment history specific to 
prostate cancer.   
5.6. 
Prior and Concomitant Medications 
Prior and concomitant medications taken during the study treatment period will be summarized 
for all patients in the mITT population by treatment group.  Medications are considered 
concomitant if medications were used during the study treatment period.  Medications will be 
coded using the World Health Organization (WHO) Drug Dictionary and summarized according 
to the Anatomical Therapeutic Chemical (ATC) Classification System and generic medication 
name.   
Use of antiandrogens initiated during the first 4 weeks of study treatment (including 
bicalutamide, flutamide, nilutamide, and enzalutamide) will be summarized separately.   
5.7. 
Prior and Current Procedures 
Prior and current procedures, including radiotherapies, taken during the study treatment period 
will be summarized by treatment group for all patients in the mITT population.  Procedures are 
considered current if they occur at or after the date of the first dose of study treatment.   


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6. 
STUDY DRUG EXPOSURE AND COMPLIANCE 
Patients in the safety population will be summarized for extent of exposure and compliance of 
study drug by actual treatment received.  Study drug exposure will be calculated based on the 
case report form (CRF) pages of “Relugolix Dosing Log” and “Leuprolide Acetate 
Administration.” Compliance for relugolix will be based on the CRF of “Study Drug 
Accountability.”   
Summary statistics on extent of exposure and compliance will be provided as follows: 
• Treatment duration in weeks;  
• Cumulative dose administered (mg) for leuprolide and total tablets taken for 
relugolix; 
• Dose intensity and relative dose intensity for leuprolide; 
• Compliance for relugolix. 
For leuprolide acetate arm: 
Treatment duration in weeks = (the date of last dose – the date of first dose + 84) / 7. 
Cumulative dose administered will be sum of all the doses administered. 
Dose intensity = cumulative dose administered / ceiling function of (treatment duration in 
weeks/12). 
Relative dose intensity = (dose intensity / 22.5 or 11.25 mg per treatment on Day 1) × 100. 
For relugolix arm:  
Treatment duration in weeks = (the date of last dose – the date of first dose + 1) / 7. 
Relugolix compliance will be calculated as follows:  
(total tablets taken / total tablets expected to be taken) × 100. 
The total tablets taken will be calculated as:   
total number of tablets dispensed - total number of tablets returned. 
The total tablets expected to be taken will be calculated as:   
3 tablets on Day 1 + 1 tablet per day × (treatment duration in Days -1). 
In the case of unreturned bottles, tablets that were dispensed will be assumed to be taken. 
However, for patients who did not return for their last scheduled visit, tablets that were dispensed 
and not returned will be subtracted from both the total tablets taken and the total tablets expected 
to be taken in the calculation of relugolix compliance.  In cases when the patient never returned 
any of the dispensed bottles, the total tablet taken, total tablets expected to be taken, and 
relugolix compliance will be set to “not able to calculate.” 
Summary statistics of relative dose intensity and study drug compliance (eg, mean, median, etc) 
will be presented along with a categorical summary (eg, < 80%, 80 to 100%, > 100%). 


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For this study, any dose of relugolix > 240 mg within a 24-hour window is an overdose, except 
for the 360-mg loading dose on Treatment Day 1.  Events of overdose will be reported within 
24 hours using a serious adverse event form, whether the overdose is associated with an adverse 
event or not.  Patients with daily dose > 240 mg reported on the relugolix dosing log will be 
flagged in the listing of study drug administration. 


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7. 
EFFICACY ANALYSES 
7.1. 
General Considerations 
Unless otherwise specified, efficacy analyses will be conducted using the mITT population 
according to the randomized treatment assignment and will be stratified by the randomization 
stratification factors (geographic region, presence of metastatic disease, and baseline age).  If the 
group of patients from any of the individual randomization stratification factors (eg, with 
presence of metastatic disease) comprises < 10% of the entire mITT population, this stratification 
factor will be collapsed for stratified analyses.  In addition, if there were < 15 patients in one of 
the 12 strata, stratification factors of presence of metastatic disease and baseline age would be 
used in the stratified analysis for more robust strata-adjusted estimation of treatment effect.  If 
there is a discrepancy > 5% between interactive web response systems (IWRS) and CRF on a 
stratification factor, the stratification factor reported in CRF will be used as primary analyses and 
that reported in IWRS will be used as sensitivity analyses, unless otherwise specified.  In the 
case of a discrepancy > 5% between IWRS and CRF on the presence of metastatic disease 
stratification factor, patients with metastatic prostate cancer will be identified from CRF instead 
of from IWRS.   
For efficacy endpoints related to testosterone test results, analytical testosterone results from the 
central bioanalytical laboratory using a liquid chromatography–tandem mass spectrometry 
method, with a lower limit of quantification of 5 ng/dL, will be used.  Unless the endpoints are 
related to testosterone recovery, results from safety follow-up, 60-day and 90-day testosterone 
recovery (refer to Table 2) will be excluded from the efficacy analyses.   
7.2. 
Multiplicity Adjustment 
The primary and the key secondary efficacy analyses will be performed at an overall two-sided 
type I error of 0.05.  A test will be deemed statistically significant if the two-sided p-value 
rounded to 4 decimal places is less than 0.05.  If the result of the primary endpoint analysis meets 
the respective evaluation criterion of the primary endpoint, the key secondary endpoints will then 
be tested with a fixed-sequence testing procedure (as illustrated in Figure 2) to maintain the 
overall familywise error rate of 0.05 for the testing of primary and key secondary endpoints. 
The key secondary endpoints with alpha protection for labelling purposes are identified and 
defined in Section 7.4.1. 
All p-values (if provided) aside from the endpoints listed in the testing order are not adjusted in 
multiplicity, thus are at a nominal level of 0.05. 
7.3. 
Primary Efficacy Endpoint 
The study has two separate evaluation criteria for the primary efficacy endpoint to support 
different regulatory requirements for assessing benefit: 
• Evaluation Criterion 1:  to determine whether the sustained castration rate for 
relugolix is ≥ 90%.  The lower bound of the 95% CI for the cumulative probability of 
sustained testosterone suppression in the relugolix treatment group will be calculated 
and must be at least 90% for this criterion to be met. 


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• Evaluation Criterion 2:  to establish the noninferiority of relugolix to leuprolide 
acetate 3-M depot injection, as assessed by the cumulative probability of sustained 
testosterone suppression.  The lower bound of the 95% CI for the difference in the 
cumulative probability of sustained testosterone suppression between the 2 treatment 
groups will be calculated and must be greater than or equal to the noninferiority 
margin of –10% for this criterion to be met. 
Evaluation Criterion 1 is a regulatory requirement from the United States Food and Drug 
Administration (FDA).  Evaluation Criterion 2 is required by European Medicines Agency 
(EMA) and Japanese Pharmaceutical and Medical Device Agency (PMDA).  For the FDA, 
Evaluation Criterion 1 is the trial success criterion for the primary efficacy endpoint, while 
Evaluation Criterion 2 is the first to be tested in the order of ranked key secondary endpoints to 
assess noninferiority of relugolix compared with leuprolide acetate after Evaluation Criterion 1 is 
met. 
7.3.1. 
Primary Efficacy Analyses 
The primary hypotheses associated with two evaluation criteria for the primary endpoint in this 
study are: 
1. Hypothesis 1, corresponding to Evaluation Criterion 1:  the cumulative probability of 
testosterone suppression to < 50 ng/dL (1.7 nmol/L) for relugolix while on study 
treatment from Week 5 Day 1 through Week 49 Day 1 is ≥ 90%. 
 
Null hypothesis H01:  πR < 0.9  versus  Alternative hypothesis Ha1:   πR ≥ 0.9 
 
2. Hypothesis 2, corresponding to Evaluation Criterion 2:  relugolix is noninferior to 
leuprolide acetate 3-M depot injection, as assessed by the cumulative probability of 
sustained testosterone suppression with a noninferiority margin of –10%. 
 
Null hypothesis H02:  πR – πL < –10%  versus Alternative hypothesis Ha2:   πR – πL ≥ –10% 
 
where πR and πL are the sustained castration rates for the relugolix and leuprolide acetate 
groups, respectively. 
The primary analysis is the calculation of the Kaplan-Meier cumulative estimate of the 
proportion of patients who achieve and maintain castrate levels of testosterone (< 50 ng/dL) from 
Week 5 Day 1 through Week 49 Day 1.   
The 95% CI for the Kaplan-Meier estimation is calculated using the exponential Greenwood 
formula via log-log transformation of the survival function. 
Variance of treatment difference will be calculated using the formula 
𝑉𝑉෠ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)൧= 𝑉𝑉෠ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡)൧+ 𝑉𝑉෠[𝑆𝑆𝐿𝐿෡(𝑡𝑡)]; 
Where each of the variance of the Kaplan-Meier estimate will be calculated using the 
Greenwood’s formula  


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𝑉𝑉෠ൣ𝑆𝑆̂(𝑡𝑡)൧= 𝑆𝑆̂(𝑡𝑡)2 ෍
𝑑𝑑𝑖𝑖
𝑛𝑛𝑖𝑖(𝑛𝑛𝑖𝑖−𝑑𝑑𝑖𝑖)
𝑡𝑡𝑖𝑖≤𝑡𝑡
  
where 𝑛𝑛𝑖𝑖 denotes the number of patients at risk at time 𝑡𝑡𝑖𝑖 and 𝑑𝑑𝑖𝑖 denotes the number of events 
observed at time 𝑡𝑡𝑖𝑖. 95% CI of treatment difference will be calculated via linear transformation 
of the difference in survival function with pooled variance, as follows: 
[(𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)) −1.96ට𝑉𝑉෠ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)൧, (𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)) + 1.96ට𝑉𝑉෠ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)൧ ]. 
Survival functions, starting at the Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337), will be 
plotted and summarized by treatment group.   
7.3.1.1. 
Definition of Testosterone Test Result at Week 5 Day 1 
Serum concentration of testosterone at Week 5 Day 1 can be obtained at targeted Study Day 29, 
with a visit window from Day 22 to Day 43 inclusive (see Table 2).  If more than one test result 
lies within the visit window, the result with the study day closest to Day 29 target date will be 
used.  If there are two results equidistant to the scheduled target study day, the earlier assessment 
will be used as testosterone test result at Week 5 Day 1. 
7.3.1.2. 
Kaplan-Meier Analysis and Censoring Rules 
In general, patients with testosterone escape (any testosterone test result rising above the 
castration level [≥ 50 ng/dL]) from Week 5 Day 1 through Week 49 Day 1 will be considered as 
an event in the Kaplan-Meier analysis.  The time from the date of the first dose to date of the first 
testosterone escape will be considered as the event time.  
Patients who have not reached castration level at Week 5 Day 1 will be considered as having had 
an event at the target day of Week 5 Day 1.   
Patients who discontinued from the study prior to Week 5 Day 1 will be censored at the target 
day of Week 5 Day 1.  In addition, patients without a Week 5 Day 1 assessment will be 
considered to have had an event at the target day of Week 5 Day 1. 
For patients reaching castrate levels at Week 5 Day 1, the following rules will be applied to the 
Kaplan-Meier analysis for estimation of sustained castration rate with consideration for missed 
visits.  Time to event or censoring, whichever occurs first, will be used in Kaplan-Meier analysis.   
a) Patients who had one or more consecutive missed visits (ie, a visit gap of > 42 days) and 
had a non-castrate assessment immediately after the missed visit(s) will be considered as 
having an escape at the target day of the earliest missed visit prior to the non-castrate 
assessment; 
b) Patients with one missed visit who has a castrate assessment immediately before and after 
the missed visit will be assumed to be castrated at the missed visit; 
c) Patients with two or more consecutive missed visits (ie, a visit gap of > 70 days) and who 
had a castrate assessment immediately before and after the missed visits will be censored 
at the last available testosterone assessment prior to the missed visits. 
Note:  A visit gap of 70 days for two missed visits was used to consider the duration between 
two expected visits (8 weeks), plus the visit windows allowed per protocol (7 days for each 


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expected visit with a total of 2 weeks as visit window for two visits).  A visit gap of 42 days 
for one missed visit was used to consider the visit of every 4 weeks, and ± 7 days as the visit 
window, per protocol.   
Otherwise, patients will be censored at the last available assessment prior to the follow-up visits, 
including patients who discontinue from the trial for reasons other than a non-castrate 
testosterone level.  
If the above censoring rules are applied to a patient in multiple instances, the date of the earliest 
censoring for missed visits will be used as the date of censoring.  
In addition, patients who had initiated therapies known to suppress testosterone (refer to 
Appendix Table 1) will be censored at the time of last testosterone assessment prior to the 
initiation of such therapies.  
The time to event or censoring, whichever comes first, will be summarized by the Kaplan-Meier 
method.  If the event time or censoring time is after Day 337, Day 337 will be used as the event 
time or censoring time. 
 
For Hypothesis 1: 
Estimation of the cumulative probability of testosterone suppression to < 50 ng/dL at Week 49 
Day 1 (Day 337) for relugolix arm will be presented along with the 95% CI. 
Similarly, estimation of the cumulative probability of testosterone suppression to < 50 ng/dL at 
Week 49 Day 1 (Day 337) for leuprolide acetate will be presented along with the 95% CI. 
For Hypothesis 2: 
Treatment difference in the cumulative probability of testosterone suppression to < 50 ng/dL at 
Week 49 Day 1 (Day 337) between relugolix and leuprolide acetate arms will be presented along 
with the 95% CI. 
7.3.2. 
Sensitivity Analyses 
To assess the robustness of the primary analyses for Evaluation Criteria 1 and 2, the following 
sensitivity analyses of the primary endpoint will be performed. 
7.3.2.1. 
Sensitivity Analysis 1 
Analyses of the primary endpoint will be repeated in the per-protocol population. 
7.3.2.2. 
Sensitivity Analysis 2 
In addition to the censoring rules under Section 7.3.1.2, patients who had received concomitant 
medications and herbal supplements that could possibly affect testosterone level during study 
treatment will be excluded from the analysis. 


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7.3.2.3. 
Sensitivity Analysis 3 
Patients who had missed two or more consecutive visits after Week 5 Day 1 (censoring rule c in 
Section 7.3.1.2) or discontinued from the study early will be considered to have an event at the 
target day of the earliest missed visit.  
7.3.2.4. 
Sensitivity Analysis 4 
In order to assess the impact of delayed testosterone suppression to castration level, analyses of 
the primary endpoint will be repeated by considering that patients who have not reached 
castration level at Week 5 Day 1 are censored at Week 5 Day 1.    
7.3.3. 
Subgroup Analyses 
Subgroup analyses of primary efficacy endpoint will be performed to determine whether 
treatment effects are consistent across clinically important subgroups.  Testosterone castration 
rates at Week 49 Day 1 (Day 337) for relugolix arm and their 95% CI will be displayed in a 
forest plot.  Similarly, the difference in testosterone castration rates at Week 49 Day 1 between 
relugolix and leuprolide arms and their 95% CI will also be displayed in a forest plot.  Subgroups 
will include but not be limited to the following:   
• Geographic region (North and South America, Europe, Asia and Rest of World);  
• Geographic region (North America, other regions); 
• Geographic region (Asia [Japan, Korea, China, and Taiwan], other regions);  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino); 
• Presence of metastatic disease (yes, no) per IWRS; 
• Presence of metastatic disease (yes, no) per CRF if > 5% discrepancy from IWRS;  
• Age category (≤ 75 years old, > 75 years old); 
• Race (white, Black/African American, Asian, or others);  
• Clinical disease state presentations (biomedical or clinical relapse, newly diagnosed 
metastatic disease, advanced localized disease);  
• Gleason score at study entry (< 8, ≥ 8); 
• Baseline testosterone level (< 250 ng/dL, ≥ 250 ng/dL); 
• Baseline PSA level (< 20 ng/mL, ≥ 20 ng/mL). 
In addition, testosterone castration rates at Week 49 Day 1 (Day 337) for the two different dose 
levels (22.5 mg vs. 11.25 mg) in leuprolide arm and their 95% CI will be provided separately.  


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7.4. 
Secondary Efficacy Endpoints 
7.4.1. 
Key Secondary Efficacy Endpoints with Alpha-Protection 
The key secondary endpoints will be tested in the following order (see Figure 2) for different 
regulatory agencies, with a fixed-sequence testing procedure to control the overall familywise 
error rate at a two-sided type I error rate of 0.05 across primary and key secondary endpoints.   
For the testing order to be submitted to the FDA, Evaluation Criterion 2 for noninferiority of the 
primary efficacy endpoint will be assessed first in the order of hierarchical hypothesis testing for 
the key secondary endpoints after Evaluation Criterion 1 is met.  
For the testing order to be submitted to EMA and PMDA, Evaluation Criterion 2 for 
noninferiority of the primary efficacy endpoint will be the primary efficacy assessment. 
Timing of analyses for primary and key secondary endpoints is also included in Table 4. 
Castration resistance free survival and time to testosterone recovery back to 280 ng/dL at 90-day 
follow-up will be tested at the final analysis only if all the above endpoints reach statistical 
significance in the primary analysis. Endpoints in the higher order will be updated with 
descriptive statistics in the final analysis.   


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Figure 2: 
Diagram of Testing Order in Primary and Key Secondary Endpoints for 
Different Regulatory Agencies 
Evaluation Criterion 1
in Sustained Castration Rate
Lower bound of 95% CI ≥ 90%
In relugolix 
Evaluation Criterion 2
in Sustained Castration Rate
Noinferiority 
Relugolix vs. leuprolide acetate
Castration Rate at Day 4
Castration Rate at Week 3 Day 1
Confirmed PSA Response Rate at 
Week 3 Day 1
FSH Level at Week 25 Day 1
Profound Castration Rate at 
Week 3 Day 1
Castration Resistance Free 
Survival in Patients with 
Metastatic PC
Time to Testosterone Recovery 
at 90-day Follow-up
Castration Resistance Free 
Survival in Patients with or 
without Metastatic PC
Evaluation Criterion 2
in Sustained Castration Rate
Noinferiority 
Relugolix vs. leuprolide acetate
Castration Rate at Day 4
Castration Rate at Week 3 Day 1
Confirmed PSA Response Rate at 
Week 3 Day 1
FSH Level at Week 25 Day 1
Profound Castration Rate at 
Week 3 Day 1
Castration Resistance Free 
Survival in Patients with 
Metastatic PC
Time to Testosterone Recovery 
at 90-day Follow-up
Castration Resistance Free 
Survival in Patients with or 
without Metastatic PC
US FDA
Agencies outside 
of US
 
Abbreviations:  CI = confidence interval; EMA = European Medicines Agency; PC = prostate cancer; US FDA = 
United States Food and Drug Administration; PMDA = Japanese Pharmaceutical and Medical Device Agency. 


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Table 4: 
Testing Order and Timing of Analysis for Primary and Key Secondary 
Endpoints for Different Regulatory Agencies 
 
Endpoints 
Testing Order for the US FDA 
Testing Order for EMA and 
PMDA 
At Primary 
Analysis 
At Final 
Analysis 
At Primary 
Analysis 
At Final 
Analysis 
Sustained castration rate per Evaluation 
Criterion 1 (≥ 90% in relugolix) 
1 
Update 
NA 
Update 
Sustained castration rate per Evaluation 
Criterion 2 (noninferiority of relugolix compared 
with leuprolide acetate) 
2 
Update 
1 
Update 
Castration rate on Week 1 Day 4 
3 
Update 
2 
Update 
Castration rate on Week 3 Day 1 
4 
Update 
3 
Update 
Confirmed PSA response rate at Week 3 Day 1 
5 
Update 
4 
Update 
Profound castration rate at Week 3 Day 1 
6 
Update 
5 
Update 
FSH level at Week 25 Day 1 
7 
Update 
6 
Update 
Castration resistance free survival during the 48-
week treatment in patients with metastatic 
prostate cancer a 
NA 
8 
NA 
7 
Castration resistance free survival during the 48-
week treatment in patients with or without 
metastatic prostate cancer a 
NA 
9 
NA 
8 
Time to testosterone recovery back to 280 ng/dL 
at the 90-day follow-up in patients participating 
in testosterone recovery follow-up a 
10 b 
NA 
9 b 
NA 
Abbreviations:  EMA = European Medicines Agency; FSA = follicle-stimulating hormone; NA = not applicable; PSA = 
prostate-specific antigen; US FDA = United States Food and Drug Administration.  
a Castration resistance free survival and time to testosterone recovery back to 280 ng/dL at the 90-day follow-up will be 
tested at the final analysis only if all the above endpoints reach statistical significance in the primary analysis. Endpoints 
in the higher order will be updated with descriptive statistics in the final analysis.  
b Analysis of time to testosterone recovery back to 280 ng/dL at the 90-day follow-up will be performed at the primary 
analysis. Testing order of time to testosterone recovery will be followed by castration resistance free survival in the final 
analysis.   


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7.4.2. 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints include the following: 
• Sustained profound castration rate from Week 5 Day 1 through Week 49 Day 1 
defined as the cumulative probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) while on study treatment from Week 5 Day 1 through Week 49 Day 1; 
• Sustained profound castration rate from Week 25 Day 1 through Week 49 Day 1 
defined as the cumulative probability of testosterone suppression to < 20 ng/dL (0.7 
nmol/L) while on study treatment from Week 25 Day 1 through Week 49 Day 1; 
• Profound castration rate at Week 1 Day 4; 
• Time to testosterone recovery back to > 50 ng/dL; 
• Time to testosterone recovery back to > 280 ng/dL or baseline; 
• PSA response rate at Week 3 Day 1 and Week 5 Day 1;  
• Proportion of patients with PSA concentration < 0.02 ng/mL (0.02 µg/L) at Week 25 
Day 1 visit; 
• Time to PSA progression; 
• FSH level over time (analysis details refer to Section 8). 
• Absolute values and changes from baseline in the scores of each domain in EORTC-
QLQ-C30 and EORTC-QLQ-PR25, at regular intervals during treatment, and during 
the Follow-Up and/or End of Treatment visits (analysis details refer to Section 7.6). 
7.4.3. 
Analyses of Secondary Efficacy Endpoints 
7.4.3.1. 
Castration Rate and Profound Castration Rate at Day 4 and Week 3 Day 1 
Castration rate at Day 4 and Week 3 Day 1 (ie. Day 15) are in the key secondary endpoints and 
will be estimated by use of the Kaplan-Meier method based on time to first testosterone 
castration, which is defined as time from the date of first dose to the date of initial testosterone 
suppression to < 50 ng/dL (1.7 nmol/L).   
The Kaplan-Meier method will be applied with the following, 
• Patients with initial testosterone suppression to < 50 ng/dL (1.7 nmol/L) will be 
considered as an event at the time of initial suppression.   
• Patients without testosterone suppression to < 50 ng/dL (1.7 nmol/L) will be censored 
at the last available assessment prior to the follow-up visits. 
Cumulative incidence curve of time to first testosterone castration will be plotted and 
summarized by treatment group.  Castration rates at Day 4 and Week 3 Day 1 based on the 
cumulative incidence curve of time to first testosterone castration will be estimated along with 
95% CI.   
Treatment difference in castration rates at Day 4 and Week 3 Day 1 between relugolix and 
leuprolide acetate will be estimated along with 95% CI using a similar method to that described 


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in Section 7.3.1.  The stratified test statistics via log-log transformation of the difference in 
cumulative incidence curve at a fixed time point is constructed by (Klein 2007). 
𝑥𝑥2 =
ቄ∑
log ቀ−log ቀ𝑆𝑆𝑅𝑅𝑠𝑠
෢(𝑡𝑡)ቁቁ−log ቀ−log ቀ𝑆𝑆𝐿𝐿𝑠𝑠
෢(𝑡𝑡)ቁቁ
𝑀𝑀
𝑠𝑠=1
ቅ
2
∑
ቐ
𝑉𝑉(𝑆𝑆𝑅𝑅𝑠𝑠
෢(𝑡𝑡))
ቂ𝑆𝑆𝑅𝑅𝑠𝑠
෢(𝑡𝑡) log ቀ𝑆𝑆𝑅𝑅𝑠𝑠
෢(𝑡𝑡)ቁቃ
2 +
𝑉𝑉(𝑆𝑆𝐿𝐿𝑠𝑠
෢(𝑡𝑡))
ቂ𝑆𝑆𝐿𝐿𝑠𝑠
෢(𝑡𝑡) log ቀ𝑆𝑆𝐿𝐿𝑠𝑠
෢(𝑡𝑡)ቁቃ
2ቑ
𝑀𝑀
𝑠𝑠=1
 
Where s is the sth stratum in the total of M strata and t = Day 4 and Week 3 Day 1 in this case.  
Each stratified test statistics at a fixed time under two samples follows a chi-square distribution 
with one-degree freedom.  If the stratified test statistics cannot be calculated due to event having 
not occurred in certain stratum, unstratified test will be used instead.  If unstratified test is still 
not estimable, the stratified version of the Mantel-Haenszel test using pooled Kaplan-Meier 
estimators in each stratum will be constructed as the following.  This test statistics follows a chi-
square distribution with one-degree freedom. 
𝜒𝜒𝑀𝑀𝑀𝑀
2
=
൜∑
𝑛𝑛𝑅𝑅𝑠𝑠𝑛𝑛𝐿𝐿𝑠𝑠
𝑛𝑛𝑅𝑅𝑠𝑠+ 𝑛𝑛𝐿𝐿𝑠𝑠
(
𝑀𝑀
𝑠𝑠=1
𝑆𝑆𝑅𝑅𝑠𝑠
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿𝑠𝑠
෢(𝑡𝑡))ൠ
2
∑
𝑛𝑛𝑅𝑅𝑠𝑠𝑛𝑛𝐿𝐿𝑠𝑠
𝑀𝑀
𝑠𝑠=1
𝑉𝑉(𝑆𝑆𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑠𝑠
෣(𝑡𝑡))
 
 
Profound castration rate at Day 4 and Week 3 Day 1 will be analyzed similarly as above with 
< 20 ng/dL (0.7 nmol/L) as testosterone suppression criterion.  Profound castration rate at 
Week 3 Day 1 is one of the key secondary endpoints and will be compared between relugolix 
and leuprolide acetate using the stratified test statistics, as above. 
Testosterone level and percentage change from baseline in testosterone level at each visit will be 
summarized by treatment group.  Categorical summary of testosterone level in the first 4 weeks 
of treatment will be also summarized.  Due to the different visit schedule in the original protocol 
versus protocol amendment 2, testosterone level in the first 4 weeks under the original protocol 
will be summarized additionally using the visit windows in Table 5.  The same rule in 
Section 4.3.6 for handling multiple assessments in one visit will be used. 
Table 5: 
Visit Windows in the First 4 Weeks under Original Protocol 
Visit 
Start Day 
Target Day 
End Day 
Week 1 Day 4 a 
1 
4 
5 
Week 2 Day 1 
6 
8 
11 
Week 3 Day 1 
12 
15 
18 
Week 4 Day 1 
19 
22 
25 
Week 5 Day1 
26 
29 
43 
a Start day of Week 1 Day 4 only includes postbaseline assessments on or after the first dose. 
 


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7.4.3.2. 
Sustained Profound Castration Rate 
Sustained profound castration rates are defined for two treatment periods: 
• Sustained profound castration rate from Week 5 Day 1 through Week 49 Day 1 is 
defined as the cumulative probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) while on treatment from Week 5 Day 1 through Week 49 Day 1; 
• Sustained profound castration rate from Week 25 Day 1 through Week 49 Day1 is 
defined as the cumulative probability of testosterone suppression to < 20 ng/dL 
(0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 Day 1.   
The Kaplan-Meier method described in Section 7.3.1.2 will be applied similarly by changing the 
castration level (< 50 ng/dL) to profound castration level (< 20 ng/dL). Sustained profound 
castration rate from Week 25 Day 1 through Week 49 Day 1 is described below.   
Definition of Testosterone Test Result at Week 25 Day 1 
Serum concentration of testosterone at Week 25 Day 1 can be obtained at Day 169 with a visit 
window from Day 156 to Day 183 inclusive.  If more than one test result lies within the visit 
window, the result with the closest study day to Day 169 will be used as testosterone test result at 
Week 25 Day 1.  If there are two results equidistant to the scheduled target day, the earlier 
assessment will be used as testosterone test result at Week 25 Day 1. 
Kaplan-Meier Analysis 
Any testosterone test result rising above the profound castration level (≥ 20 ng/dL) between 
Week 25 Day 1 and Week 49 Day 1 will be considered as an event in the Kaplan-Meier analysis. 
Patients who have not reached profound castration level at Week 25 Day 1 will be considered as 
having had an event at the target day of Week 25 Day 1.   
Patients who discontinued from the study prior to Week 25 Day 1 will be censored at the target 
day of Week 25 Day 1.  In addition, patients without a Week 25 Day 1 assessment will be 
considered to have had an event at the target day of Week 25 Day 1. 
For patients reaching profound castration levels at Week 25 Day 1, the following rules will be 
applied to the Kaplan-Meier analysis for estimation of sustained profound castration rate with 
consideration for missed visits.  Time to event or censoring, whichever occurs first, will be used 
in Kaplan-Meier analysis.   
a) Patients who had one or more consecutive missed visits (ie, a visit gap of > 42 days) and 
had a non-profound castrated assessment immediately after the missed visit(s) will be 
considered as having an escape at the target day of the earliest missed visit prior to the 
non-profound castrated assessment; 
b) Patients with one missed visit who has a profound castrated assessment immediately 
before and after the missed visit will be assumed to be profound castrated at the missed 
visit; 
c) Patients with two or more consecutive missed visits (ie, a visit gap of > 70 days) and who 
had a profound castrated assessment immediately before and after the missed visits will be 
censored at the last available testosterone assessment prior to the missed visits. 


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7.4.3.3. 
Prostate-Specific Antigen Response Rate at Week 3 Day 1 and Week 5 Day 1 
Proportion of patients with PSA reduction from baseline at Week 3 Day 1 and Week 5 Day 1 
will be summarized along with 95% exact CI.  Patients without PSA assessment at Week 3 Day 
1 and Week 5 Day 1 will be considered as nonresponders.  The following two criteria will be 
considered for PSA reduction: 
• > 50% reduction from baseline; 
• > 90% reduction from baseline. 
Confirmed PSA response at Week 3 Day 1 is one of the key secondary endpoints and defined as 
> 50% reduction in PSA from baseline at Week 3 Day 1 followed with confirmation at Week 5 
Day 1.  Treatment comparison between relugolix and leuprolide acetate will be performed using 
a stratified Cochran-Mantel-Haenszel test. 
Change from baseline in PSA at Week 3 Day 1 and Week 5 Day 1 will be also summarized.   
7.4.3.4. 
Undetectable Prostate-Specific Antigen Rate at Week 25 Day 1 
Proportion of patients who have a PSA concentration < 0.02 ng/mL (0.02 µg/L) at Week 25 
Day 1 will be summarized by treatment group along with 95% exact CI.  Patients with missing 
PSA assessment at Week 25 Day 1 will be considered as nonresponders.   
7.4.3.5. 
Time to Testosterone Recovery 
Testosterone levels will be followed for up to 90 days in approximately 100 patients randomized 
to relugolix and approximately 50 patients randomized to leuprolide acetate who complete 48 
weeks of treatment and who do not plan to start alternative androgen deprivation therapy within 
the following 12 weeks (or within 24 weeks following the last injection of leuprolide acetate). As 
the enrollment for the follow-up of testosterone recovery has been completed for the patients 
enrolled under protocol amendment 2, analysis of time to testosterone recovery will be 
performed in the primary analysis and there will be no updates in the final analysis.  
Patients will be censored at the time of last follow-up visit or initiation of treatments known to 
suppress testosterone (refer to Appendix Table 1), whichever comes earlier. 
Time to testosterone recovery will be summarized using the Kaplan-Meier method with the 
following 3 testosterone recovery levels:  
• ≥ 50 ng/dL (1.7 nmol/L); 
• Above baseline level or 280 ng/dL; 
• Above 280 ng/dL (as one of the key secondary endpoints).  
Cumulative incidence of time to testosterone recovery at the 30-day, 60-day and 90-day follow-
up visits will be estimated by treatment group along with 95% CI.   
The unstratified test via log-log transformation of the difference in cumulative incidence of time 
to testosterone recovery back to 280 ng/dL will be compared at the 90-day follow-up visit 
(unstratified test version as in Section 7.4.3.1).     


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7.4.3.6. 
Time to Prostate-Specific Antigen Progression 
Prostate-specific antigen progression is defined per Prostate Cancer Clinical Trials Working 
Group 3 Guidelines (Scher et al, 2016) as the following: 
1. With declining PSA from baseline:  The first increase in PSA of ≥ 25% and ≥ 2 ng/mL 
above the nadir with confirmation by a consecutive PSA measurement at least 3 weeks 
later.   
The date of initial PSA progression will be considered as the date of event for the 
Kaplan-Meier analysis.   
The initial PSA progression can be confirmed with later PSA measurements as long as all 
PSA values in between from the initial PSA progression indicated PSA progression.  For 
example, patient had initial PSA progression at Day 78, the second PSA progression at 
Day 92, and the third PSA progression at Day 106.  The patient will be considered as 
having PSA progression at Day 78 with confirmation at Day 106.     
2. Without declining PSA from baseline:  PSA increase of 25% or greater and 2 ng/mL 
from baseline beyond Week 12 (> 84 days after the date of the first dose).  
Patients without confirmed PSA progression will be censored at the last available assessment 
prior to the follow-up visits.  As a sensitivity analysis, patients will be censored at the last 
available assessment prior to the follow-up visits or at the time of initiating any treatment that 
can affect or alter PSA levels (refer to Appendix Table 2), whichever comes earlier.   
Time to PSA progression is defined as the time from the date of first dose to the date of the 
initial PSA progression which was subsequently confirmed and will be analyzed using the 
Kaplan-Meier method.  Treatment comparison via hazard ratio will be performed using Cox 
proportional hazard model. 
7.4.3.7. 
Castration Resistance Free Survival 
Castration resistance free survival will not be analyzed for the primary analyses but will be 
analyzed at the final analyses when approximately 390 patients with metastatic disease have 
been randomized to the study and have had the opportunity to be evaluated for 48 weeks of study 
treatment and completed the 30-day safety follow-up or discontinued early. 
Castration resistance free survival is in the key secondary endpoints and will be analyzed under 
metastatic patients only and mITT population.  PSA results and deaths from follow-up visits will 
be excluded from the analysis.  Patients with metastatic disease will be identified through 
presence of distant metastasis (M1) at study entry reported in the CRF.  If the discrepancy 
between IWRS and CRF is > 5%, sensitivity analysis based on the presence of metastatic disease 
reported in the IWRS will be performed. 
Castration resistance free survival is defined as the time from the date of first dose to the date of 
PSA progression while castrated or death due to any reason, whichever occurs earlier.  A 
confirmed PSA progression prior to testosterone escape or the date of testosterone censoring will 
be considered as an event.  Patients will be censored at the last PSA assessment prior to follow-
up visits, the date of censoring for testosterone, or the date of testosterone escape, whichever 
comes earlier. 


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As a sensitivity analysis, patients will be censored at the last available assessment prior to the 
follow-up visits, the date of censoring for testosterone, the date of testosterone escape, or the 
time of initiating androgen receptor inhibitors (eg, enzalutamide), whichever comes earlier. 
Castration resistance free survival will be analyzed using the Kaplan-Meier method.  Treatment 
comparison with hazard ratio will be performed using Cox proportional hazard model and p-
value will be provided using unstratified log-rank test on patients with metastatic disease and 
stratified log-rank test on mITT population. Proportionality in survival curves between two 
treatment groups will be assessed. CRFS rate at Week 49 Day 1 (Day 337) will be estimated 
along with 95% CI. 
7.5. 
Exploratory Efficacy Endpoints and Analyses 
7.5.1. 
Overall Survival 
Overall survival is defined as time from randomization to date of death prior to data cut-off date.  
The Kaplan-Meier method will be used to describe survival distributions by treatment group.  
Patients will be censored at the last contact date prior to data cut-off date if patient is known to 
be alive prior to data cut-off date.   
7.5.2. 
Pharmacogenomics Analyses 
A separate SAP may be provided for pharmacogenomic analysis on the presence of 
polymorphisms in germline genes related to the hypothalamic-pituitary androgen pathway, 
prostate cancer risk, or to drug-metabolizing enzymes and transporter proteins that might be 
implicated in the drug disposition, safety, or efficacy of relugolix. 
7.6. 
Patient Reported Outcomes 
Patient reported outcome questionnaires (EORTC QLQ-C30, EORTC QLQ-PR25, and EuroQoL 
EQ-5D-5L) are completed by patients at Day 1, Week 5, Week 13, Week 25, Week 37, Week 49, 
and the 30-day safety follow-up visit.  They are also completed in the 60-day and 90-day 
testosterone recovery follow up if patients are participating in the testosterone recovery follow 
up. 
7.6.1. 
EORTC QLQ-C30 and QLQ-PR25 
The scoring procedure for EORTC QLQ-C30 and QLQ-PR25 is shown in Table 6: 
Table 6:   
Scoring Procedure 
 
Domain 
Number of Items 
Item Rangea 
Item Numbers 
EORTC QLQ-C30 
Global Health Status 
2 
6 
29, 30 
Functional Scales 
 
 
 
     Physical functioning 
5 
3 
1 to 5 
     Role functioning 
2 
3 
6, 7 


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For all scales, the raw score is the average of component items: 
RawScore = (I1 + I2 + … + In)/n, 
Where n is the number of responded items within the scale.   
Missing Items 
For multi-item scales, if at least half of the items from the scale have been answered, use all the 
items that were completed and apply the above raw score calculation.  Otherwise, set the scale 
score to missing.  For single-item scales, set the score to missing if the response of the item is 
missing.   
Transformation of Scale Scores 
Apply the below linear transformation to 0 – 100 to obtain the score: 
Functional Scales: 
     Emotional functioning 
4 
3 
21 to 24 
     Cognitive functioning 
2 
3 
20, 25 
     Social functioning 
2 
3 
26, 27 
Symptom Scales 
 
 
 
     Fatigue 
3 
3 
10, 12, 18 
     Nausea and vomiting 
2 
3 
14, 15 
     Pain 
2 
3 
9, 19 
     Dyspnoea 
1 
3 
8 
     Insomnia 
1 
3 
11 
     Appetite loss 
1 
3 
13 
     Constipation 
1 
3 
16 
     Diarrhoea 
1 
3 
17 
     Financial difficulties 
1 
3 
28 
EORTC QLQ-PR25 
Symptom Scales 
 
 
 
    Urinary symptoms 
8 
3 
31 to 37, 39 
    Incontinence aid use 
1 
3 
38 
    Bowel symptoms 
4 
3 
40 to 43 
    Hormonal treatment-related symptoms 
6 
3 
44 to 49 
Functional Scales 
 
 
 
     Sexual activity 
2 
3 
50, 51 
     Sexual functioning 
4 
3 
52 to 55 
a Item range is the difference between the possible maximum and the minimum response to individual items 
(eg, range for items taking values from 1 to 4 is 3). 
 


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Score = ቄ 1 −
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−1
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
 ቅ× 100 
Symptom Scales/Global Health Status: 
Score = { 
𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅−1
𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
 } × 100 
A high scale score represents a higher response level.  For example, a high score for a functional 
scale represents a high/healthy level of functioning while a high score for a symptom scale 
represents a high level of symptomatology/problems. 
Analyses on Scale Scores 
Scores and change from baseline scores from each scale will be summarized by each visit and 
treatment group. 
For each scale, a mixed model using repeated measures will be performed with baseline scores, 
treatment, visit, randomization stratification factors (per EDC if the discrepancy between IWRS 
and CRF is > 5%), and treatment by visit interaction included as fixed effects.  Change from 
baseline in each scale for each patient at each visit will be included as the dependent variable.  
An unstructured covariance matrix will be used in the mixed effect model.  The least square 
means from the mixed model using repeated measures will be provided for each treatment group 
at each visit. 
7.6.2. 
EuroQoL EQ-5D-5L 
The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ Visual Analogue Scale 
(EQ VAS).   
The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression).  Each dimension has 5 levels:  no problems (1 as 
numerical score), slight problems (2 as numerical score), moderate problems (3 as numerical 
score), severe problems (4 as numerical score), and extreme problems (5 as numerical score).  
There should be only ONE response for each dimension.  If more than one box is ticked for a 
single dimension, it should be treated as missing values.  For each dimension, the count and 
proportion of improvement by level or at least one level will be tabulated by treatment group and 
each visit.  The denominator for the proportion will be based on the number of patients who 
provided non-missing responses to the dimensions at baseline.   
The EQ VAS records the patient’s self-rated health on a 20-cm vertical visual analogue scale.  It 
asks respondents to “mark an X on the scale to indicate how your health is TODAY” and then to 
“write the number you marked on the scale in the box below.”  If there is a discrepancy between 
where the respondent has placed the X and the number respondent has written in the box, 
administrator should use the number in the box.  The non-missing EQ VAS score will be 
summarized, including 25th and 75th percentiles, at each visit by treatment group. 


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8. 
PHARMACODYNAMIC ANALYSES 
Predose concentrations and change from baseline at each visit will be summarized in predose 
concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
dihydrotestosterone, and sex hormone-binding globulin.  FSH concentration level at Week 25 
Day 1 between relugolix and leuprolide acetate will be compared using the two-sample t-test.   


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9. 
PHARMACOKINETIC ANALYSES 
Plasma concentrations in relugolix will be summarized and listed.   
For patients from China and patients from Japan in the pharmacokinetic subset, pharmacokinetic 
parameters Cmax, AUC0-τ, and tmax from Day 1 and Week 2 Day 1 visit will be determined. 
A separate SAP will be detailed for further population pharmacokinetic analyses.   


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10. 
SAFETY ANALYSES 
Unless otherwise specified, safety analyses will be conducted using the safety population 
according to the treatment actually received.     
10.1. 
Adverse Events 
Per protocol, adverse event reporting period refers to adverse events planned to be collected from 
the time of the first dose of study drug through the safety follow up visit approximately 30 days 
after the end of treatment period, or the date of initiation of another investigational agent or 
hormonal therapy or surgical intervention following the end of treatment, whichever occurs first.  
Serious adverse events reported to the investigator after the safety reporting period should be 
reported to the sponsor if the investigator assesses the event as related to the study drug 
treatment. 
The severity of all treatment-emergent adverse events will be evaluated by the investigator based 
on the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(NCI CTCAE v4.03) and will be coded to preferred term and system organ class using the 
Medical Dictionary for Regulatory Activities (MedDRA) 22.0 or higher.     
Treatment-emergent adverse event is defined as any adverse event that occur after administration 
of the first dose of study drug and prior to the end of the adverse event reporting period, except 
for drug related serious adverse events. 
Adverse event summaries will be based on treatment emergent adverse events, unless otherwise 
specified.  Any procedure-related adverse event reported during screening will be listed and 
flagged in listings by patient. 
Tabular summaries with the number and percentage of patients with the following adverse events 
(but not limited to) will be provided: 
• Overview of adverse events 
• All adverse events 
− By system organ class and preferred term 
− By decreasing frequency of preferred term 
− By system organ class, preferred term, and maximum severity 
− Study drug-related per investigator by system organ class and preferred term 
• Grade 3 or higher adverse events 
− By system organ class and preferred term 
− By decreasing frequency of preferred term 
− Study drug-related per investigator by system organ class and preferred term 
• Adverse events leading to study drug withdrawn 
− By system organ class and preferred term 
− By decreasing frequency of preferred term 


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• Adverse events leading to study drug interruption  
− By system organ class and preferred term 
− By decreasing frequency of preferred term 
• Adverse events resulting in fatal outcome 
− By decreasing frequency of preferred term 
• Serious adverse events  
− By system organ class and preferred term 
− By decreasing frequency of preferred term 
− By system organ class, preferred term, and maximum severity 
− By system organ class, preferred term, and relationship to study drug 
• Adverse events of clinical interest (alanine aminotransferase [ALT] or aspartate 
aminotransferase [AST] ≥ 3 × upper limit of normal [ULN]) 
− By decreasing frequency of preferred term 
− By system organ class, preferred term, and maximum severity 
In addition, adverse event categories defined in Table 7 will be summarized by decreasing 
frequency of preferred term. 
Table 7:   
Constitution of Adverse Event Categories 
Category 
Search Criteria 
Loss of bone mineral density 
Osteoporosis/Osteopenia SMQ (broad) 
All PTs including the term “Fracture,” excluding “Tooth fracture” 
and “Fracture of penis” 
QTc prolongation 
Torsades de Pointes/QT prolongation SMQ (broad) 
Hepatic transaminase elevations  
Drug-related hepatic disorders SMQ (narrow) 
Carbohydrate and lipid metabolic effects 
Dyslipidaemia SMQ (broad) 
Hyperglycemia/New onset diabetes mellitus SMQ (narrow) 
Adverse Cardiovascular events 
Major Adverse Cardiovascular Events: 
Myocardial infarction SMQ (broad) 
Central nervous system haemorrhages and cerebrovascular 
conditions SMQ (broad) 
Deaths due to all causes 
 
Ischemic heart disease 
Ischaemic heart disease SMQ (broad) 


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Vasomotor symptoms 
The following 5 PTs will be included:  
1. Hyperhidrosis 
2. Feeling hot  
3. Hot flush  
4. Night sweats  
5. Flushing 
Mood Disorders 
Depression and suicide/self-injury SMQ (broad) 
Hypersensitivity 
Hypersensitivity SMQ (narrow) 
Abbreviations:  PT = preferred term; SMQ = Standardised MedDRA Queries. 
10.2. 
Laboratory Data 
Laboratory parameters, including chemistry and hematology panels, specified as per protocol 
and collected from the central laboratory, will be tabulated and presented in by-patient listings.  
Urinalysis and hepatitis virus serological test results, if any, will be provided in by-patient 
listings only.    
The NCI CTCAE grading scale with numeric component will be used to categorize toxicity 
grade for laboratory parameters (CTCAE v4.03).  Parameters that have criteria available for both 
low and high values (eg, hypercalcemia for a high value of calcium and hypocalcemia for a low 
value of calcium) will be summarized for both criteria (low and high).  Patients will only be 
counted once for each criterion.  The same patient can be counted for both criteria if the patient 
has laboratory values meeting each criterion.  Shift tables will be provided for each gradable 
parameter to summarize baseline toxicity grade versus worst postbaseline toxicity grade.  For 
laboratory parameters that are not gradable by the CTCAE, a shift table based upon the normal 
range (low, normal, and high) will be provided for each parameter to summarize the baseline 
versus worst postbaseline results.   
Boxplots of laboratory values over time will be plotted for key laboratory parameters.  These 
laboratory parameters include but are not limited to hematology (hemoglobin, platelets, 
leukocytes, neutrophils), creatinine, glomerular filtration rate, and hepatic function panel (ALT, 
AST, ALP, and total bilirubin [TBL]).   
The change from baseline to each postbaseline study visit will be presented by treatment group 
for each laboratory test.   
The number and proportion of patients with liver test elevations will be presented by treatment 
group.  Liver test elevations are assessed by using postbaseline results for ALT, AST, ALP, and 
TBL based on the definitions presented in Table 8.    


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Table 8:   
Categories of Liver Function Test Elevations 
Laboratory Test 
Category  
ALT or AST 
ALT or AST > ULN - < 3 × ULN 
ALT or AST ≥ 3 × to < 5 × ULN 
ALT or AST ≥ 5 × to < 8 × ULN 
ALT or AST ≥ 8 × to < 10 × ULN 
ALT or AST ≥ 10 × to < 20 × ULN 
ALT or AST ≥ 20 × ULN 
Total bilirubin 
Total bilirubin > 2 × ULN 
ALT or AST and total bilirubin 
ALT or AST ≥ 3 × ULN + total bilirubin > 2 × ULN  
ALT or AST, total bilirubin, and ALP 
ALT or AST ≥ 3 x ULN + total bilirubin > 2 × ULN + ALP < 2 × ULN 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ULN = upper limit of normal. 
 
The number and percent of patients with either ALT or AST ≥ 3 times the ULN and TBL 
> 2 times ULN concurrently, defined as measurements occurred on the same day, will also be 
presented.   
Worst postbaseline ALT and TBL values will be evaluated using the evaluation of drug induced 
serious hepatotoxicity (eDISH) concept.   
Selected chemistry and hematology test results meeting pre-defined limits of change at any time 
and based on last observation on treatment will be also summarized per pre-defined threshold 
(refer to Appendix 2). 
10.3. 
Other Safety Analyses 
10.3.1. 
Electrocardiograms 
Electrocardiogram assessment will be read by local reading.  Overall interpretation will be 
presented in by-patient listing.   
10.3.2. 
Visual Acuity 
Visual acuity will be measured using the tumbling E chart with Visual Acuity Score.  A 10-foot 
standard distance will be used and each correctly identified “E” will increase the Visual Acuity 
Score by one point.  Visual Acuity Score at baseline and at each scheduled postbaseline 
assessment time point will be presented in by-patient listing.  Visual acuity score ≤ 90 or 
decrease from baseline ≥ 10 points will be flagged in the by-patient listing. 
10.3.3. 
Vital Signs 
Blood pressure (systolic and diastolic), heart rate, and weight measurements will be summarized 
at baseline and each subsequent scheduled assessment by treatment group.  Change from 
baseline will be calculated and presented for each parameter at all scheduled postbaseline 
assessment timepoints.  All vital sign data will also be provided in by-patient listing.   


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Potentially clinically significant abnormalities in vital signs are defined in Table 9 and will be 
summarized by treatment group.  Potentially clinically significant abnormalities will also be 
flagged in by-patient listing.   
Table 9:   
Categories of Potentially Clinically Significant Abnormalities in Vital Signs  
Vital Sign Parameter 
Category  
Systolic blood pressure 
 
≥ 140 mmHg 
≥ 180 mmHg  
≤ 90 mmHg 
Increase of ≥ 20 mmHg from baseline 
Decrease of ≥ 20 mmHg from baseline 
Diastolic blood pressure  
≥ 90 mmHg 
≥ 105 mmHg 
≤ 50 mmHg 
Increase of ≥ 15 mmHg from baseline 
Decrease of ≥ 15 mmHg from baseline 
Heart rate 
≥ 120 bpm 
< 45 bpm 
Increase of ≥ 15 bpm from baseline 
Decrease of ≥ 15 bpm from baseline 
 


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REFERENCES 
Klein J, Logan B, Harhoff M, Andersen PK. Analyzing Survival Curves at a Fixed Point in Time. Stat Med. 2007 
Oct 30; 26 (24): 4505-19. 
Scher H, Morris M, Stadler W, Higano C, Basch E, Fizazi K, et al. Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations from the Prostate Cancer Clinical Trials Working Group 
3.  J Clin Onco.  2016 Apr 20; 34 (12):1402-18. 
 
 


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REVISION HISTORY 
Table 10:   
Revision History 
Version 
Effective Date 
Comments 
1.0 
12SEP2019 
New document 
2.0 
29OCT2019 
1. Naming change from “time to castration resistance” to 
“castration resistance free survival”. 
2. Updates on Kaplan-Meier analysis for the primary endpoint, 
sustained castration rate from Week 5 Day 1 to Week 49 
Day 1, to align with FDA review comments in Sections 7.3.1.1, 
7.3.1.2, 7.3.2.2 and 7.3.2.3. 
3. Corrections in test statistics of difference in cumulative 
incidence curve at a fixed time point in Section 7.4.3.1. 
4. Censoring rule b of analysis on sustained profound castration 
changed to align with sustained castration rate in 
Section 7.4.3.2. 
3.0 
06NOV2019 
1. Aligned with FDA review comments, changed ≤ 50 ng/dL to < 
50 ng/dL for castration level and  changed ≤ 20 ng/dL to < 20 
ng/dL for profound castration level. 
2. To address FDA review comments, added “sustained profound 
castration rate from Week 5 Day 1 through Week 49 Day 1 as a 
secondary endpoint, in Table 1, Sections 7.4.2 and 7.4.3.2. 
3. To address FDA review comments, similar censoring rules for 
the primary analysis of sustained castration rate applied to 
sustained profound castration rates in Section 7.4.3.2.   
 


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APPENDIX 1:  LIST OF MEDICATIONS THAT HAVE IMPACT ON 
TESTOSTERONE OR PROSTATE-SPECIFIC ANTIGEN LEVEL 
The following lists of medications that are likely to affect analysis of efficacy are identified and 
will be finalized prior to the database lock. Any changes in this appendix after the finalization of 
the SAP will not be considered as changes in the planned analysis. 
 
Appendix Table 1: Medication List of Therapies Known to Suppress Testosterone 
Generic Name 
WHO Drug Dictionary Preferred Term 
degarelix 
DEGARELIX 
 
DEGARELIX ACETATE 
goserelin 
GOSERELIN 
 
GOSERELIN ACETATE 
leuprolide 
LEUPROLIDE 
leuprorelin 
LEUPRORELIN 
 
LEUPRORELIN ACETATE 
abarelix 
ABARELIX 
histrelin 
HISTRELIN 
triptorelin 
TRIPTORELIN 
 
TRIPTORELIN ACETATE 
 
TRIPTORELIN EMBONATE 
 
 
 
 
 
 
 
 


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Appendix Table 2: Medication List of Treatments that Can Affect or Alter Prostate-
Specific Antigen  
Generic Name 
WHO Drug Dictionary Preferred Term 
cabazitaxel 
CABAZITAXEL 
cisplatin 
CISPLATIN 
docetaxel 
DOCETAXEL 
doxorubicin 
DOXORUBICIN 
 
DOXORUBICIN HYDROCHLORIDE 
etoposide 
ETOPOSIDE 
fluorouracil 
FLUOROURACIL 
ifosfamide 
IFOSFAMIDE 
paclitaxel 
PACLITAXEL 
bicalutamide 
BICALUTAMIDE 
chlormadinone acetate 
CHLORMADINONE ACETATE 
enzalutamide 
ENZALUTAMIDE 
flutamide 
FLUTAMIDE 
nilutamide 
NILUTAMIDE 
epalutmide 
EPALUTMIDE 
estramustine 
ESTRAMUSTINE 
sipuleucel-T 
SIPULEUCEL-T 
 
 
 


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APPENDIX 2:  LIST OF PRE-DEFINED THRESHOLD IN SELECTED 
CHEMISTRY AND HEMATOLOGY TEST RESULTS 
Chemistry Laboratory 
Liver Function 
 
  ALT > ULN and < 3X ULN 
  Total BILI > ULN 
  ALT >= 3X ULN and < 5X ULN 
  Total BILI >2X ULN 
  ALT >= 5X ULN and < 10X ULN 
 
  ALT >= 10X ULN and < 20X ULN 
  ALT or AST >= 3X ULN and Total BILI > 2X ULN 
  ALT >= 20X ULN 
  ALT or AST >= 3X ULN and Total BILI > 2X ULN 
and ALP < 2X ULN 
 
  ALT > ULN and < 3X ULN 
  AST > ULN and < 3X ULN 
 
  AST >= 3X ULN and < 5X ULN 
  GGT > ULN and < 3X ULN 
  AST >= 5X ULN and < 10X ULN 
  GGT >= 3X ULN and < 5X ULN 
  AST >= 10X ULN and < 20X ULN 
  GGT >= 5X ULN and < 10X ULN 
  AST >= 20X ULN 
  GGT >= 10X ULN and < 20X ULN 
 
  GGT >= 20X ULN 
  ALT or AST > ULN and < 3X ULN 
  GGT > ULN and < 3X ULN 
  ALT or AST >= 3X ULN and < 5X ULN 
 
  ALT or AST >= 5X ULN and < 10X ULN 
 
  ALT or AST >= 10X ULN and < 20X ULN 
 
  ALT or AST >= 20X ULN 
 
 
 
Renal Function 
 
  CR > 1.5 mg/dL and > BL 
  GFR < 15 mL/min per 1.73 m2 
  CR > 50% increase from BL 
  GFR >= 15 - < 30 mL/min per 1.73 m2 
 
  GFR >= 30 - < 60 mL/min per 1.73 m2 
 
  GFR >= 60 - < 90 mL/min per 1.73 m2 
 
  GFR >= 90 mL/min per 1.73 m2 
 
 


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Chemistry Laboratory 
Metabolic Parameters 
 
  Fasting Glucose 
Highest Postbaseline Glucose 
     < 100 mg/dL at BL 
   Gluc >= 200 mg/dL 
          < 100 mg/dL at week 48 
   Gluc >= 200 mg/dL and >= 126 BL 
          >= 100 - < 126mg/dL at week 48 
   Gluc >= 500 mg/dL 
          >= 126 mg/dL at week 48 
   Gluc >= 500 mg/dL and >= 126 BL 
 
 
      >= 100 - < 126 mg/dL at BL 
Total CHOL > 200 mg/dL and > BL 
          < 100 mg/dL at week 48 
Total CHOL increase > 30 mg/dL from BL 
          >= 100 - < 126 mg/dL at week 48 
 
          >= 126 mg/dL at week 48 
HDL < LLN and < BL 
 
LDL > ULN and > BL 
     >= 126 mg/dL at BL 
TRIG > ULN and > BL 
         < 100 mg/dL at week 48 
 
         >= 100 - < 126 mg/dL at week 48 
 
         >= 126 mg/dL at week 48 
 
 
 
Electrolytes and other Chemistry Parameters 
 
 ALB < LLN and < BL 
CK > 2X ULN and > BL 
 ALB > ULN and > BL 
CK > 5X ULN and > BL 
 
CK > 10X ULN and > BL 
 ALP > 2X ULN and > BL 
 
 ALP > 5X ULN and > BL 
MG < LLN and < BL 
 ALP > 10X ULN and > BL 
MG > ULN and > BL 
 
 
 CA < LLN and < BL 
PHOS < LLN and < BL 
 CA > ULN and > BL 
PHOS > ULN and > BL 
 
 


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 K < LLN and < BL 
NA < LLN and < BL 
 K > ULN and > BL 
NA > ULN and > BL 
 
 
Hematology Laboratory 
HCT < LLN and < BL 
NEUT < LLN and < BL 
HCT decrease >= 10 from BL 
NEUT > ULN and > BL 
 
 
HGB <= 10.5 g/dL and < BL 
BASO < LLN and < BL 
HGB decrease > 1 g/dL from BL 
BASO > ULN and > BL 
 
 
MCV < LLN and < BL 
EOS < LLN and < BL 
MCV > ULN and > BL 
EOS > ULN and > BL 
 
EOS > 5% and > BL 
WBC < LLN and < BL 
 
WBC > ULN and > BL 
PLT < LLN and < BL 
 
PLT < 100 X 109/L and < BL 
LYM < LLN and < BL 
PLT > ULN and > BL 
LYM > ULN and > BL 
 
 
HbA1c >= 6.5 and > BL 
MONO < LLN and < BL 
HbA1c increase > 1.0 from BL 
MONO > ULN and > BL 
 
BL = baseline; LLN = lower limit of normal; ULN=upper limit of normal.