Clinical trial NCT03654274
Conditions: Endometriosis
Keywords: Endometriosis Dysmenorrhea Pain Dyspareunia Pelvic Pain
Sponsor: Myovant Sciences GmbH
Start date: 2018-05-22; Completion date: 2023-01-31
Enrollment: 802 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term efficacy and safety of relugolix 40 milligram (mg) once daily co-administered with low-dose estradiol (E2) and norethindrone acetate (NETA) for up to 104 weeks on endometriosis-associated pain in participants who previously completed a 24-week treatment period in one of the parent studies (MVT-601-3101 or MVT-601-3102).

Detailed description:
This study is an international phase 3 open-label, single-arm, long-term efficacy and safety extension study that will enroll eligible participants who have completed their participation in one of the phase 3 randomized, double-blind, placebo-controlled parent studies, MVT-601-3101 (SPIRIT 1 - NCT03204318) or MVT-601-3102 (SPIRIT 2 - NCT03204331). All participants will receive relugolix 40 mg orally once daily co-administered with low-dose E2 (1.0 mg) and NETA (0.5 mg) for 80 weeks.

Approximately 800 women with endometriosis-associated pain will be enrolled, after having completed a 24-week treatment period in one of the parent studies. The objectives of the study are to evaluate long-term efficacy and safety through up to 104 weeks of treatment (including treatment during the parent study) of relugolix co-administered with low-dose E2/NETA.

Baseline procedures for this extension study will be performed on the same day as the Week 24 Visit of the parent study. This visit, referred to as the "Week 24/Baseline Visit, will be defined as the date of completion of the last Week 24 procedure in the parent study. Participants will have received their last dose of study drug in the parent study on the day prior to the Week 24/Baseline Visit and will receive their first dose of study drug for this extension study in the clinic after the participant is determined to be eligible for this extension study and has provided informed consent to participate. The administration of the first dose of study drug for MVT-601-3103 will define enrollment into this study. Study participants will then take the open-label study treatment orally, once daily for 80 weeks.

Arms: arm 1: Relugolix co-administered with E2/NETA for 80 weeks.
Interventions: intervention 1: Relugolix intervention 2: Estradiol/norethindrone acetate
Intervention descriptions: intervention 1: Relugolix 40-mg tablet administered orally once daily intervention 2: Capsule containing co-formulated tablet of E2 (1.0 mg) and NETA (0.5 mg) administered orally once daily

Protocol documents:
Prot_000.pdf: 
MVT-601-3103 
Clinical Study Report Appendices 
Myovant Sciences GmbH 
1 
CONFIDENTIAL 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
Protocol Original 
Protocol Amendment 1 
Protocol Amendment 1 Summary of Changes 
Protocol Amendment 2 
Protocol Amendment 2 Summary of Changes 
Protocol Amendment 3 
Protocol Amendment 3 Summary of Changes 
Protocol Amendment 3.1 
Protocol Amendment 3.1 Summary of Changes 
 


1 
CLINICAL STUDY PROTOCOL 
Study Title: 
Investigational Product: 
Protocol Number: 
Indication: 
Sponsor: 
Regulatory Identifiers: 
Version and 
Effective Date: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Relugolix 
MVT-601-3103 
Treatment of Endometriosis-Associated Pain 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
IND# 076642 
EudraCT # 2017-004066-10 
Original:  
25-OCT-2017
06-NOV-2017
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:  MVT-601-3103 
 
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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 
 
 
 


Clinical Study Protocol:  MVT-601-3103 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SPONSOR SIGNATURE PAGE ..................................................................................................2 
INVESTIGATOR STATEMENT ................................................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
LIST OF ABBREVIATIONS .......................................................................................................8 
1.
PROTOCOL SYNOPSIS ...........................................................................................9 
1.1. 
Schedule of Activities .................................................................................................17 
2.
INTRODUCTION ....................................................................................................21 
2.1. 
Endometriosis-Associated Pain ..................................................................................21 
2.2. 
Relugolix .....................................................................................................................22 
2.2.1. 
Indication ....................................................................................................................22 
2.2.2. 
Pharmacology .............................................................................................................23 
3.
STUDY OBJECTIVES AND ENDPOINTS ..........................................................23 
4.
INVESTIGATIONAL PLAN ..................................................................................26 
4.1. 
Overall Study Design ..................................................................................................26 
4.2. 
Discussion of Study Design, Including Dosing ..........................................................28 
4.3. 
Selection of Study Population ....................................................................................30 
4.3.1. 
Inclusion/Exclusion Criteria .......................................................................................30 
4.4. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number .......................................................................................................................32 
4.5. 
Removal of Patients from Therapy .............................................................................33 
4.6. 
Contraception/Pregnancy Avoidance .........................................................................34 
5.
TREATMENTS ........................................................................................................35 
5.1. 
Treatments Administered ............................................................................................35 
5.2. 
Identity of Investigational Product .............................................................................35 
5.2.1. 
Product Characteristics ...............................................................................................35 
5.3. 
Randomization and Stratification ...............................................................................36 
5.4. 
Directions for Administration .....................................................................................36 
5.5. 
Dose Reduction/Dose Administration ........................................................................36 


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5.6. 
Storage, Packaging, and Labeling ..............................................................................36 
5.7. 
Blinding ......................................................................................................................37 
5.8. 
Study Drug Accountability and Treatment Compliance ............................................37 
5.9. 
Prior and Concomitant Medications and Non-Drug Therapies ..................................37 
5.9.1. 
Prohibited Medications ...............................................................................................37 
5.9.2. 
Permitted Medications ................................................................................................40 
5.9.3. 
Prohibited Non-Drug Therapies .................................................................................41 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................41 
6.1. 
Schedule of Observations and Procedures ..................................................................41 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) ................................41 
6.3. 
Early Termination Visit and Follow-up Visit .............................................................42 
6.4. 
Unscheduled Visits .....................................................................................................43 
6.5. 
Study Procedures ........................................................................................................43 
6.5.1. 
Efficacy-Related Procedures ......................................................................................43 
6.5.2. 
Safety-Related Procedures ..........................................................................................44 
7. 
SAFETY CONSIDERATIONS ...............................................................................47 
7.1. 
Adverse Event Definitions ..........................................................................................47 
7.1.1. 
Adverse Event .............................................................................................................47 
7.1.2. 
Serious Adverse Event ................................................................................................48 
7.2. 
Adverse Event Reporting ............................................................................................49 
7.2.1. 
Adverse Event Reporting Period ................................................................................50 
7.3. 
Assigning Causal Relationship to Study Drug ...........................................................50 
7.4. 
Assigning Severity Rating for Adverse Events ..........................................................51 
7.5. 
Adverse Events of Clinical Interest Reporting ...........................................................51 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities ......................................................................................................51 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities ............................................................................................52 
7.6. 
Serious Adverse Event Reporting ...............................................................................52 
7.7. 
Study Drug Overdose Management ............................................................................53 
7.8. 
Pregnancy Reporting ..................................................................................................54 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures ........................................54 


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7.10. 
Benefit/Risk Assessment ............................................................................................54 
8. 
DATA QUALITY ASSURANCE ............................................................................57 
8.1. 
Clinical Procedures .....................................................................................................57 
8.2. 
Monitoring ..................................................................................................................57 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ........................58 
9.1. 
Randomization Methods .............................................................................................58 
9.2. 
Analysis Populations ..................................................................................................58 
9.3. 
Sample Size Justification ............................................................................................58 
9.4. 
Efficacy Analyses .......................................................................................................58 
9.5. 
Safety Analyses ..........................................................................................................60 
9.6. 
Pharmacodynamics Analyses .....................................................................................61 
9.7. 
Exploratory Analyses ..................................................................................................62 
9.8. 
Interim Analyses .........................................................................................................62 
9.9. 
Steering Committee ....................................................................................................62 
10. 
RESPONSIBILITIES ...............................................................................................62 
10.1. 
Investigator Responsibilities .......................................................................................62 
10.1.1. 
Good Clinical Practice ................................................................................................62 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................63 
10.1.3. 
Informed Consent .......................................................................................................63 
10.1.4. 
Confidentiality ............................................................................................................63 
10.1.5. 
Study Files and Retention of Records ........................................................................64 
10.1.6. 
Electronic Case Report Forms ....................................................................................65 
10.1.7. 
Investigational Product Accountability ......................................................................65 
10.1.8. 
Inspections ..................................................................................................................65 
10.1.9. 
Protocol Compliance ..................................................................................................65 
10.2. 
Sponsor Responsibilities .............................................................................................66 
10.2.1. 
Protocol Modifications ...............................................................................................66 
10.2.2. 
Study Report ...............................................................................................................66 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ......................66 
10.3. 
Joint Investigator/Sponsor Responsibilities ................................................................66 
10.3.1. 
Access to Information Monitoring..............................................................................66 
10.3.2. 
Access to Information for Auditing or Inspections ....................................................67 
10.3.3. 
Study Discontinuation ................................................................................................67 


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10.3.4. 
Publications .................................................................................................................67 
REFERENCES .............................................................................................................................68 
APPENDICES ..............................................................................................................................70 
 Protocol-Specified Rescue Analgesics ...................................................................70 
Appendix 1.
 Daily eDiary ...........................................................................................................71 
Appendix 2.
 Endometriosis Health Profile-30 ............................................................................95 
Appendix 3.
 European Quality of Life Five-Dimension Five-Level Scale.................................99 
Appendix 4.
 Patient Global Impression of Change and Patient Global Assessments ...............101 
Appendix 5.
 Endometriosis Health Profile - Work Domain .....................................................103 
Appendix 6.
 Assessment of Abnormal Liver Function Tests ...................................................104 
Appendix 7.
 
LIST OF TABLES 
Table 1-1 Schedule of Activities for Study MVT-601-3103 ......................................................17 
Table 5-1 Description of MVT-601-3003 Study Drugs ..............................................................35 
Table 5-2 Prohibited Medications ...............................................................................................37 
Table 6-1 Clinical Laboratory Tests ...........................................................................................45 
Table 7-1 Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................51 
Table 7-2 Protocol Risk Assessment and Mitigation Strategies .................................................55 
 
Appendix Table 1 Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .........104 
Appendix Table 2 Investigations of Alternative Causes for Abnormal Liver Tests .................105 
 
LIST OF FIGURES 
Figure 4-1 MVT-601-3103 Study Schematic ...............................................................................28 
 
 
 


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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EHP 
Endometriosis Health Profile 
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMPP 
nonmenstrual pelvic pain 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 
PLD 
phospholipidosis 
QTc 
corrected QT (interval) 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
ULN 
upper limit of normal 
US 
United States 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


Clinical Study Protocol:  MVT-601-3103 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Safety and Efficacy Extension Study to Evaluate Relugolix Co-Administered 
with Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain 
Protocol Number 
MVT-601-3103 
Location 
Multinational, including North and South America, Europe, Africa, 
New Zealand, and Australia 
Study Centers 
Approximately 320 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with endometriosis-associated pain 
Number of Patients 
Planned 
Approximately 800 
Study Objectives 
In women with endometriosis-associated pain, the study objectives are as 
follows: 
Primary Efficacy Objective 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated pain. 


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Secondary Efficacy Objectives 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on the following: 
o Function, as measured by the Endometriosis Health Profile (EHP)-30 
Pain Domain; 
o Dysmenorrhea, as measured by the Numerical Rating Scale (NRS) for 
dysmenorrhea; 
o Patient Global Impression of Change (PGIC) for dysmenorrhea; 
o Nonmenstrual pelvic pain (NMPP), as measured by the NRS for 
NMPP; 
o PGIC for NMPP; 
o Dyspareunia, measured by the NRS; 
o PGIC for dyspareunia; 
o Dyspareunia-related functional effects (Subject Modified Biberoglu 
and Behrman [sB&B]); 
o Patient Global Assessment (PGA) for pain; 
o PGA for function; 
o Endometriosis-associated quality of life, as measured by the EHP-30 
Control and Powerlessness, Social Support, Emotional Well-Being, 
and Self-Image domains; 
o Dysmenorrhea-related functional effects (sB&B); 
o NMPP-related functional effects (sB&B). 
 
Safety Objectives 
• 
To evaluate the safety of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate for up to 52 weeks, 
among patients who previously completed a 24-week treatment period in 
one of the parent studies (MVT-601-3101 or MVT-601-3102), including: 
o Adverse events; 
o Changes in bone mineral density. 
 
Pharmacodynamic Objective 
• 
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 


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Exploratory Objective 
• 
To evaluate the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate on endometriosis-
associated quality of life (EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life outcomes (European 
Quality of Life Five-Dimension Five-Level Scale [EQ-5D-5L]) for up to 
52 weeks among patients who previously completed a 24-week treatment 
period in one of the parent studies (MVT-601-3101 or MVT-601-3102). 
Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term efficacy 
and safety study that will enroll eligible patients who have completed their participation in one of the 
phase 3 randomized, double-blind, placebo-controlled parent studies (MVT-601-3101 or 
MVT-601-3102).  All patients will receive oral relugolix 40 mg once daily co-administered with 
low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 28 weeks.  Approximately 
800 women with endometriosis-associated pain will be enrolled.  The objectives of the study are to 
evaluate long-term efficacy and safety through up to 52 weeks of treatment (including treatment during 
the parent study) of relugolix co-administered with low-dose estradiol/norethindrone acetate.  Eligible 
patients will have completed participation in one of the parent studies and consented to participate in 
this extension study.  Baseline procedures will be done at the same visit for this extension study 
(referred to as the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit from 
the parent study, and will be defined as the date of completion of the last Week 24 procedure in the 
parent study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent study have 
been completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 24/Baseline 
visit.  No MVT-601-3103 study procedures will be performed until the consent form for this extension 
study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit, and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  Therefore, results of testing required for eligibility must be available on or prior 
to the Week 24/Baseline visit.  The administration of the first dose of study drug for MVT-601-3103 
will define enrollment into this study.  Study participants will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once 
daily for 28 weeks. 
During the 28-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients will 
continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, analgesic 
use, and the functional effects of endometriosis-associated pain (sB&B) in the electronic diary 
(eDiary).  Only study-specific rescue analgesic medications will be allowed starting with the 
Week 24/Baseline visit and through the Follow-Up visit and these medications will be taken for control 
of pain and not prophylactically.  Health-related quality of life questionnaires; PGIC for dysmenorrhea, 
NMPP, and dyspareunia; and PGA for pain and function will be completed during the visits on an 
electronic tablet or on paper, according to the Schedule of Activities (Section 1.1). 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment of 
bone mineral density via dual-energy x-ray absorptiometry (DXA). 
 


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Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, and bone mineral density with 
DXA. 
Patients with a bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit relative to the parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (±1) months after the last dose of study medication. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption 
(eg, medical procedure or medications) will be contacted again by telephone 3 (+0.5) months after the 
Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 
visit, then the Follow-up visit and the follow-up procedures performed under this protocol, including 
the follow-up bone densitometry scan at 6 (±1) months and status of menstruation recovery, may be 
waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1. Completed 24 weeks of study drug treatment and study participation in either MVT-601-3101 
or MVT-601-3102; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any study-
specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures 
for this study will be done under the informed consent for the parent study. 
3. Is not expected to undergo gynecological surgery or other surgical procedures for treatment of 
endometriosis (including ablation, shaving, or excision) during the study, including during the 
Follow-Up Period, and the patient does not desire such treatment during this time frame; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Has agreed to continue to use only study-specified analgesic medications during the study and 
is not known to be intolerant to these; 
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days after 
the last dose of study drug.  However, the patient is not required to use the specified 
nonhormonal contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), 
at least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
c. Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
nonhormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 


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abstinence is not acceptable. 
Exclusion Criteria:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study. 
1. Has had gynecological surgery or other surgical procedures for treatment of endometriosis at 
any time during the parent study (MVT-601-3101 or MVT-601-3102); 
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is 
treated with opioids or requires analgesics for ≥ 7 days per month; 
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, bilateral 
hip replacement, spinal hardware in the lumbar spine); 
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study 
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA 
assessment of bone mineral density; 
5. Anticipated to use any prohibited medications as detailed in Section 5.9.1; 
6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to 
the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
syndromes, etc); psoriasis not requiring or anticipated to require systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, 
if available, any subsequent visit in one of the parent studies (MVT-601-3101 or MVT-601-
3102): 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the 
upper limit of normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome 
or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 1 month after the last dose of study drug, or plans to donate ova during the study period 
or within 2 months after the last dose of study drug; 
11. The presenting visual acuity score has decreased by 10 or more points at the Week 24/Baseline 
visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 


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12. Is inappropriate for participation in this study because of conditions that may interfere with 
interpretation of study results or prevent the patient from complying with study requirements, 
as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 28 weeks (Open-Label 
Treatment Period). 
Concomitant Medicinal Products Systematically Prescribed for All Study 
Patients 
Two protocol-specified analgesics include a first-line non-steroidal anti-
inflammatory drug and a second-line opioid or opioid/acetaminophen 
combination for endometriosis-related pain relief as required.  The specific 
analgesic drugs offered may differ for different countries or regions.  The 
analgesics for each patient will be the same as those prescribed for her during 
the parent study. 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made 
between the parent study Baseline and the end of the extension study 
(Week 52) for the following parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg 
norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate 
in the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this 
extension study for all change from baseline-related endpoints.  The pain 
scores during the Baseline Pain Assessment Period of the parent study will 
establish the patient’s baseline for both the parent study and the extension 
study. 
 
Primary Efficacy Endpoints 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their NMPP NRS scores. 


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Secondary Efficacy Endpoints 
• 
Change from the parent study Baseline to Week 52 in the EHP-30 Pain 
Domain scores; 
• 
Change from the parent study Baseline to Week 52/end of treatment 
(EOT) in the mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for 
dysmenorrhea at Week 52/EOT; 
• 
Change from the parent study Baseline to Week 52/EOT in the mean 
NMPP NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for 
NMPP at Week 52/EOT; 
• 
Change from the parent study Baseline to Week 52/EOT in the mean 
dyspareunia NRS scores; 
• 
Proportion of patients who are better or much better on the PGIC for 
dyspareunia at Week 52/EOT; 
• 
Change from the parent study Baseline to Week 52/EOT in the mean 
dyspareunia functional impairment on the sB&B scale; 
• 
Change from the parent study Baseline to Week 52/EOT in severity 
scores on the PGA for pain; 
• 
Change from the parent study Baseline to Week 52/EOT in function 
impairment on the PGA for function; 
• 
Change from the parent study Baseline to Week 52/EOT in each of the 
non-pain EHP-30 domains (Control and Powerlessness, Social Support, 
Emotional Well-Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period to 
Week 52/EOT in dysmenorrhea-related functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period to 
Week 52/EOT in NMPP-related functional effects (sB&B). 
 
Safety Endpoints 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline to Week 52 in bone 
mineral density at the lumbar spine (L1-L4), femoral neck, and total hip 
as assessed by DXA. 
 
Pharmacodynamic Endpoint 
• 
Change from parent study Baseline to Week 52 in pre-dose concentrations 
of serum estradiol. 
 
Exploratory Endpoints 
• 
Change from Baseline to Week 52/EOT in the EHP-30 scale total score; 
• 
Change from Baseline to Week 52/EOT in the EHP Work Domain score; 
• 
Change from parent study Baseline to Week 52/EOT in the EQ-5D-5L. 


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Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Parent Study Groups A, B, and C) for the Intent-to-Treat Population.  The analyses methods 
for efficacy endpoints are similar to those used for the parent studies, unless otherwise specified in the 
statistical analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic medications, 
proportion of responders based on NMPP scores and use of rescue analgesic medications) will be 
calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with DXA.  Safety data 
analyses will use data from all patients from the parent studies who receive any amount of study drug 
(ie, from parent study Baseline to Week 52). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, high 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.  Laboratory values will be classified 
by toxicity grade based on the National Cancer Institute CTCAE.  Laboratory shift tables of the parent 
study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  The absolute 
change and percent change from parent study Baseline and Z-scores will be summarized by visit and 
parent study treatment group. 
The mean percentage change at Week 52 from parent study Baseline in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3101 
or MVT-601-3102) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, 
bone mineral density loss for the relugolix add-back treatment will be considered insignificant. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3101 or MVT-601-3102) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 


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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3103 
PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Informed Consent 
Xd 
Review Eligibility 
Criteria 
X 
Concomitant Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
X 
X 
Xh 
Complete Physical Exam 
Xg 
X 
Xh 
Visual Acuityi 
Xg 
Signs and Symptoms-
Directed Physical Examj 
X 
X 
X 
X 
X 
X 
Xh 
X 
12-Lead ECGk
Xg 
X 
Xh 
Clinical Laboratory Testsl 
Xg,m 
X 
X 
X 
X 
X 
X 
Xm 
Xh 
X 
Pharmacodynamics 
Samplen
Xg,m 
Xm 
Xh,m 
Urinalysis 
Xg 
X 
Xh 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 


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PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Daily eDiaryo 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
Site Review of eDiary 
Data 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Bone Densitometryp 
Xg 
X 
Xq,r 
Xh 
Endometrial Biopsy 
Xg,s 
Xh 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
Xh 
Dispense or prescribe 
protocol-specified 
analgesic drugst
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
Treatment Compliance 
X 
X 
X 
X 
X 
X 
X 
Xh 
Take Study Drug Dose in 
Clinic 
Xu 
X 
Xh 
Daily Self-Administration 
of Study Treatmentv 
X 
Take Protocol-specified 
Rescue Analgesics as 
Neededw
X 
EHP-30 Questionnairex 
Xg 
X 
X 
X 
Xh 
Patient Global 
Assessment for Painx
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
Patient Global 
Assessment for Functiony 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
Patient Global Impression 
of Changex
Xg 
X 
X 
Xh 


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PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
EHP Work Domainy
Xg 
X 
Xh 
EQ-5D-5L Questionnairex 
Xg 
X 
Xh 
Adverse Event 
Collectionz 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery
Xaa 
Abbreviations:  BP, blood pressure; DXA, dual-energy x-ray absorptiometry; ECG, electrocardiogram; eDiary, electronic diary; EHP, Endometriosis Health Profile; EQ-5D-5L, 
European Quality of Life Five-Dimension Five-Level Scale; exam, examination; HR, heart rate; NRS, Numerical Rating Scale; sB&B, Subject Modified Biberoglu and Behrman. 
a.
The Week 52 visit should occur on or after the 1-year anniversary of Study Day 1 of the parent study.
b.
Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents.
c.
The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 visit.
d.
May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3103 is defined by
administration of the first dose of MVT-601-3103 study drug.
e.
Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up Period.  Concomitant
medications with start date prior to the first dose of study drug for MVT-601-3103 should be reported as concomitant medications in the parent study (MVT-
601-3101 or MVT-601-3102).  If concomitant medication is ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report
Form Completion Guidelines for instructions for recording the follow-up status.
f.
Concomitant medications are recorded both for the parent study and for MVT-601-3103 at the Week 24/Baseline visit.  (See footnote e for further details).
g.
This is a parent study (MVT-601-3101 or MVT-601-3102) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3103 and is
covered under the informed consent for the parent study.
h.
The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal laboratory
test).
i.
See parent study protocols (MVT-601-3101 or MVT-601-3102) for instructions on testing visual acuity.
j.
The exam may include a gynecologic examination, if indicated based on signs and symptoms.
k.
The 12-lead ECGs will be submitted for central reading.
l.
Clinical chemistries will be collected at each visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, and Week 52.  At the
Week 24/Baseline visit and Week 52 visit, additional tests include:  fasting (at least 8 hours) glucose, lipid profile, and hemoglobin A1c.
m. Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period.


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n.
For Week 24/Baseline samples, see the parent protocol (MVT-601-3101 or MVT-601-3102).  At Week 52/Early Termination, collect samples for analysis of
estradiol concentrations only.  On days when pharmacodynamics samples are collected, administer the study treatment after the pharmacodynamics sample
collections are completed.
o.
At the Week 24/Baseline visit, transition the patient within her eDiary from the parent study to MVT-601-3103.  The eDiary data collection will include NRS
pain scores, menstruation information (including severity of bleeding), analgesic drug use, date and time of study drug administration, and sB&B scale scores.
p.
Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading.
q.
This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier.  However, the
procedure may be done if it will aid in the evaluation of an ongoing adverse event.
r.
Patients with a bone mineral density loss of > 3% at their Week 52/Early Termination visit relative to parent study Baseline measurement will undergo a follow-
up bone densitometry scan at 6 (±1) months and will be contacted to question them about medications and conditions (eg, pregnancy) that might affect bone
mineral density through the time of follow-up bone densitometry.  The follow-up bone densitometry will be submitted for central reading.
s.
Endometrial biopsies are to be done per instructions in the parent study.  See the Laboratory Manual for guidance on handling and shipping the biopsy sample to
the central laboratory for analysis.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who participated in MVT-
601-3101 only (see MVT-601-3101 protocol for details).
t.
Please see Appendix 1 for list of protocol-specified analgesics and see the Study Reference Manual for information on where and how to obtain protocol-
specified analgesic medications by country.  At the Week 52 visit, patients who will not be proceeding to another extension study will be re-dispensed or
prescribed protocol-specified analgesic drugs, if needed, to ensure sufficient supply until the Follow-Up visit.  For patients proceeding to another extension
study, refer to the protocol for that next study.
u.
Pregnancy test must be negative before the study drug dose is administered.
v.
Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  The first dose of study
drug for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed. Therefore, results of
testing required for eligibility (eg, DXA) must be available on or prior to the Week 24/Baseline visit.  The last dose of study drug will be taken in the clinic
during the Week 52/Early Termination visit.
w.
Patients may only take their study-specified analgesics for pain.  Analgesics should not be taken prophylactically (ie, in anticipation of pain).
x.
The patient will enter her response(s) into an electronic tablet device at the site.
y.
The patient will enter her response onto a paper questionnaire at the site.
z.
Collect adverse events from the time that the first dose of study drug for MVT-601-3103 is administered.  Adverse events with onset prior to the first dose of
study drug for MVT-601-3103 should be reported as an adverse event in the parent study (MVT-601-3101 or MVT-601-3102).  If events originating in the
parent study are ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report Form Completion Guidelines for instructions
for recording the follow-up status.
aa. Patients whose menses have not resumed as of the Follow-up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted again by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and questioned about factors 
that may affect resumption of menses. 


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2.
INTRODUCTION
2.1. 
Endometriosis-Associated Pain
Endometriosis is a common chronic condition occurring primarily in women of reproductive age.  
It is one of the most common gynecologic disorders, evident in 70 to 90% of women with pelvic 
pain symptoms [Practice Committee of the American Society for Reproductive Medicine, 2014].  
The exact prevalence of endometriosis is unknown but estimates range from 2 to 10% of women 
of reproductive age [Dunselman, 2014].  Symptoms range from minimal to severely debilitating. 
The pathogenesis of endometriosis is the presence of endometrial glands and stroma outside the 
uterine cavity.  Although the ectopic endometriotic lesions are most commonly found in the 
pelvis, they may also be located in the bowel, in the pleural cavity, and elsewhere.  Women with 
endometriosis have an increased risk of abdominopelvic pain, dysmenorrhea, and dyspareunia 
compared with controls without endometriosis [Practice Committee of the American Society for 
Reproductive Medicine, 2014].  In a study of 940 women with endometriosis, the most common 
symptom leading to diagnosis was dysmenorrhea in approximately 90%, pelvic pain in 
approximately 80%, and dyspareunia in approximately 45%, with 34% of women diagnosed on 
the basis of all three symptoms [Sinaii, 2008].  Presenting symptoms of infertility (25%) and 
endometrioma (ovarian mass) (20%) were also common [Sinaii, 2008]. 
The mechanisms of pain in endometriosis are generally postulated to involve production of 
substances such as growth factors and cytokines, the direct and indirect effects of active bleeding 
from endometriotic implants, and irritation of pelvic floor nerves or direct invasion of those 
nerves by infiltrating endometriotic implants [Practice Committee of the American Society for 
Reproductive Medicine, 2014]. 
According to the American Society for Reproductive Medicine Practice Committee, 
“Endometriosis is a chronic disease that requires a lifelong management plan with the goal of 
maximizing the use of medical treatment and avoiding repeated surgical procedures” [Practice 
Committee of the American Society for Reproductive Medicine, 2014]. 
Although hysterectomy with bilateral salpingo-oopherectomy is a definitive treatment of 
endometriosis, the American Society of Reproductive Medicine recommends that this option be 
reserved as a last resort for women with debilitating endometriosis symptoms who have 
completed childbearing and have failed to respond to alternative treatments [Practice Committee 
of the American Society for Reproductive Medicine, 2014].  Other surgical options for treatment 
of endometriosis include uterosacral nerve ablation, presacral neurectomy, and laparoscopic 
resection.  Rates of recurrent dysmenorrhea 1 and 3 years after laparoscopic surgery with 
uterosacral nerve ablation were not better than with laparoscopic surgery without nerve ablation 
in a large randomized trial.  Presacral neurectomy, which involves interrupting the sympathetic 
innervation to the uterus, improves pain but is a technically challenging procedure associated 
with significant risk of bleeding from the adjacent venous plexus.  Patients may also experience 
constipation and/or urinary retention postoperatively.  Laparoscopic treatment of endometriosis 
was found to be more effective at reducing pain than diagnostic laparoscopy in a meta-analysis 
of 5 randomized controlled studies.  While laparoscopic treatment is effective, pain can recur, 
and the option of performing multiple surgeries is limited by risks that include the development 


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of pelvic pain from adhesions and decreased ovarian reserve, resulting in reduced fertility.  In 
one retrospective study, subsequent surgery was performed after laparoscopic treatment in 21%, 
47%, and 45% of women after 2, 5, and 7 years, respectively [Practice Committee of the 
American Society for Reproductive Medicine, 2014]. 
Medical management of endometriosis includes analgesics and treatments aimed at 
decidualization followed by atrophy of endometrial tissue with reduction or antagonism of 
estrogen production and induction of amenorrhea.  Compared to normal endometrium, 
endometriotic implants are characterized by overproduction of prostaglandins and local 
production of estrogens and cytokines, which synergize the activities of each other and promote 
implantation of ectopic endometrium.  In addition, the implants have upregulated estrogen 
synthesis pathways [Practice Committee of the American Society for Reproductive Medicine, 
2014].  Interventions that reduce ovarian estrogen production reduce this synergistic process, 
thereby reducing or eliminating endometriosis-associated pain. 
Medical hormonal options include hormonal contraceptives, progestins, gonadotropin-releasing 
hormone (GnRH) agonists, danazol, and aromatase inhibitors.  Because of lack of data 
supporting use of one treatment over another, the treatment choice is based upon symptom 
severity, patient preferences, side effects, efficacy, contraceptive needs, costs, and availability 
[Dunselman, 2014].  The main adverse effects of GnRH agonists relate to induction of a 
hypoestrogenic state (eg, bone mineral density loss and vasomotor symptoms) whereas danazol 
produces androgenic adverse effects such as hirsutism, weight gain, and deepening of the voice.  
Some patients treated with GnRH agonists also experience an initial “flare effect” (increased 
pain and bleeding), and this can result in premature discontinuation of treatment.  Side effects of 
progestin treatment can include irregular uterine bleeding, weight gain, mood changes such as 
depression, and bone mineral density loss with long-term use of certain agents. 
The goal of the relugolix phase 3 development plan is to demonstrate that relugolix can decrease 
dysmenorrhea and nonmenstrual pelvic pain (NMPP) in women with endometriosis safely 
through 12 months of therapy and to evaluate effects on pain-related quality of life and function.  
By enhancing the safety and tolerability of the active treatment arm with the co-administration of 
low-dose hormonal add-back therapy, the program ultimately aims to bring to women suffering 
endometriosis-associated pain a long-term oral medical therapy that significantly reduces pain 
and improves quality of life and provides an alternative to invasive procedures. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix Investigator Brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once-daily oral medication for the treatment of endometriosis-associated pain.  The proposed 
dose of relugolix is 40 mg administered orally once daily and the proposed doses of estradiol and 
norethindrone acetate are 1.0 mg and 0.5 mg once daily, respectively. 


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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 gonadotropin-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 
luteinizing hormone and follicle-stimulating hormone fall rapidly, followed by a decline over a 
few days in estradiol and progesterone levels.  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. 
3.
STUDY OBJECTIVES AND ENDPOINTS
Descriptive assessments of long-term efficacy and safety will be made between the parent study 
Baseline and the end of the extension study (Week 52) for the following parent study treatment 
groups: 
•
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily co-
administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent study;
•
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg
estradiol and 0.5 mg norethindrone acetate in the parent study;
•
Parent Study Group C:  Randomized to placebo in the parent study.
The parent study Baseline will be used as the reference point for this extension study for all 
change from baseline-related endpoints.  The pain scores during the Baseline Pain Assessment 
Period of the parent study will establish the patient’s baseline for both the parent study and the 
extension study. 
In women with endometriosis-associated pain, the study objectives and corresponding endpoints 
are as follows: 


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Objectives 
Endpoints 
Primary Efficacy 
•
To evaluate long-term efficacy of relugolix
40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate for up
to 52 weeks, among patients who previously
completed a 24-week treatment period in one
of the parent studies (MVT-601-3101 or
MVT-601-3102), on endometriosis-associated
pain.
•
Proportion of women who respond or
maintain response at Week 52/Early
Termination, based on their dysmenorrhea
Numerical Rating Scale (NRS) scores;
•
Proportion of women who respond or
maintain response at Week 52/Early
Termination, based on their NMPP NRS
scores.
Secondary Efficacy 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or MVT-601-
3102), on the following: 
•
Function, as measured by the Endometriosis
Health Profile (EHP)-30 Pain Domain;
•
Change from the parent study Baseline to
Week 52 in the EHP-30 Pain Domain scores;
•
Dysmenorrhea, as measured by the NRS for
dysmenorrhea;
•
Change from the parent study Baseline to
Week 52/end of treatment (EOT) in the mean
dysmenorrhea NRS score;
•
Patient Global Impression of Change (PGIC)
for dysmenorrhea;
•
Proportion of patients who are better or much
better on the PGIC for dysmenorrhea at
Week 52/EOT;
•
NMPP, as measured by the NRS for NMPP;
•
Change from the parent study Baseline to
Week 52/EOT in the mean NMPP NRS score;
•
PGIC for NMPP;
•
Proportion of patients who are better or much
better on the PGIC for NMPP at
Week 52/EOT;
•
Dyspareunia, measured by the NRS;
•
Change from the parent study Baseline to
Week 52/EOT in the mean dyspareunia NRS
scores;
•
PGIC for dyspareunia;
•
Proportion of patients who are better or much
better on the PGIC for dyspareunia at
Week 52/EOT;
•
Dyspareunia-related functional effects
(Subject Modified Biberoglu and Behrman
[sB&B]);
•
Change from the parent study Baseline to
Week 52/EOT in the mean dyspareunia
functional impairment on the sB&B scale;
•
Patient Global Assessment (PGA) for pain;
•
Change from the parent study Baseline to
Week 52/EOT in severity scores on the PGA
for pain;


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Objectives 
Endpoints 
• 
PGA for function; 
• 
Change from the parent study Baseline to 
Week 52/EOT in function impairment on the 
PGA for function; 
• 
Endometriosis-associated quality of life, as 
measured by the EHP-30 Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image domains; 
• 
Change from the parent study Baseline to 
Week 52/EOT in each of the non-pain EHP-
30 domains (Control and Powerlessness, 
Social Support, Emotional Well-Being, and 
Self-Image); 
• 
Dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
dysmenorrhea-related functional effects 
(sB&B); 
• 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
NMPP-related functional effects (sB&B). 
Safety 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 52 weeks, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including: 
 
• 
Adverse events; 
• 
Incidence of adverse events; 
• 
Changes in bone mineral density. 
• 
Percent change from the parent study Baseline 
to Week 52 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by dual-energy x-ray 
absorptiometry (DXA). 
Pharmacodynamic 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 52 weeks, among patients 
who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
estradiol. 
• 
Change from parent study Baseline to 
Week 52 in pre-dose concentrations of serum 
estradiol. 


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Objectives 
Endpoints 
Exploratory 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life (EHP-
30 total score), work (EHP Work Domain), 
and patient-reported quality of life outcomes 
(European Quality of Life Five-Dimension 
Five-Level Scale [EQ-5D-5L]) for up to 
52-weeks among patients who previously 
completed a 24-week treatment period in one 
of the parent studies (MVT-601-3101 or 
MVT-601-3102). 
• 
Change from Baseline to Week 52/EOT in the 
EHP-30 scale total score; 
• 
Change from Baseline to Week 52/EOT in the 
EHP Work Domain score; 
• 
Change from parent study Baseline to Week 
52/EOT in the EQ-5D-5L. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety study that will enroll eligible patients who have completed their participation 
in one of the phase 3 randomized, double-blind, placebo-controlled parent studies (MVT-601-
3101 or MVT-601-3102).  All patients will receive oral relugolix 40 mg once daily 
co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 
28 weeks.  Approximately 800 women with endometriosis-associated pain will be enrolled.  The 
objectives of the study are to evaluate long-term efficacy and safety through up to 52 weeks of 
treatment (including treatment during the parent study) of relugolix co-administered with low-
dose estradiol/norethindrone acetate.  Eligible patients will have completed participation in one 
of the parent studies and consented to participate in this extension study.  Baseline procedures 
will be done at the same visit for this extension study (referred to as the “Week 24/Baseline 
visit” in this study) that coincides with the Week 24 visit from the parent study, and will be 
defined as the date of completion of the last Week 24 procedure in the parent study.  The Week 
24/Baseline visit will include vital signs, physical examination, laboratory assessments, a 12-lead 
electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, and 
endometrial biopsy (if required).  When Week 24 procedures in the parent study have been 
completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the 
Week 24/Baseline visit.  No MVT-601-3103 study procedures will be performed until the 
consent form for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit, and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Therefore, results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline visit.  The administration of the first dose of study 


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drug for MVT-601-3103 will define enrollment into this study.  Study participants will then take 
the open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 28 weeks. 
During the 28-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the 
electronic diary (eDiary).  Only study-specific rescue analgesic medications will be allowed 
starting with the Week 24/Baseline visit and through the Follow-Up visit and these medications 
will be taken for control of pain and not prophylactically.  Health-related quality of life 
questionnaires; PGIC for dysmenorrhea, NMPP, and dyspareunia; and PGA for pain and 
function will be completed during the visits on an electronic tablet or on paper, according to the 
Schedule of Activities (Section 1.1). 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment 
of bone mineral density via DXA. 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, and bone mineral density 
with DXA. 
Patients with a bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit relative to the parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (± 1) months after the last dose of study medication. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted again by telephone 3 
(+ 0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 4-1. 


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Figure 4-1 
MVT-601-3103 Study Schematic 
4.2. 
Discussion of Study Design, Including Dosing 
The SPIRIT EXTENSION study (MVT-601-3103) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3101 and MVT-601-3102) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with endometriosis-associated pain.  This 
28-week extension study provides additional efficacy and safety data up to 52 weeks to 
demonstrate the benefit and safety of relugolix co-administered with low-dose estradiol (1 mg) 
and norethindrone acetate (0.5 mg).  The primary objectives of the study are to assess long-term 
efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 52 weeks on dysmenorrhea and NMPP, common and burdensome 
symptoms of endometriosis.  The study will also evaluate safety of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up to 52 weeks, among 
patients who previously completed a 24-week treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including adverse events and change in bone mineral 
density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily (N = 101) suppressed 
estradiol levels to below 20 pg/mL in the majority of women, and results were similar to those in 
the group of women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the 
relugolix 40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary 
endpoint of the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 


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demonstrated the 40-mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from endometriosis-associated pain to move forward into phase 3 clinical 
development and, based on the DXA data from the phase 2 study, are not expected to prevent 
bone mineral density loss in a significant majority of women over 52 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 52 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in dysmenorrhea and NMPP.  It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2017; Lee, 2016; Franke, 2000] or endometriosis-associated 
pain [Wu, 2014].  The estradiol/norethindrone acetate combination proposed for evaluation in 
this phase 3 study is currently approved in the United States (US) as long-term hormone 
replacement therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal 
women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 
lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Activella US Prescribing Information, 2013]) would not provide sufficient serum estradiol 


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concentrations to protect against the loss of bone mineral density resulting from the 
hypoestrogenic state induced by once daily administration of relugolix 40 mg. 
The doses of estradiol and norethindrone acetate used in this study (1.0 mg and 0.5 mg, 
respectively) were used in the parent studies (MVT-601-3101 and MVT-601-3102) and represent 
less than one fifth the estrogenic effects of an oral contraceptive pill containing 30 µg of ethinyl 
estradiol.  Therefore, this low-dose hormonal add-back therapy is added solely to improve the 
safety of relugolix therapy, and it is expected to have either a neutral or a marginal detrimental 
effect on efficacy, while mitigating the side effects of relugolix on bone mineral density loss and 
vasomotor symptoms. 
In summary, relugolix at a dose of 40 mg once daily resulted in a significant decrease in 
endometriosis-associated pain in a well-designed large phase 2 study.  However, its 
administration was associated with a degree of bone mineral density loss unacceptable for long-
term treatment.  This phase 3 study extension study will assess long-term efficacy and safety of 
relugolix 40 mg co-administered with low-dose estradiol and norethindrone acetate to decrease 
dysmenorrhea and NMPP and to prevent the bone mineral density loss and ameliorate some of 
the other side effects of a hypoestrogenic state such as hot flushes. 
This open-label extension study will allow for a description of long-term efficacy data and safety 
for an additional 28 weeks of treatment, providing approximately 1 year of efficacy and safety 
data from the women originally randomized to relugolix in studies (MVT-601-3101 and 
MVT-601-3102).  This study design will allow eligible patients with endometriosis-associated 
pain, who were randomized to placebo in the parent study, to receive relugolix co-administered 
with low-dose hormonal add-back therapy during the extension. 
4.3. 
Selection of Study Population 
The study population will include approximately 800 premenopausal women aged 18 to 51 years 
with endometriosis-associated pain. 
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. 
4.3.1. 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization): 
1. Completed 24 weeks of study drug treatment and study participation in either MVT-601-
3101 or MVT-601-3102; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
study-specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline 
procedures for this study will be done under the informed consent for the parent study. 


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3. Is not expected to undergo gynecological surgery or other surgical procedures for
treatment of endometriosis (including ablation, shaving, or excision) during the study,
including during the Follow-Up Period, and the patient does not desire such treatment
during this time frame;
4. Has a negative urine pregnancy test at the Week 24/Baseline visit;
5. Has agreed to continue to use only study-specified analgesic medications during the study
and is not known to be intolerant to these;
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in
Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days
after the last dose of study drug.  However, the patient is not required to use the specified
nonhormonal contraceptive methods if she:
a.
Has a sexual partner(s) who was vasectomized at least 6 months prior to the
Week 24/Baseline visit;
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as
Essure™), at least 6 months prior to the Week 24/Baseline visit (patients with Essure
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there
must be no evidence of post-Essure syndrome;
c.
Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus;
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the
use of nonhormonal contraception as noted above;
e.
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic
abstinence is not acceptable.
Exclusion Criteria 
1. Has had gynecological surgery or other surgical procedures for treatment of
endometriosis at any time during the parent study (MVT-601-3101 or MVT-601-3102);
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis,
that is treated with opioids or requires analgesics for ≥ 7 days per month;
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg,
bilateral hip replacement, spinal hardware in the lumbar spine);
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week
24 DXA assessment of bone mineral density;
5. Anticipated to use any prohibited medications as detailed in Section 5.9.1;


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6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc); psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the 
upper limit of normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
11. The presenting visual acuity score has decreased by 10 or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 
12. Is inappropriate for participation in this study because of conditions that may interfere 
with interpretation of study results or prevent the patient from complying with study 
requirements, as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
4.4. 
Method of Assigning Patients to Treatment Group and Patient 
Identification Number 
Eligible patients who sign consent will be identified with the same Patient Identification (ID) 
Number assigned to the patient during the parent study.  This extension study is a single-arm 


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study, and thus all eligible patients are assigned to the same treatment group of relugolix 40 mg 
co-administered with low-dose of estradiol and norethindrone acetate (see Section 5.1 for 
treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 52 visit defines completion of the study.  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 Early Termination visit (see the Week 52 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication). 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• Any adverse event that is intolerable to the patient and 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; 
• If it is discovered after enrollment that a patient failed to meet protocol entry criteria and 
continued participation poses an unacceptable risk to the patient’s health; 
• If the following 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): 
o ALT or AST > 8 x ULN; or 
o ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
o ALT or AST > 3 x ULN in conjunction with elevated total bilirubin > 2 x ULN or 
international normalized ratio (INR) > 1.5; or 
o ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%); 
• QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec read 
by a cardiologist; 
• Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial biopsy; 
• If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or 
femoral neck compared with the parent study Baseline; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  Gross noncompliance includes < 75% 
compliance with the study drug over > 2 consecutive months; missing multiple study 
visits; and persistent (> 2 consecutive months) with < 50% of the required number of 
days of eDiary completion.  Investigators will follow up with the patient and encourage 
compliance with study drug or eDiary prior to discontinuing her from the study; 
• If the patient becomes pregnant at any time after providing a signed informed consent 
form, the patient must be withdrawn immediately (see Section 7.8 for information on 
pregnancy reporting). 


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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 noncompliance.  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 three 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.” 
4.6. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones for contraception are excluded, and 
patients must agree to use nonhormonal contraception throughout the study unless any of the 
following apply: 
•
Has a sexual partner(s) who was vasectomized at least 6 months prior to the
Week 24/Baseline visit;
•
Had a bilateral tubal occlusion (including ligation and blockage methods such as
Essure™) at least 6 months prior to the Week 24/Baseline visit (patients with Essure
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there must
be no evidence of post-Essure syndrome;
•
Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus;
•
Is not sexually active with men; periodic sexual relationship(s) with men requires the use
of nonhormonal contraception as described below;
•
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic
abstinence is not acceptable.
The only acceptable methods of contraception for those for whom one of the above methods do 
not apply are: 
•
Condom (male or female condom) with or without spermicide (cream, spray, foam, gel,
suppository, or polymer film);
•
Diaphragm with spermicide (condom may or may not be used);
•
Cervical cap with spermicide (condom may or may not be used); or
•
Vaginal sponge impregnated with spermicide used with a condom.
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed at monthly intervals during the study (including just 
prior to receiving the first dose of study drug), and patients will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures.  Patients who become 


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pregnant during the study will be withdrawn from the study and followed for pregnancy outcome 
(see Section 7.8). 
5.
TREATMENTS
5.1. 
Treatments Administered 
In this extension study, all patients will receive the following open-label oral study treatment: 
•
28 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol
and 0.5 mg norethindrone acetate.
Each patient will be instructed to take one tablet and one capsule per day. 
Table 5-1 
Description of MVT-601-3003 Study Drugs 
Name of Investigational 
Product 
Relugolix 
Estradiol / Norethindrone 
Acetate 
Formulation Description 
Round film-coated pink tablet 
A Swedish orange, over-
encapsulated round film-coated 
white tablet with back-fill 
material 
Dosage Form 
Tablet 
Capsule 
Unit Dose Strength 
40 mg 
Estradiol 1.0 mg / norethindrone 
acetate 0.5 mg 
Route of Administration/ 
Duration 
Oral once daily/ 
28 weeks 
Oral once daily/ 
28 weeks 
Two protocol-specified analgesics include a first-line non-steroidal anti-inflammatory drug 
(NSAID) and a second-line opioid or opioid/acetaminophen combination for endometriosis-
related pain relief as required.  The specific analgesic drugs offered may differ for different 
countries or regions.  A list of study-specified analgesics is provided in Appendix 1. 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name 1-(4-{1-[(2,6-difluorophenyl)methyl]-5-
[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl}phenyl)-3-methoxyurea.
Estradiol (1.0 mg) and norethindrone acetate (0.5 mg) is a fixed-dose combination product. 
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 common 
excipients. 


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The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing 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. 
On Week 24/Baseline and Week 52 clinic visit days, study drug will be administered in the clinic 
rather than at home (see Schedule of Activities in Section 1.1). 
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 cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20°C to 25°C with excursion to 15°C to 30°C permitted until it is used or 
returned to the sponsor (or designee).  Study drug should be stored protected from light.  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.  Further guidance and information for final 
disposition of unused study drug are provided in the Study Reference Manual and Pharmacy 
Manual.  The investigator is responsible for study drug accountability, reconciliation, and record 
maintenance, including receipt, reconciliation, and final disposition records and their secure 
storage. 
Study drug will be labeled with the study protocol number, medication or kit number, contents, 
directions for use, storage directions, clinical study statement, and any other labeling required by 
regulatory bodies in the study locations and will list Myovant Sciences GmbH as the sponsor.  
Patients will be instructed to store study drug at room temperature out of the reach of children. 


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All labels for relugolix and the estradiol/norethindrone acetate combination to be distributed will 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices:  Manufacture of investigational medicinal products (July 
2010) and/or other local regulations as applicable. 
Please see Appendix 1 for a list of protocol-specified analgesics.  Further details on analgesic 
medication are provided in the Study Reference Manual. 
5.7. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and should bring all unused and used 
study drug to each study visit. 
Study drug accountability will be conducted and results will be recorded.  If a patient is 
persistently noncompliant with the study treatment, it may be appropriate to withdraw the patient 
from the study (see Section 4.5).  All patients should be reinstructed about the dosing 
requirement during study contacts.  The authorized study personnel conducting the re-education 
must document the process in the patient’s source records. 
Because of the importance to both safety and efficacy evaluation, patients who are grossly 
noncompliant with eDiary completion must undergo an Unscheduled visit to evaluate reasons for 
noncompliance and to develop a plan to improve compliance.  Failure to improve compliance 
may result in the sponsor withdrawing the patient from further study treatment (including study 
analgesics) and/or discontinuation from the study (see Section 4.5 for details). 
All patients should be reinstructed about the dosing requirement and eDiary compliance during 
study contacts.  The authorized study personnel conducting the re-education must document the 
process in the patient’s source records. 
5.9. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.9.1. 
Prohibited Medications 
Table 5-2 provides examples of prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Drugs and drug classes in Table 5-2 are prohibited at any time 
during the study through the Follow-Up visit, except as noted in the table.  Consult the medical 
monitor if there is any uncertainty regarding patient use of a particular drug or drug class. 
Table 5-2 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zoledronic acid 
 


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Drug Class 
Examples 
Comments 
GnRH analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
 
Anti-androgens 
danazol 
 
Anticonvulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
Note: All other anticonvulsants are 
allowed 
Aromatase inhibitors 
anastrozole 
letrozole 
 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
Hormonal contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
NuvaRing 
 
Selective estrogen 
receptor modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
 
Selective progesterone 
receptor modulators  
mifepristone 
ulipristal acetate 
 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
 
Intrauterine devices 
levonorgestrel 
copper 
 
Bone agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 


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Drug Class 
Examples 
Comments 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use of systemic 
glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study.   
Note:  topical, inhaled, intranasal, 
otic, ophthalmic, intraarticular, or 
intralesional subcutaneous are 
permitted without restriction. 
Short duration (< 21 days) higher-
dose glucocorticoids required for 
acute events are permitted during 
the study. 
P-glycoprotein inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavirf 
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 and strong 
P-glycoprotein inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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. 


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Drug Class 
Examples 
Comments 
Analgesic drugs other 
than those specified for 
use during the study 
Acetaminophen/paracetamol (other 
than any included in a study-
specified analgesic) 
aspirin > 325 mg/day 
NSAIDs (other than study-specified 
NSAIDs) 
gabapentin 
pregabalin 
carbamazepine 
metamizole 
Note:  Aspirin ≤ 325 mg per day is 
allowed 
Antidepressants 
New treatment or 
changed doses of SSRI, 
SNRI, or TCA 
antidepressants 
SNRI examples: 
duloxetine 
venlafaxine 
desvenlafaxine 
SSRI examples: 
citalopram 
fluoxetine 
paroxetine 
fluvoxamine 
TCA examples: 
amitriptyline 
doxepin 
desipramine 
nortriptyline 
SSRI, SNRI, or TCA allowed if 
given at the same dose as used 
during the 3 months prior to the 
Run-In Period of MVT-601-3101 or 
MVT-601-3102. 
New start, dose change or 
discontinuation of these drugs is not 
allowed during the study.  Changes 
made for safety reasons are allowed 
with approval of the medical 
monitor. 
Abbreviation:  GnRH, gonadotropin-releasing hormone; NSAID, nonsteroidal anti-inflammatory drug; SNRI, 
serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic 
antidepressant. 
a. 
Roxithromycin is allowed 
b. All other angiotensin converting enzyme inhibitors are allowed 
c. 
Tacrolimus is allowed 
d. Amlodipine and nifedipine are allowed 
e. 
Fluconazole is allowed 
f. 
Integrase inhibitors are allowed 
g. Clopidogrel is allowed 
 
5.9.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded, including the drug generic 
name, dose amount, route of administration, start date, and stop date. 
5.9.2.1. 
Analgesics 
All analgesics will be collected in the eDiary and recorded in the electronic Case Report Forms 
(eCRFs). 


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5.9.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of endometriosis is prohibited from the Week 24/Baseline visit until the 
patient’s final study visit unless urgently needed for patient safety. 
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 6.5.  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 2 periods:  Open-Label Treatment 
Period and Safety Follow-Up Period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3101 or MVT-601-3102 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study, and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week 24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• Informed consent (unless signed previously); 
• Record concomitant medications; 
• Dispense study treatment; 
• Dispense or prescribe protocol-specified analgesic drugs; 
• Transition the patient within her eDiary from the parent study to MVT-601-3103 
• Take study drug dose in clinic; and 
• Record adverse events, if any. 
The Week 24 visit date in the parent study is defined as the date that the last procedures for the 
Week 24 visit were completed, acknowledging that the Week 24 visit procedures may be 
completed on different dates.  Patients will have received their last dose of study drug in the 
parent study on the day prior to the Week 24/Baseline visit, and will receive their first dose of 
study drug for this extension study in the clinic after the patient is determined to be eligible for 
this extension study and has provided informed consent to participate.  Therefore, results of 
testing required for eligibility must be available on or prior to the Week 24/Baseline visit. 


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Patients will continue recording data in their eDiary daily and taking protocol-specified 
analgesics as needed.  Following the Week 24/Baseline visit, on-treatment study visits will occur 
at Weeks 28, 32, 36, 40, 44, 48, and 52. 
Accountability for study drug will be performed at each visit.  Instructions for analgesic 
medication usage will be reinforced at each visit. 
Questionnaires are administered on the electronic tablet and on paper at each visit.  These 
procedures should occur before any other types of study procedures are performed. 
Patients will bring their eDiary, analgesic medications, and study drug to each visit.  The site 
must document the start and stop dates of the patient’s menses. 
An endometrial biopsy will have been performed at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 (see MVT-601-3101 protocol for details).  Safety 
monitoring for this study includes physical examination, clinical laboratory tests, pregnancy 
tests, and adverse event collection at each visit.  Clinical chemistries will be collected at each 
visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, and 
Week 52.  At the Week 24/Baseline visit and Week 52 visit, additional tests include fasting (at 
least 8 hours, other than water) glucose, lipid profile, and hemoglobin A1c. 
ECGs will be done at the Week 24/Baseline and at the Week 52/Early Termination visits.  Bone 
densitometry will occur at the Week 24/Baseline, Week 36, and Week 52/Early Termination 
visits. Week 52/Early Termination.  Bone densitometry and ECGs will be submitted for central 
reading. 
Study drug compliance will be reviewed at each visit.  Fasting (other than water) for at least 
8 hours is required prior to blood sampling on Week 24/Baseline and Week 52/Early 
Termination visits and for 1 hour after administration of the study drug in the clinic.  Laboratory 
requisitions must indicate whether or not the patient was not fasted for their chemistry and lipid 
testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment Period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 52 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 52; however, for 
patients whose last dose of study drug is during Week 32 or earlier, the bone densitometry does 
not need to be performed.  This procedure may be performed, however, at the investigator’s 
discretion, if it aids in follow-up of an ongoing adverse event(s). 
Patients (including those who complete the Week 52 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
endometriosis, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 52 visit, the Follow-up visit may be 
waived. 


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The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the Follow-
up visit. 
6.4. 
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 source 
documentation.  The following activities should be completed at Unscheduled visits:  recording 
of reason for the visit, 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, urine pregnancy testing, pharmacodynamic sampling, 
12-lead ECG, study drug compliance and dispensation, eDiary review, dispensation or 
prescription of protocol-specified analgesics, etc, may be conducted as needed.  See the Schedule 
of Activities (Section 1.1) for tests that may be performed, as indicated at an Unscheduled visit.  
The investigator should consult with the medical monitor, if needed, to discuss Unscheduled visit 
testing.  The investigator should obtain approval from the sponsor to perform an unscheduled 
endometrial biopsy or DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Pharmacodynamics Sample Collection 
A blood sample for the pharmacodynamic analysis of serum estradiol will be collected pre-dose 
at the visits indicated in the study Schedule of Activities (see Section 1.1), other than at the 
Week 52 or the Early Termination visit, when no dose is administered.  These pharmacodynamic 
samples will be analyzed at a central laboratory.  These results will not be shared with the sites at 
any time. 
6.5.1.2. 
Patient eDiary 
All women enrolled in the study will continue to use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete daily eDiary entries including NRS pain scores, 
menstruation information, analgesic drug use, date and time of study drug administration, and 
sB&B scale scores. 
The site should review the eDiary data at every visit. 
Queries will be handled by the vendor managing the eDiary data through the clinical site.  The 
eDiary data will act as its own source data and these data will be reviewed by the investigator to 
identify any potential adverse events.  Analgesic medications will be transcribed onto the case 
report form. 


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6.5.1.3. 
Endometriosis Health Profile-30 
The EHP-30 is used to evaluate the functional impact and the quality of life of patients with 
endometriosis (see Appendix 3).  Patients will complete the EHP-30 questionnaire at the site at 
visits indicated in Section 1.1 before other types of study procedures, such as blood draws and 
physical examinations, are performed.  The EHP-30 will be completed on a tablet device at the 
study site. 
6.5.1.4. 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes (see 
Appendix 4).  Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are 
each assessed on a 5-level categorical scale. 
Patients will complete the EQ-5D-5L questionnaire at the site at visits indicated in Section 1.1 
before other types of study procedures, such as blood draws and physical examinations, are 
performed.  The EQ-5D-5L will be completed on a tablet device at the study site. 
6.5.1.5. 
Patient Global Assessment and Patient Global Impression of Change 
These simple questions are used by the patient to qualitatively describe severity of pain or effects 
on function (PGA) or impression of change in pain severity (PGIC) (see Appendix 5) on a 
schedule described in the Schedule of Activities (Section 1.1).  Patients should answer these 
questions before other types of study procedures, such as blood draws and physical 
examinations, are performed.  The PGA for pain severity and the PGIC will be completed on a 
tablet device at the study site.  The PGA for function will be completed on a paper questionnaire 
at the study site. 
6.5.1.6. 
Endometriosis Health Profile Work Domain 
This 5-question paper questionnaire will be completed by the patient to describe the effects of 
endometriosis on their work (Appendix 6).  Patients will complete the EHP Work Domain 
questionnaire at visits indicated in Section 1.1 before other types of study procedures, such as 
blood draws and physical examinations, are performed.  The EHP Work Domain will be 
completed on a paper questionnaire at the study site. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 


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6.5.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest. 
6.5.2.3. 
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. 
6.5.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Laboratory 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 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatine kinase 
Hemoglobin A1c 
Bilirubin total 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Alkaline phosphatase 
White blood cell count 
White blood cell differential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelet count 
Red blood cell morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and clarity 
pH 
Leucocyte esterase 
Ketones 
Nitrite 
Specific gravity 
Urine Microscopy (reflex 
testing based on abnormal 
urine analysis) 


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Hormones 
Lipids 
Pregnancy 
Estradiol 
Total cholesterol 
Low density lipoprotein 
High density lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
serum hormone levels.  Each study site will conduct urine pregnancy tests locally. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal values, determined to 
be clinically significant, should be reported as adverse events. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 
6.5.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at the time points described in the Schedule of Activities 
(Section 1.1).  ECGs will be measured using standardized equipment provided by the central 
core laboratory with the patient in a semi-supine or supine position after 5 minutes of rest.  The 
ECGs will be assessed by central review and a report provided to the site.  The investigator or 
sub-investigator (or a qualified individual at the investigational site) will interpret the ECG 
report provided by the central reviewer using one of the following categories:  normal or 
abnormal.  The investigator or sub-investigator will judge if any of the findings are clinically 
significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3 and L4), total hip, and femoral neck (same leg within each patient) at the time 
points described in the Schedule of Activities (Section 1.1).  The scans will be read by the central 
imaging laboratory in accordance with the imaging charter.  Training, quality review, and 
readings will be done by a central radiology laboratory as described in the central radiology 
charter for bone mineral density. 
Throughout the study, the same DXA apparatus will used at each site and operated in the same 
scan mode for all scans for an individual patient and should be the same as used for the patient 
during the parent study (MVT-601-3101 and MVT-601-3102).  The central core imaging 
laboratory will collect and evaluate all DXA scans for acceptability.  Bone mineral density 
changes for individual patients will be monitored by the central imaging laboratory over the 
course of the study. 
Patients with a bone mineral density loss of > 3% at lumbar spine or total hip at their 
Week 52/Early Termination visit relative to parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (± 1) months and will be contacted to obtain information 


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about medications and conditions (eg, pregnancy) that might affect bone mineral density through 
the time of the follow-up bone densitometry.  The follow-up bone densitometry will be 
submitted for central reading. 
Patients who experience a bone mineral density loss from the parent study Baseline of ≥ 7% at 
any of the anatomical sites assessed will be discontinued from the extension study and will 
undergo another bone densitometry scan as described above.  Patients should be assessed for 
secondary causes of bone loss and followed up further if not improving on the 6-month follow-
up scan, unless an alternative etiology has been identified. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the follow-up bone densitometry scan at 6 (±1) months conducted under this 
protocol may be waived. 
6.5.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted again by 
telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and will 
be asked about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, ECGs, and bone mineral density assessments. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
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; 


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• 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; 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); 
the condition that leads to the procedure is an adverse event; 
• Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• 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); 
• Endometriosis-associated pain is not considered an adverse event in this study because it 
is being quantitatively measured as the primary efficacy endpoint. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE).  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. 
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 participant 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 


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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) which 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 which 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 Institutional Review Board (IRB) or Independent Ethics Committee 
(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 eDiary entries, including bleeding and answers to the other patient-reported 
outcome measures, 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. 


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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 the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for endometriosis, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  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. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
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 
following definitions are to be used for the relationship of the adverse event to study drug: 
•
Probably related:  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
readministration (rechallenge) or withdrawal (dechallenge).
•
Possibly related:  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. 


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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.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 
Table 7-1 
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 Open-Label 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 SAE criteria.  Additional instructions for evaluating patients 
with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 7. 
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]. 


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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 the 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%).
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;
•
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 Safety Reporting 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. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest (defined in Section 7.5), and events of overdose is available on the Serious Adverse 
Event report form and is as follows: 


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Ori gi nal, Versi o n :  2 5- O C T - 2 0 1 7 
M y o va nt Scie nces G m b H  
5 3 
C O N FI D E N TI A L  
Se n d c o m p lete d S af et y Re p ort F or ms t o Q ui ntilesI M S S afet y & Ris k M a n a ge me nt: 
Site L oc ati o n 
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber 
( Sec o n d ar y re p orti n g met h o d) 
All st u d y sites  
 
 
 
F or q uesti o ns o n Seri o us A d verse E ve nt/ A d vers e E ve nt of Cli nic al I nterest  re p orti n g, 
ple ase c all:  
•  
N ort h/ S o ut h A merica:  
 
•  
E ur o pe, Asia- Pacific, a n d Africa:  see re gi o n -s pecific p h o ne n u m bers acc o m pa n yi n g t he 
Safet y R e p orti n g F or m 
T he i nitial re p ort s h o ul d i ncl u de: 
•  
St u d y n u m b er ( M V T- 6 0 1- 3 1 0 3); 
•  
Site a d dress a n d n u m ber; 
•  
I n v esti gat or na me; 
•  
Patie nt I D n u m ber, se x, a n d a ge; 
•  
Details of st u d y dr u g a d mi nistrati o n ; 
•  
T he date of t h e re p ort ; 
•  
A descri pti o n of t he seri o us a d verse e ve nt (e ve nt t er m, seri o us ness of t h e e ve nt, date of 
o nset, i nte nsit y); 
•  
Ca usal relati o ns hi p t o t he st u d y dr u g. 
If t he patie nt die d, t he re p ort s h o uld i ncl u de t he ca use of deat h as t he e v e nt ter m ( wit h deat h as 
o utc o me) a n d w h et her or n ot t he e ve nt lea di n g t o deat h was relate d t o st u d y dr u g treat me nt, as 
well as t he a ut o ps y fi n di n gs if a v aila ble.  
D o n ot dela y re p orti n g a s us pecte d seri o us a d vers e e ve nt i n or der t o o btai n a d diti o nal 
i nf or mati o n.  A n y a d diti o nal i nf or mati o n, if c ollect e d, ca n b e re p orte d as a f oll o w- u p t o t he 
i nitial re p ort.  All seri o us a d verse e ve nts will be f oll o we d u ntil res ol uti o n, u ntil t he e ve nt has 
sta bilize d, a n d/ or reac h e d a ne w bas eli ne.  All seri o us a d verse e ve nts c o nti n ui n g at t he 
c o m pleti o n of t he st u d y m ust be assesse d or f oll o we d t o deter mi ne o utc o m e. 
7. 7.  
St u d y Dr u g  O ve r d ose M a n a ge me nt 
T he m e dical m o nit or m ust be c o ntacte d i n t he e ve nt of a n y st u d y dr u g o ver d ose. 
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of st u d y dr u g, t o or b y 
a st u d y p atie n t, at a d ose a b o ve t hat assi g ne d t o t h at i n di vi d ual patie n t acc or di n g t o t he st u d y 
pr ot oc ol. 
F or t his st u d y, a n y d ose of rel u g oli x > 8 0 m g  wit hi n a 2 4- h o ur wi n d o w is a n o ver d ose a n d a n y 
d ose of estra di ol/ n oret hi n dr o ne acetate > 2 x t he pr ot oc ol d ose is a n o ver d os e (ie, m ore t h a n 
2 ca ps ules ta ke n wit hi n a 2 4- h o ur wi n d o w).  T h ere is n o k n o w n a nti d ote f or a n o ver d os e. 
P P D
P P D
P P D


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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 according to Section 7.6, whether or not the overdose 
is associated with an adverse event; 
• If possible, obtain a plasma sample for pharmacokinetic 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); 
• 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 any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  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 
form, 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. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.5.2 details the requirements for measurement of safety parameters including vital 
signs, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on endometriosis-associated pain.  Low-dose hormonal 
add-back therapy with estradiol and norethindrone acetate will be evaluated for maintenance of 
bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 


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(corrected QT [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 
reproductive toxicity, and metabolic and cardiovascular changes (insulin resistance, 
dyslipidemia, increased weight) with an increased risk of diabetes mellitus and possible 
increased risk of cardiovascular disease.  Additionally, there are potential risks associated with 
the addition of estradiol/norethindrone acetate.  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 strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
and Week 52/Early 
Termination visits with 
specified discontinuation and 
follow-up criteria and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
Period will be reported 
within 24 hours of study 
personnel awareness. 


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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Phospholipidosis 
Data from nonclinical studies in rats and 
monkeys showed histopathological 
changes consistent with phospholipidosis 
(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, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
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. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each visit. 
 


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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 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 (GCP) 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 GCP.  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 (WHO-DDE), 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. 


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9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  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 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 28 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the Intent-to-Treat (ITT) Population, defined as all 
patients who were randomized in a parent study (MVT-601-3101 or MVT-601-3102) and who 
have received any amount of randomized study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of randomized study drug. 
The analysis methods for safety and efficacy endpoints are the same as those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Justification 
Because this is an extension study, the sample size will be determined by the number of patients 
who have completed a parent study and who are eligible and willing to participate in the 
extension study.  It is estimated that approximately 800 patients (67% of the total of 1200 
patients who will be randomized into the parent studies) will participate in this study. 
9.4. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the ITT Population.  
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
The point estimates and 2-sided 95% confidence intervals (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic 
medications, proportion of responders based on NMPP scores and use of rescue analgesic 
medications) will be calculated. 


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A responder at a given time point and for a specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that type of pain from Baseline greater than or equal 
to a pre-determined threshold and who did not have an increase in the use of rescue analgesic 
medications for endometriosis-associated pain compared with the use at Baseline. Patients who 
had a pain reduction less than the pre-determined threshold or who had an increase in the use of 
analgesics for endometriosis-associated pain will be considered non-responders.  The pain 
reduction thresholds will be determined for NMPP and dysmenorrhea separately (see the SAP 
for details) for the parent studies and these same thresholds will be applied to this study. 
Baseline values are calculated using the Baseline pain assessment period, which is defined as the 
period from the date of the first dose of placebo in the parent study Run-In Period through the 
day prior to the date of randomization.  Patients’ average NRS pain scores and use of rescue 
analgesic medications for endometriosis-associated pain (dysmenorrhea or NMPP) will be 
compared between a given visit-specific pain assessment period (eg, Week 28, Week 32, etc.) 
and the Baseline pain assessment period.  The visit-specific pain assessment period is defined as 
the last 35 calendar days immediately prior to and including the last dose of study drug treatment 
received prior to the visit date. 
For any pain assessment period (Baseline or visit-specific), the average NRS scores will be 
calculated for dysmenorrhea and NMPP separately.  An average NRS score for dysmenorrhea is 
calculated as the average NRS score over the days with menses during a given pain assessment 
period.  An average NRS score for NMPP is calculated as the average NRS score over the days 
without menses during a given pain assessment period.  The analgesic use for a given pain 
assessment period is summarized by total dose count defined as the average daily dose count 
taken during the given pain assessment period multiplied by 35.  Additional details on 
calculating dose counts and on the precise definition of an increase in analgesic use will be 
provided in the SAP. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies. 
• Change from the parent study Baseline to Week 52 in the EHP-30 Pain Domain scores; 
• Change from the parent study Baseline to Week 52/EOT in the mean dysmenorrhea NRS 
score; 
• Proportion of patients who are better or much better on the PGIC for dysmenorrhea at 
Week 52/EOT; 
• Change from the parent study Baseline to Week 52/EOT in the mean NMPP NRS score; 
• Proportion of patients who are better or much better on the PGIC for NMPP at 
Week 52/EOT; 
• Change from the parent study Baseline to Week 52/EOT in the mean dyspareunia NRS 
scores; 
• Proportion of patients who are better or much better on the PGIC for dyspareunia at 
Week 52/EOT; 
• Change from the parent study Baseline to Week 52/EOT in the mean dyspareunia 
functional impairment on the sB&B scale; 
• Change from the parent study Baseline to Week 52/EOT in severity scores on the PGA 
for pain; 


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•
Change from the parent study Baseline to Week 52/EOT in function impairment on the
PGA for function;
•
Change from the parent study Baseline to Week 52/EOT in each of the non-pain EHP-30
domains (Control and Powerlessness, Social Support, Emotional Well-Being, and Self-
Image);
•
Change from the parent study Baseline pain assessment period to Week 52/EOT in
dysmenorrhea-related functional effects (sB&B);
•
Change from the parent study Baseline pain assessment period to Week 52/EOT in
NMPP-related functional effects (sB&B).
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with 
DXA.  Safety summaries by treatment group will be performed using treatment groups defined 
based on the actual randomized treatment received in the parent study.   
The treatment-emergent period will be defined as the period of time from the first dose date of 
randomized study drug in the parent study through 30 days after the last dose of study drug, or 
the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for endometriosis, whichever occurs 
first.  Safety will be assessed through summaries of adverse events, the frequency of treatment 
discontinuations due to adverse events, laboratory evaluations, and bone densitometry results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute CTCAE.  All adverse events will be coded to preferred term, high level term, 
and system organ class using MedDRA 20.0 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 to do the 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 
parent study Baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from parent study Baseline to each post-baseline study visit will be presented 
by parent study treatment group for each laboratory test. 


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For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  ECGs will also be read 
centrally.  The distributions of QTc interval will be summarized at each visit.  All data will be 
listed and summarized by visit.  The change from parent study Baseline to each post-baseline 
study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for percent change at 
Week 52 from parent study Baseline in bone mineral density will be provided based on mixed 
effects model (assumed missing at random) for each parent study treatment group. 
All data will be listed and summarized by visit.  The absolute change and percent change from 
parent study Baseline to Weeks 36 and 52 and associated 95% CIs will be presented by the 
parent study treatment group for each bone mineral density parameter.  The number and 
percentage of patients meeting a bone mineral density decline of at least 4%, 5%, 6%, or 7% by 
body area (lumbar spine, total hip, or femoral neck) will be estimated with 95% CIs by the parent 
study treatment group. 
Additional analyses will be performed to examine the correlation between bone mineral density 
loss with demographic and baseline characteristics and with treatment exposure.  Details will be 
provided in the SAP. 
9.6. 
Pharmacodynamics Analyses 
The change from the parent study Baseline to Week 52 in pre-dose concentrations of serum 
estradiol will be summarized.  Percentage of patients with concentrations of serum estradiol 
levels < 10 pg/mL and < 20 pg/mL will be provided. 


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9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed: 
• Change from Baseline to Week 52/EOT in the EHP-30 scale total score; 
• Change from Baseline to Week 52/EOT in the EHP Work Domain score; 
• Change from parent study Baseline to Week 52/EOT in the EQ-5D-5L. 
9.8. 
Interim Analyses 
There are no planned interim efficacy analyses. 
9.9. 
Steering Committee 
The study will be overseen by a Steering Committee consisting of experts in the field of 
women’s health and staff members of Myovant Sciences GmbH.  The Steering Committee will 
participate in the design, conduct, analyses, and publication of the study. 
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 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, 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, 1998, 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 1 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 
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. 
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. 


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10.1.5. 
Study Files and Retention of Records 
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 two 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 drug (drug dispensing, return, 
and accountability 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 indication; and 
• Date of study completion and reason for early termination, 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, United States, 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, decoding procedures for blinded studies, 
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. 
10.1.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed as specified in the Study Reference 
Manual.  The eCRF casebook for each study patient will be signed by the investigator or 
sub-investigator (as appropriate) listed on the 1572 and/or other appropriate local health 
authority documents.  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. 
10.1.7. 
Investigational Product Accountability 
The investigator or investigator’s designee (eg, pharmacist) is responsible for ensuring adequate 
accountability (including dates and kit numbers) of all used and unused study drug (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, accountability, and returned or destroyed study 
product.  Dispensing records will document quantities received from the sponsor and quantities 
dispensed to patients, including kit 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 once the study monitor has reviewed 
and returned used and unused study drug for accountability purposes.  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. 
10.1.8. 
Inspections 
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. 
10.1.9. 
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).  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 
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 GCP 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.  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. 
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). 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
study must be submitted to Myovant for corporate review.  The Clinical Study Agreement 
among the institution, principal investigator, and Myovant will detail the procedures for, and 
timing of, Myovant’s review of publications. 


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REFERENCES 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 02 October 2017. 
Archer DF, Chwalisz K, Feldman R, et al.  Elagolix for the management of heavy menstrual 
bleeding (HMB) associated with uterine fibroids (UF): Results from a phase 2A proof-of-
concept study. Fertil Steril. 2017 Jul;108(1);152-60.e4. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J 
Obstet Gynec.1992 Feb;166(2):740-5. 
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for 
add-back therapy with gonadotropin-releasing hormone agonists in women with 
endometriosis. Reprod Sci. 2012 Mar;19(6):563-71. 
Dunselman GA, Vermeulen N, Becker Cet al. European Society of Human Reproduction and 
Embryology. ESHRE guideline: management of women with endometriosis. Hum 
Reprod. 2014 Mar;29(3):400-12. 
Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. US Dept. of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research, Center for Biologics 
Evaluation and Research. July 2009. 
Franke HR, van de Weijer PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist 
plus add-back’ hormone replacement therapy for treatment of endometriosis: a 
prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000 
Sep;74(3):534-9. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstet Gynecol. 1998 Jan;91(1):16-24. 
Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on hypoestrogenic 
problems by postoperative gonadotropin-releasing hormone agonist treatment in 
endometriosis. Obstet Gynecol Sci. 2016 Jan;59(1):32-8. 
Morris EP, Rymer J, Robinson J, Fogelman I. Efficacy of tibolone as add-back therapy’ in 
conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine 
fibroids. Fertil Steril. 2008 Feb;89(2):421-8. 
Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic 
pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reprod Health. 2015 Mar;21(1):16-23. 
Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P. Differences in 
characteristics among 1,000 women with endometriosis based on extent of disease. Fertil 
Steril. 2008 Mar;89(3):538-45. 


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Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
therapy in treatment of endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014 
Sep;290(3):513-23. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
in the treatment of endometriosis-associated pain. Fertil Steril. 2004 Nov;82(5):1303-8. 


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APPENDICES 
 Protocol-Specified Rescue Analgesics 
Appendix 1.
Analgesics should be prescribed in accordance with the respective country’s approved product 
labeling.  The subject’s historical use of opioid analgesics should be taken into consideration 
when prescribing these drugs. 
Country 
First-Tier Drug 
(dose strength) 
Second-Tier Drug 
(dose strength) 
Argentina 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Australia 
ibuprofen (200 mg) 
codeine (30 mg) / paracetamol (500 mg) 
Belgium 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Brazil 
ibuprofen (200 mg) 
codeine (30 mg) / paracetamol (500 mg) 
Bulgaria 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Canada 
ibuprofen (200 mg) 
codeine (30 mg) / acetaminophen (300 mg) 
Chile 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Czech Republic 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Finland 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Georgia 
ibuprofen (200 mg) 
none 
Germany 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Hungary 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Italy 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
New Zealand 
ibuprofen (200 mg) 
30 mg codeine 
Poland 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Portugal 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Romania 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
South Africa 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Spain 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
Sweden 
ibuprofen (200 mg) 
codeine (30 mg) / paracetamol (500 mg) 
Ukraine 
ibuprofen (200 mg) 
tramadol (37.5 mg) / paracetamol (325 mg) 
United Kingdom 
ibuprofen (200 mg) 
codeine (30 mg) / paracetamol (500 mg) 
United States 
ibuprofen (200 mg) 
hydrocodone (5 mg) / acetaminophen (325 mg) 
All second-tier drugs that contain acetaminophen or paracetamol are fixed-dose combination products (eg, single 
tablet containing both drugs). 


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Daily eDiary 
Appendix 2.
 


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Endometriosis Health Profile-30 
Appendix 3.
ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
Never 
Rarely 
Sometimes 
Often 
Always 
1. 
Been unable to go to social events 
because of the pain?  
2. 
Been unable to do jobs around the 
house because of the pain?  
3. 
Found it difficult to stand because 
of the pain? 
4. 
Found it difficult to sit because 
of the pain? 
5. 
Found it difficult to walk because 
of the pain? 
6. 
Found it difficult to exercise or do 
the leisure activities you would like 
to do because of the pain? 
Please verify that you have checked one box for each question 
before moving on to the next page. 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
7. 
Lost your appetite and/or been 
unable to eat because of the pain? 
 
 
 
 
 
 
8. 
Been unable to sleep properly 
because of the pain? 
 
 
 
 
 
 
9. 
Had to go to bed/lie down because 
of the pain? 
 
 
 
 
 
 
10. Been unable to do the things you 
want because of the pain? 
 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
 
12. Generally felt unwell? 
 
 
 
 
 
 
13. Felt frustrated because your 
symptoms are not getting better? 
 
 
 
 
 
 
14. Felt frustrated because you are not 
able to control your symptoms? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page. 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
Never 
Rarely 
Sometimes 
Often 
Always 
15. Felt unable to forget your 
symptoms? 
16. Felt as though your symptoms 
are ruling your life? 
17. Felt your symptoms are taking 
away your life? 
18. Felt depressed?
19. Felt weepy/tearful?
20. Felt miserable?
21. Had mood swings?
22. Felt bad-tempered or short-
tempered? 
Please verify that you have checked one box for each question 
before moving on to the next page. 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
Never 
Rarely 
Sometimes 
Often 
Always 
23. Felt violent or aggressive?
24. Felt unable to tell others how 
you feel? 
25. Felt others do not understand 
what you are going through? 
26. Felt as though others think 
you are whining? 
27. Felt alone?
28. 
Felt frustrated that you cannot 
always wear the clothes you  
would choose? 
29. Felt your appearance has been 
affected? 
30. Lacked confidence?
Please verify that you have checked one box for each question. 


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European Quality of Life Five-Dimension Five-Level Scale 
Appendix 4.
 


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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 




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Patient Global Assessment (for pain) 
How would you rate your pelvic pain right now? 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly button 
Absent 
Mild 
Moderate 
Severe 
Very Severe 
Patient Global Assessment (for function) 
How much were your daily activities limited by endometriosis over the last 4 weeks?  
Not at all 
Minimally 
Moderately 
Significantly  
Very significantly 
 


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Endometriosis Health Profile - Work Domain 
Appendix 6.
 


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Assessment of Abnormal Liver Function Tests 
Appendix 7.
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) 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 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]), Alkaline Phosphatase, and INR Tests 
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities improve 
If ALT or AST ≥ 3 × 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;
•
CBC 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;
•
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or
gastroenterologist).
CBC, complete blood count; 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.


1 
CLINICAL STUDY PROTOCOL 
Study Title: 
Investigational Product: 
Protocol Number: 
Indication: 
Sponsor: 
Regulatory Identifiers: 
Version and 
Effective Date: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Relugolix 
MVT-601-3103 
Treatment of Endometriosis-Associated Pain 
Myovant Sciences GmbH 
Viaduktstrasse 8              
4051 Basel 
Switzerland 
IND# 076642 
EudraCT # 2017-004066-10 
Original:  06-NOV-2017 
Amendment 1: 20-MAR-2018 
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. 


P P D
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Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
9 
CONFIDENTIAL 
LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EHP 
Endometriosis Health Profile 
EOT 
end of treatment 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NMPP 
nonmenstrual pelvic pain 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 
PLD 
phospholipidosis 
QTc 
corrected QT (interval) 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
ULN 
upper limit of normal 
US 
United States 


Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
10 
CONFIDENTIAL 
Term 
Explanation 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
11 
CONFIDENTIAL 
1.
PROTOCOL SYNOPSIS
Study Title 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Safety and Efficacy Extension Study to Evaluate Relugolix Co-Administered 
with Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain 
Protocol Number 
MVT-601-3103 
Location 
Multinational, including North and South America, Europe, Africa, 
New Zealand, and Australia 
Study Centers 
Approximately 320 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with endometriosis-associated pain 
Number of Patients 
Planned 
Approximately 800 
Study Objectives 
In women with endometriosis-associated pain, the study objectives are as 
follows: 
Primary Efficacy Objective 
•
To evaluate long-term efficacy of relugolix 40 mg once daily
co-administered with low-dose estradiol and norethindrone acetate for up
to 52 weeks, among patients who previously completed a 24-week
treatment period in one of the parent studies (MVT-601-3101 or
MVT-601-3102), on endometriosis-associated pain.


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
18 
CONFIDENTIAL 
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Parent Study Groups A, B, and C) for the mITT Population.  The analyses methods for 
efficacy endpoints are similar to those used for the parent studies, unless otherwise specified in the 
statistical analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic medications, 
proportion of responders based on NMPP scores and use of rescue analgesic medications) will be 
calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with DXA.  Safety data 
analyses will use data from all patients from the parent studies who receive any amount of study drug 
(ie, from parent study Baseline to Week 52). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, high 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.  Laboratory values will be classified 
by toxicity grade based on the National Cancer Institute CTCAE.  Laboratory shift tables of the parent 
study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  The absolute 
change and percent change from parent study Baseline and Z-scores will be summarized by visit and 
parent study treatment group. 
The mean percentage change at Week 52 from parent study Baseline in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3101 
or MVT-601-3102) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, 
bone mineral density loss for the relugolix add-back treatment will be considered insignificant. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3101 or MVT-601-3102) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
19 
CONFIDENTIAL 
1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3103 
PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
 
 
X 
 
 
 
X 
Xh 
 
Complete Physical Exam 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Visual Acuityi 
Xg 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-
Directed Physical Examj 
 
X 
X 
X 
X 
X 
X 
 
Xh 
X 
12-Lead ECGk 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Clinical Laboratory Testsl 
Xg,m 
X 
X 
X 
X 
X 
X 
Xm 
Xh 
X 
Pharmacodynamics 
Samplen 
Xg,m 
 
 
 
 
 
 
Xm 
Xh,m 
 
Urinalysis 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
20 
CONFIDENTIAL 
PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Daily eDiaryo 
Xg 
X 
X 
X 
X 
X 
X 
X 
 
X 
Site Review of eDiary 
Data 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Bone Densitometryp 
Xg 
 
 
X 
 
 
 
Xq,r 
Xh 
 
Endometrial Biopsy 
Xg,s 
 
 
 
 
 
 
 
Xh 
 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Dispense or prescribe 
protocol-specified 
analgesic drugst 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose in 
Clinic 
Xu 
 
 
 
 
 
 
X 
Xh 
 
Daily Self-Administration 
of Study Treatmentv 
 
X 
 
 
Take Protocol-specified 
Rescue Analgesics as 
Neededw 
X 
EHP-30 Questionnairex 
Xg 
 
 
X 
 
 
X 
X 
Xh 
 
Patient Global 
Assessment for Painx 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
[on paper] Patient Global 
Assessment for Functiony 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Patient Global Impression 
of Changex 
Xg 
 
 
X 
 
 
 
X 
Xh 
 


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
23 
CONFIDENTIAL 
2. 
INTRODUCTION 
2.1. 
Endometriosis-Associated Pain 
Endometriosis is a common chronic condition occurring primarily in women of reproductive age.  
It is one of the most common gynecologic disorders, evident in 70 to 90% of women with pelvic 
pain symptoms [Practice Committee of the American Society for Reproductive Medicine, 2014].  
The exact prevalence of endometriosis is unknown but estimates range from 2 to 10% of women 
of reproductive age [Dunselman, 2014].  Symptoms range from minimal to severely debilitating. 
The pathogenesis of endometriosis is the presence of endometrial glands and stroma outside the 
uterine cavity.  Although the ectopic endometriotic lesions are most commonly found in the 
pelvis, they may also be located in the bowel, in the pleural cavity, and elsewhere.  Women with 
endometriosis have an increased risk of abdominopelvic pain, dysmenorrhea, and dyspareunia 
compared with controls without endometriosis [Practice Committee of the American Society for 
Reproductive Medicine, 2014].  In a study of 940 women with endometriosis, the most common 
symptom leading to diagnosis was dysmenorrhea in approximately 90%, pelvic pain in 
approximately 80%, and dyspareunia in approximately 45%, with 34% of women diagnosed on 
the basis of all three symptoms [Sinaii, 2008].  Presenting symptoms of infertility (25%) and 
endometrioma (ovarian mass) (20%) were also common [Sinaii, 2008]. 
The mechanisms of pain in endometriosis are generally postulated to involve production of 
substances such as growth factors and cytokines, the direct and indirect effects of active bleeding 
from endometriotic implants, and irritation of pelvic floor nerves or direct invasion of those 
nerves by infiltrating endometriotic implants [Practice Committee of the American Society for 
Reproductive Medicine, 2014]. 
According to the American Society for Reproductive Medicine Practice Committee, 
“Endometriosis is a chronic disease that requires a lifelong management plan with the goal of 
maximizing the use of medical treatment and avoiding repeated surgical procedures” [Practice 
Committee of the American Society for Reproductive Medicine, 2014]. 
Although hysterectomy with bilateral salpingo-oopherectomy is a definitive treatment of 
endometriosis, the American Society of Reproductive Medicine recommends that this option be 
reserved as a last resort for women with debilitating endometriosis symptoms who have 
completed childbearing and have failed to respond to alternative treatments [Practice Committee 
of the American Society for Reproductive Medicine, 2014].  Other surgical options for treatment 
of endometriosis include uterosacral nerve ablation, presacral neurectomy, and laparoscopic 
resection.  Rates of recurrent dysmenorrhea 1 and 3 years after laparoscopic surgery with 
uterosacral nerve ablation were not better than with laparoscopic surgery without nerve ablation 
in a large randomized trial.  Presacral neurectomy, which involves interrupting the sympathetic 
innervation to the uterus, improves pain but is a technically challenging procedure associated 
with significant risk of bleeding from the adjacent venous plexus.  Patients may also experience 
constipation and/or urinary retention postoperatively.  Laparoscopic treatment of endometriosis 
was found to be more effective at reducing pain than diagnostic laparoscopy in a meta-analysis 
of 5 randomized controlled studies.  While laparoscopic treatment is effective, pain can recur, 
and the option of performing multiple surgeries is limited by risks that include the development 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
24 
CONFIDENTIAL 
of pelvic pain from adhesions and decreased ovarian reserve, resulting in reduced fertility.  In 
one retrospective study, subsequent surgery was performed after laparoscopic treatment in 21%, 
47%, and 45% of women after 2, 5, and 7 years, respectively [Practice Committee of the 
American Society for Reproductive Medicine, 2014]. 
Medical management of endometriosis includes analgesics and treatments aimed at 
decidualization followed by atrophy of endometrial tissue with reduction or antagonism of 
estrogen production and induction of amenorrhea.  Compared to normal endometrium, 
endometriotic implants are characterized by overproduction of prostaglandins and local 
production of estrogens and cytokines, which synergize the activities of each other and promote 
implantation of ectopic endometrium.  In addition, the implants have upregulated estrogen 
synthesis pathways [Practice Committee of the American Society for Reproductive Medicine, 
2014].  Interventions that reduce ovarian estrogen production reduce this synergistic process, 
thereby reducing or eliminating endometriosis-associated pain. 
Medical hormonal options include hormonal contraceptives, progestins, gonadotropin-releasing 
hormone (GnRH) agonists, danazol, and aromatase inhibitors.  Because of lack of data 
supporting use of one treatment over another, the treatment choice is based upon symptom 
severity, patient preferences, side effects, efficacy, contraceptive needs, costs, and availability 
[Dunselman, 2014].  The main adverse effects of GnRH agonists relate to induction of a 
hypoestrogenic state (eg, bone mineral density loss and vasomotor symptoms) whereas danazol 
produces androgenic adverse effects such as hirsutism, weight gain, and deepening of the voice.  
Some patients treated with GnRH agonists also experience an initial “flare effect” (increased 
pain and bleeding), and this can result in premature discontinuation of treatment.  Side effects of 
progestin treatment can include irregular uterine bleeding, weight gain, mood changes such as 
depression, and bone mineral density loss with long-term use of certain agents. 
The goal of the relugolix phase 3 development plan is to demonstrate that relugolix can decrease 
dysmenorrhea and nonmenstrual pelvic pain (NMPP) in women with endometriosis safely 
through 12 months of therapy and to evaluate effects on pain-related quality of life and function.  
By enhancing the safety and tolerability of the active treatment arm with the co-administration of 
low-dose hormonal add-back therapy, the program ultimately aims to bring to women suffering 
endometriosis-associated pain a long-term oral medical therapy that significantly reduces pain 
and improves quality of life and provides an alternative to invasive procedures. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix Investigator Brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once-daily oral medication for the treatment of endometriosis-associated pain.  The proposed 
dose of relugolix is 40 mg administered orally once daily and the proposed doses of estradiol and 
norethindrone acetate are 1.0 mg and 0.5 mg once daily, respectively. 


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
29 
CONFIDENTIAL 
completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the 
Week 24/Baseline visit.  No MVT-601-3103 study procedures will be performed until the 
consent form for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit, and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Therefore, results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline visit.  The administration of the first dose of study 
drug for MVT-601-3103 will define enrollment into this study.  Study participants will then take 
the open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 28 weeks. 
During the 28-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the 
electronic diary (eDiary).  Only study-specific rescue analgesic medications should be used 
starting with the Week 24/Baseline visit and through the Follow-Up visit and these medications 
will be taken for control of pain and not prophylactically.  Health-related quality of life 
questionnaires; PGIC for dysmenorrhea, NMPP, and dyspareunia; and PGA for pain and 
function will be completed during the visits on an electronic tablet or on paper, according to the 
Schedule of Activities (Section 1.1). 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment 
of bone mineral density via DXA. 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, and bone mineral density 
with DXA. 
Patients with a bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit (or most recent scan, if the Week 52/ET scan was not done) 
relative to the parent study Baseline measurement will undergo another bone densitometry scan 
at 6 (± 1) months after the last dose of study medication. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted again by telephone 3 
(+ 0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 4-1. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
30 
CONFIDENTIAL 
Figure 4-1 
MVT-601-3103 Study Schematic 
 
 
 
4.2. 
Discussion of Study Design, Including Dosing 
The SPIRIT EXTENSION study (MVT-601-3103) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3101 and MVT-601-3102) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with endometriosis-associated pain.  This 
28-week extension study provides additional efficacy and safety data up to 52 weeks to 
demonstrate the benefit and safety of relugolix co-administered with low-dose estradiol (1 mg) 
and norethindrone acetate (0.5 mg).  The primary objectives of the study are to assess long-term 
efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 52 weeks on dysmenorrhea and NMPP, common and burdensome 
symptoms of endometriosis.  The study will also evaluate safety of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up to 52 weeks, among 
patients who previously completed a 24-week treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including adverse events and change in bone mineral 
density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily (N = 101) suppressed 
estradiol levels to below 20 pg/mL in the majority of women, and results were similar to those in 
the group of women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the 
relugolix 40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary 
endpoint of the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
31 
CONFIDENTIAL 
demonstrated the 40-mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from endometriosis-associated pain to move forward into phase 3 clinical 
development and, based on the DXA data from the phase 2 study, are not expected to prevent 
bone mineral density loss in a significant majority of women over 52 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 52 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in dysmenorrhea and NMPP.  It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2017; Lee, 2016; Franke, 2000] or endometriosis-associated 
pain [Wu, 2014].  The estradiol/norethindrone acetate combination proposed for evaluation in 
this phase 3 study is currently approved in the United States (US) as long-term hormone 
replacement therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal 
women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 
lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Activella US Prescribing Information, 2013]) would not provide sufficient serum estradiol 


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
38 
CONFIDENTIAL 
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 common 
excipients. 
The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing 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. 
On Week 24/Baseline and Week 52 clinic visit days, study drug will be administered in the clinic 
rather than at home (see Schedule of Activities in Section 1.1).  
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 cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location at room 
temperature.  Follow storage conditions described on the drug labeling.  Study drug should be 
stored protected from light.  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.  Further guidance 
and information for final disposition of unused study drug are provided in the Study Reference 
Manual and Pharmacy Manual.  The investigator is responsible for study drug accountability, 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
39 
CONFIDENTIAL 
reconciliation, and record maintenance, including receipt, reconciliation, and final disposition 
records and their secure storage. 
Study drug will be labeled with the study protocol number, medication or lot/batch number, 
contents, directions for use, storage directions, clinical study statement, and any other labeling 
required by regulatory bodies in the study locations and will list Myovant Sciences GmbH as the 
sponsor.  Patients will be instructed to store study drug at room temperature out of the reach of 
children. 
All labels for relugolix and the estradiol/norethindrone acetate combination to be distributed will 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices:  Manufacture of investigational medicinal products (July 
2010) and/or other local regulations as applicable. 
Please see Appendix 1 for a list of protocol-specified analgesics.  Further details on analgesic 
medication are provided in the Study Reference Manual. 
5.7. 
Rescue Analgesic Medications 
Management of endometriosis-associated pain often requires treatment with analgesics and some 
patients require treatment with opioid drugs. Two tiers of pain medications are specified for this 
trial. The study-specified pain medications for each patient will be the same as for the parent 
study. Only study-specific Tier 1 and Tier 2 analgesic medications (see Appendix 1) should be 
taken starting with the Baseline/Week 24 visit and subsequently. Analgesic medications will be 
taken for control of pain and not prophylactically.  
If a patient develops uncontrolled endometriosis-associated pain during the study despite use of 
the study-specified analgesics or an intolerance to a study-specified analgesic, please contact the 
medical monitor. 
Short-term use of non-study specified analgesics for the treatment of an intercurrent event (eg, 
injury or surgery) is allowed, if required. Such events should be reported as adverse events. 
Investigators must instruct the patient on the use of ibuprofen 200 mg tablets (ie, number of 
tablets per dose, dosing frequency, maximum number of tablets per day). For patients who may 
need the Tier 2 analgesic medication, a prescription should also be written for this at the time of 
enrollment into this study. This is to ensure that patients do not endure unnecessary pain during 
the conduct of the study. 
Quantities of opioids prescribed should be based on the patient’s expected usage until the next 
study visit. Prescriptions for Tier 1 and Tier 2 rescue analgesic medications should be in 
accordance with their full prescribing information (ie, the local product labeling) and 
prescriptions for opioids should not provide for any refills. Patients should be counseled on the 
safe use of opioids. 
Patients who are not prescribed the Tier 2 medication at the time of enrollment in this study, for 
example, because requirement for analgesics beyond the Tier 1 medication is not expected (eg, 
based on pain level and/or recent analgesic requirements) should be advised to contact the 
investigator if pain is inadequately controlled with the Tier 1 medication alone. To avoid 
experiencing extended periods of uncontrolled pain, patients who require the Tier 2 medication 


Clinical Study Protocol:  MVT-601-3103 
 
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40 
CONFIDENTIAL 
should get a prescription from the investigator and initiate treatment with the Tier 2 medication 
as soon as feasible.  
Use of protocol-specified rescue analgesic medications and any other analgesics taken for any 
type of pain, must be recorded by the patient in the e-Diary.   
5.8. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and should bring all unused and used 
study drug to each study visit.  At the Week 24/Baseline visit and Week 52/ET visit, all used and 
unused study drug kits should be retained at the site.  New study drug should be dispensed as 
described in Section 1.1 (Schedule of Activities).  At all other visits, only used study drug kits 
should be retained at the site. 
Study drug accountability will be conducted and results will be recorded.  If a patient is 
persistently noncompliant with the study treatment, it may be appropriate to withdraw the patient 
from the study (see Section 4.5).  All patients should be reinstructed about the dosing 
requirement during study contacts.  The authorized study personnel conducting the re-education 
must document the process in the patient’s source records. 
Because of the importance to both safety and efficacy evaluation, patients who are grossly 
noncompliant with eDiary completion must undergo an Unscheduled visit to evaluate reasons for 
noncompliance and to develop a plan to improve compliance.  Failure to improve compliance 
may result in the sponsor withdrawing the patient from further study treatment (including study 
analgesics) and/or discontinuation from the study (see Section 4.5 for details). 
All patients should be reinstructed about the dosing requirement and eDiary 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 prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Drugs and drug classes in Table 5-2 are prohibited at any time 
during the study through the Follow-Up visit, except as noted in the table.  Consult the medical 
monitor if there is any uncertainty regarding patient use of a particular drug or drug class. 


Clinical Study Protocol:  MVT-601-3103 
 
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Table 5-2 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zoledronic acid 
 
GnRH analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
 
Anti-androgens 
danazol 
 
Anticonvulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
Note: All other anticonvulsants are 
allowed 
Aromatase inhibitors 
anastrozole 
letrozole 
 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
Hormonal contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
NuvaRing 
 
Selective estrogen 
receptor modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
 
Selective progesterone 
receptor modulators  
mifepristone 
ulipristal acetate 
 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
 
Intrauterine devices 
levonorgestrel 
copper 
 


Clinical Study Protocol:  MVT-601-3103 
 
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CONFIDENTIAL 
Drug Class 
Examples 
Comments 
Bone agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use of systemic 
glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study.   
Note:  topical, inhaled, intranasal, 
otic, ophthalmic, intraarticular, or 
intralesional subcutaneous are 
permitted without restriction. 
Short duration (< 21 days) higher-
dose glucocorticoids required for 
acute events are permitted during 
the study. 
P-glycoprotein inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavirf 
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. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
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CONFIDENTIAL 
Drug Class 
Examples 
Comments 
Moderate and strong 
P-glycoprotein inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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. 
Analgesic drugs other 
than those specified for 
use during the study1 
Acetaminophen/paracetamol (other 
than any included in a study-
specified analgesic) 
aspirin > 325 mg/day 
NSAIDs (other than study-specified 
NSAIDs) 
gabapentin 
pregabalin 
carbamazepine 
metamizole 
Note:  Aspirin ≤ 325 mg per day is 
allowed 
Antidepressants 
New treatment or 
changed doses of SSRI, 
SNRI, or TCA 
antidepressants 
SNRI examples: 
duloxetine 
venlafaxine 
desvenlafaxine 
SSRI examples: 
citalopram 
fluoxetine 
paroxetine 
fluvoxamine 
TCA examples: 
amitriptyline 
doxepin 
desipramine 
nortriptyline 
SSRI, SNRI, or TCA allowed if 
given at the same dose as used 
during the 3 months prior to the 
Run-In Period of MVT-601-3101 or 
MVT-601-3102. 
New start, dose change or 
discontinuation of these drugs is not 
allowed during the study.  Changes 
made for safety reasons are allowed 
with approval of the medical 
monitor. 


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Clinical Study Protocol:  MVT-601-3103 
 
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Myovant Sciences GmbH 
46 
CONFIDENTIAL 
An endometrial biopsy will have been performed at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 (see MVT-601-3101 protocol for details).  Safety 
monitoring for this study includes physical examination, clinical laboratory tests, pregnancy 
tests, and adverse event collection at each visit.  Clinical chemistries will be collected at each 
visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, and 
Week 52.  At the Week 24/Baseline visit and Week 52 visit, additional tests include fasting (at 
least 8 hours, other than water) glucose, lipid profile, and hemoglobin A1c. 
ECGs will be done at the Week 24/Baseline and at the Week 52/Early Termination visits.  Bone 
densitometry will occur at the Week 24/Baseline, Week 36, and Week 52/Early Termination 
visits. Week 52/Early Termination.  
Bone densitometry and ECGs will be submitted for central reading. 
Study drug compliance will be reviewed at each visit.  Fasting (other than water) for at least 
8 hours is required prior to blood sampling on Week 24/Baseline and Week 52/Early 
Termination visits and for 1 hour after administration of the study drug in the clinic.  Laboratory 
requisitions must indicate whether or not the patient was not fasted for their chemistry and lipid 
testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment Period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 52 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 52; however, for 
patients whose last dose of study drug is during Week 32 or earlier or within 4 weeks after 
completion of the Week 36 scan, the bone densitometry does not need to be performed.  This 
procedure may be performed, however, at the investigator’s discretion, if it aids in follow-up of 
an ongoing adverse event(s). 
Patients (including those who complete the Week 52 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
endometriosis, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 52 visit, the Follow-up visit may be 
waived. 
The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the Follow-
up visit. 
6.4. 
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 


Clinical Study Protocol:  MVT-601-3103 
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
investigator.  The date and reason for the Unscheduled visit should be recorded in the source 
documentation.  The following activities should be completed at Unscheduled visits:  recording 
of reason for the visit, 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, urine pregnancy testing, pharmacodynamic sampling, 
12-lead ECG, study drug compliance and dispensation, eDiary review, dispensation or 
prescription of protocol-specified analgesics, etc, may be conducted as needed.  See the Schedule 
of Activities (Section 1.1) for tests that may be performed, as indicated at an Unscheduled visit.  
The investigator should consult with the medical monitor, if needed, to discuss Unscheduled visit 
testing.  The investigator should obtain approval from the sponsor to perform an unscheduled 
endometrial biopsy or DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Pharmacodynamics Sample Collection 
A blood sample for the pharmacodynamic analysis of serum estradiol will be collected pre-dose 
at the visits indicated in the study Schedule of Activities (see Section 1.1), other than at the 
Week 52 or the Early Termination visit, when no dose is administered.  These pharmacodynamic 
samples will be analyzed at a central laboratory.  These results will not be shared with the sites at 
any time. 
6.5.1.2. 
Patient eDiary 
All women enrolled in the study will continue to use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete daily eDiary entries including NRS pain scores, 
menstruation information, analgesic drug use, date and time of study drug administration, and 
sB&B scale scores. 
The site should review the eDiary data at every visit. 
6.5.1.3. 
Endometriosis Health Profile-30 
The EHP-30 is used to evaluate the functional impact and the quality of life of patients with 
endometriosis (see Appendix 3).  Patients will complete the EHP-30 questionnaire at the site at 
visits indicated in Section 1.1 before other types of study procedures, such as blood draws and 
physical examinations, are performed.  The EHP-30 will be completed on a tablet device at the 
study site. 
6.5.1.4. 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes (see 
Appendix 4).  Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are 
each assessed on a 5-level categorical scale. 


Clinical Study Protocol:  MVT-601-3103 
 
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Patients will complete the EQ-5D-5L questionnaire at the site at visits indicated in Section 1.1 
before other types of study procedures, such as blood draws and physical examinations, are 
performed.  The EQ-5D-5L will be completed on a tablet device at the study site. 
6.5.1.5. 
Patient Global Assessment and Patient Global Impression of Change 
These simple questions are used by the patient to qualitatively describe severity of pain or effects 
on function (PGA) or impression of change in pain severity (PGIC) (see Appendix 5) on a 
schedule described in the Schedule of Activities (Section 1.1).  Patients should answer these 
questions before other types of study procedures, such as blood draws and physical 
examinations, are performed.  The PGA for pain severity and the PGIC will be completed on a 
tablet device at the study site.  The PGA for function will be completed on a paper questionnaire 
at the study site. 
6.5.1.6. 
Endometriosis Health Profile Work Domain 
This 5-question paper questionnaire will be completed by the patient to describe the effects of 
endometriosis on their work (Appendix 6).  Patients will complete the EHP Work Domain 
questionnaire at visits indicated in Section 1.1 before other types of study procedures, such as 
blood draws and physical examinations, are performed.  The EHP Work Domain will be 
completed on a paper questionnaire at the study site. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 
6.5.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest. 
6.5.2.3. 
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. 
6.5.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Laboratory 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 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
49 
CONFIDENTIAL 
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 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatine kinase 
Hemoglobin A1c 
Bilirubin total 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Alkaline phosphatase 
White blood cell count 
White blood cell differential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelet count 
Red blood cell morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and clarity 
pH 
Leucocyte esterase 
Ketones 
Nitrite 
Specific gravity 
Urine Microscopy (reflex 
testing based on abnormal 
urine analysis) 
Hormones 
Lipids 
Pregnancy 
Estradiol 
Total cholesterol 
Low density lipoprotein 
High density lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
serum hormone levels.  Each study site will conduct urine pregnancy tests locally. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal values, determined to 
be clinically significant, should be reported as adverse events. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
50 
CONFIDENTIAL 
6.5.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at the time points described in the Schedule of Activities 
(Section 1.1).  ECGs will be measured using standardized equipment provided by the central 
core laboratory with the patient in a semi-supine or supine position after 5 minutes of rest.  The 
ECGs will be assessed by central review and a report provided to the site.  The investigator or 
sub-investigator (or a qualified individual at the investigational site) will interpret the ECG 
report provided by the central reviewer using one of the following categories:  normal or 
abnormal.  The investigator or sub-investigator will judge if any of the findings are clinically 
significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3 and L4), total hip, and femoral neck (same leg within each patient) at the time 
points described in the Schedule of Activities (Section 1.1).  The scans will be read by the central 
imaging laboratory in accordance with the imaging charter.  Training, quality review, and 
readings will be done by a central radiology laboratory as described in the central radiology 
charter for bone mineral density. 
Throughout the study, the same DXA apparatus will used at each site and operated in the same 
scan mode for all scans for an individual patient and should be the same as used for the patient 
during the parent study (MVT-601-3101 and MVT-601-3102).  The central core imaging 
laboratory will collect and evaluate all DXA scans for acceptability.  Bone mineral density 
changes for individual patients will be monitored by the central imaging laboratory over the 
course of the study. 
Patients with a bone mineral density loss of > 3% at lumbar spine or total hip at their 
Week 52/Early Termination visit (or most recent scan if the Week 52/ET scan was not done) 
relative to parent study Baseline measurement will undergo another bone densitometry scan at 
6 (± 1) months and will be contacted to obtain information about medications and conditions (eg, 
pregnancy) that might affect bone mineral density through the time of the follow-up bone 
densitometry.  The follow-up bone densitometry will be submitted for central reading. 
Patients who experience a bone mineral density loss from the parent study Baseline of ≥ 7% at 
any of the anatomical sites assessed will be discontinued from the extension study and will 
undergo another bone densitometry scan as described above.  Patients should be assessed for 
secondary causes of bone loss and followed up further if not improving on the 6-month follow-
up scan, unless an alternative etiology has been identified. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the follow-up bone densitometry scan at 6 (±1) months conducted under this 
protocol may be waived. 
6.5.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 


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Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
52 
CONFIDENTIAL 
•
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);
•
Endometriosis-associated pain is not considered an adverse event in this study because it
is being quantitatively measured as the primary efficacy endpoint.
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE).  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. 
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 participant 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 admitted to a hospital, 
independent of the duration of that hospitalization.  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) which 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 which 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 


Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
53 
CONFIDENTIAL 
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 Institutional Review Board (IRB) or Independent Ethics Committee 
(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 eDiary entries, including bleeding and answers to the other patient-reported 
outcome measures, 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 the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 


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Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Effecti ve:  2 0 -M A R - 2 0 1 8 
M y o va nt Scie nces G m b H  
5 6 
C O N FI D E N TI A L  
7. 5. 2.  
Criteri a f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g i n Ass oci ati o n w it h Li ver 
Test A b n or m aliti es  
St u d y dr u g treat me nt s h o ul d be disc o nti n ue d per m a ne ntl y if all of t he f o ll o wi n g 4 criteria are 
met (ie, p ote ntial se ver e dr u g-i n d uc e d li ver i nj ur y/ H y’s la w cas e):  
1.  A S T or A L T i ncr eases t o ≥ 3 x U L N; A N D  
2.  T otal bilir u bi n i ncreases t o >  2 x U L N or I N R >  1. 5; A N D 
3.  Al kali ne p h os p hatase v al ue d oes n ot reac h 2 x U L N ; A N D  
4.  N o alter nati ve ca use e x plai ns t he c o m bi nati o n of t he a b o ve la b orat or y a b n or malities; 
i m p orta nt alter nati ve ca uses i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g: 
•  He pat o biliar y tract diseas e ; 
•  Viral he patitis (e g, he p atitis A/ B/ C/ D/ E, E pstei n -Barr vir us) ; 
•  E x p os ure t o he pat ot o xic a ge nts/ dr u gs or he p at ot o xi ns, i ncl u di n g her b al a n d dietar y 
s u p ple me nts, pla nts, a n d m us hr o o ms; 
•  Alc o h olic he patitis ; 
•  N o nalc o h olic steat o he p atitis;  
•  A ut oi m m u ne he patitis.  
If a n alter nati ve ca use for he pat ot o xicit y is i de ntifi e d, t he n it s h o ul d be deter mi ne d ( base d o n t he 
se verit y of t he he p at ot o xicit y or e ve nt) w h et her st u d y dr u g treat me nt s h o ul d be wit h hel d or 
per ma ne ntl y disc o nti n ue d as a p pr o priat e f or t he s afet y of t he p atie nt. 
7. 6.  
Seri o us A d verse E ve nt Re p orti n g 
Usi n g a Safet y Re p orti n g F or m, all seri o us a d v ers e e ve nts m ust be re p orte d wit hi n 2 4  h o urs of 
t he st u d y site pers o n nel’s k n o wle d ge of t he e ve nt, re gar dless of t he i n vesti gat or ass ess me nt of 
t he relati o ns hi p of t he e v e nt t o st u d y dr u g. 
T he c o ntact i nf or mati o n f or s u b missi o n of seri o us a d verse e ve nts, a d v erse e ve nts of cli nical 
i nterest ( defi n e d i n Secti o n 7. 5 ), a n d e v e nts of o v er d ose is a vaila bl e o n t he Seri o us A d verse 
E ve nt re p ort f or m a n d is as f oll o ws: 
Se n d c o m p lete d S af et y Re p ort F or ms t o I Q VI A R D S I nc. (f or merl y Q ui ntilesI M S): 
Site L oc ati o n 
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber 
( Sec o n d ar y re p orti n g met h o d) 
All st u d y sites  
 
 
 
F or q uesti o ns o n Seri o us A d verse E ve nt/ A d vers e E ve nt of Cli nic al I nterest  re p orti n g, 
ple ase c all:  
•  
N ort h/ S o ut h A merica:  
 
•  
E ur o pe, Asia- Pacific, a n d Africa:  see re gi o n -s pecific p h o ne n u m bers acc o m pa n yi n g t he 
Safet y R e p orti n g F or m 
T he i nitial re p ort s h o ul d i ncl u de: 
P P D
P P D
P P D


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
58 
CONFIDENTIAL 
7.8. 
Pregnancy Reporting 
If any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  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 
form, 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. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.5.2 details the requirements for measurement of safety parameters including vital 
signs, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on endometriosis-associated pain.  Low-dose hormonal 
add-back therapy with estradiol and norethindrone acetate will be evaluated for maintenance of 
bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 
reproductive toxicity, and metabolic and cardiovascular changes (insulin resistance, 
dyslipidemia, increased weight) with an increased risk of diabetes mellitus and possible 
increased risk of cardiovascular disease.  Additionally, there are potential risks associated with 
the addition of estradiol/norethindrone acetate.  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 strategy for this protocol are outlined in Table 7-2. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
59 
CONFIDENTIAL 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
and Week 52/Early 
Termination visits with 
specified discontinuation and 
follow-up criteria and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
Period will be reported 
within 24 hours of study 
personnel awareness. 
Phospholipidosis 
Data from nonclinical studies in rats and 
monkeys showed histopathological 
changes consistent with phospholipidosis 
(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, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
60 
CONFIDENTIAL 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
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. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each visit. 
 
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. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
61 
CONFIDENTIAL 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice (GCP) 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 GCP.  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 (WHO-DDE), 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. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  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. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
62 
CONFIDENTIAL 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 28 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the modified Intent-to-Treat (mITT) Population, 
defined as all patients who were randomized in a parent study (MVT-601-3101 or MVT-601-
3102) and who have received any amount of randomized study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of randomized study drug. 
The analysis methods for safety and efficacy endpoints are the same as those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Justification 
Because this is an extension study, the sample size will be determined by the number of patients 
who have completed a parent study and who are eligible and willing to participate in the 
extension study.  It is estimated that approximately 800 patients (67% of the total of 1200 
patients who will be randomized into the parent studies) will participate in this study. 
9.4. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the mITT Population.  
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
The point estimates and 2-sided 95% confidence intervals (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic 
medications, proportion of responders based on NMPP scores and use of rescue analgesic 
medications) will be calculated. 
A responder at a given time point and for a specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that type of pain from Baseline greater than or equal 
to a pre-determined threshold and who did not have an increase in the use of rescue analgesic 
medications for endometriosis-associated pain compared with the use at Baseline. Patients who 
had a pain reduction less than the pre-determined threshold or who had an increase in the use of 
analgesics for endometriosis-associated pain will be considered non-responders.  The pain 
reduction thresholds will be determined for NMPP and dysmenorrhea separately (see the SAP 
for details) for the parent studies and these same thresholds will be applied to this study. 
Baseline values are calculated using the Baseline pain assessment period, which is defined as the 
period from the date of the first dose of placebo in the parent study Run-In Period through the 
day prior to the first dose of randomized study drug.  Patients’ average NRS pain scores and use 


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
64 
CONFIDENTIAL 
For endpoint of proportion of responders at Week 52/EOT based on EHP-30 Pain Domain 
scores, a responder is defined using the same within-patient score change threshold determined 
from the parent studies.  
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP.   
 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with 
DXA.  Safety summaries by treatment group will be performed using treatment groups defined 
based on the actual randomized treatment received in the parent study.   
The treatment-emergent period will be defined as the period of time from the first dose date and 
time of randomized study drug in the parent study through 30 days after the last dose of study 
drug, or the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for endometriosis, whichever occurs 
first.  Safety will be assessed through summaries of adverse events, the frequency of treatment 
discontinuations due to adverse events, laboratory evaluations, and bone densitometry results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute CTCAE.  All adverse events will be coded to preferred term, high level term, 
and system organ class using MedDRA 20.0 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 to do the 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 
parent study Baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from parent study Baseline to each post-baseline study visit will be presented 
by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  ECGs will also be read 
centrally.  The distributions of QTc interval will be summarized at each visit.  All data will be 
listed and summarized by visit.  The change from parent study Baseline to each post-baseline 
study visit will be presented by treatment group for each ECG parameter. 


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Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
66 
CONFIDENTIAL 
9.8. 
Interim Analyses 
There are no planned interim efficacy analyses. 
9.9. 
Steering Committee 
The study will be overseen by a Steering Committee consisting of experts in the field of 
women’s health and staff members of Myovant Sciences GmbH.  The Steering Committee will 
participate in the design, conduct, analyses, and publication of the study. 
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 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, 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, 1998, 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 1 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. 


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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. 
10.1.7. 
Investigational Product Accountability 
The investigator or investigator’s designee (eg, pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, accountability, 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 once the study monitor has reviewed 
and returned used and unused study drug for accountability purposes.  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. 
10.1.8. 
Inspections 
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. 
10.1.9. 
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. 
Safety Reporting 
The sponsor will comply with safety reporting requirements consistent with US FDA, EU 
National competent authority, and Health Canada Guidance 2.8.4, Health Canada Food and 
Drugs Act and Regulations, Division 5, Part C.05.014, and applicable ICH and regional 
regulatory safety reporting requirements. 


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10.2.2. 
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 appropriate IRB or IEC 
for information and approval in accordance with local requirements and to the appropriate Health 
Authority (eg, FDA, Health Canada, EU National competent authority), if required.  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. 
10.2.3. 
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).  An abbreviated report may be prepared in 
certain cases. 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
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 GCP 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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REFERENCES 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 02 October 2017. 
Archer DF, Chwalisz K, Feldman R, et al.  Elagolix for the management of heavy menstrual 
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Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J 
Obstet Gynec.1992 Feb;166(2):740-5. 
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for 
add-back therapy with gonadotropin-releasing hormone agonists in women with 
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Dunselman GA, Vermeulen N, Becker Cet al. European Society of Human Reproduction and 
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Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
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Franke HR, van de Weijer PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist 
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Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstet Gynecol. 1998 Jan;91(1):16-24. 
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problems by postoperative gonadotropin-releasing hormone agonist treatment in 
endometriosis. Obstet Gynecol Sci. 2016 Jan;59(1):32-8. 
Morris EP, Rymer J, Robinson J, Fogelman I. Efficacy of tibolone as add-back therapy’ in 
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Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic 
pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reprod Health. 2015 Mar;21(1):16-23. 
Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P. Differences in 
characteristics among 1,000 women with endometriosis based on extent of disease. Fertil 
Steril. 2008 Mar;89(3):538-45. 


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Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
therapy in treatment of endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014 
Sep;290(3):513-23. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
in the treatment of endometriosis-associated pain. Fertil Steril. 2004 Nov;82(5):1303-8. 
 


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Daily eDiary 
Appendix 2.
 


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Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Effecti ve:  2 0 -M A R - 2 0 1 8 
M y o va nt Scie nces G m b H  
9 9 
C O N FI D E N TI A L  
 
E n d o metri osis He alt h Pr ofile- 3 0 
A p pe n di x 3.
E N D O M E T RI O SI S H E A L T H P R O FI L E Q U E S TI O N N AI R E ( E H P - 3 0) 
P A R T 1: C O R E Q U E S TI O N N AI R E  
D U RI N G T H E L A S T 4  W E E K S ,  
B E C A U S E O F Y O U R E N D O M E T RI O SI S , H O W O F T E N H A V E Y O U ... 
 
N e v er  
R ar el y  
S o m eti m e s  
Oft e n 
Al w a y s  
1.  
B e e n u n a bl e t o g o t o s o ci al e v e nt s 
b e c a u s e of t h e p ai n ?  
 
 
 
 
 
 
2.  
B e e n u n a bl e t o d o j o b s ar o u n d t h e 
h o u s e b e c a u s e of t h e p ai n ?  
 
 
 
 
 
 
3.  
F o u n d it diffi c ult t o st a n d b e c a u s e 
of t h e p ai n ?  
 
 
 
 
 
 
4.  
F o u n d it diffi c ult t o sit b e c a u s e  
o f t h e p ai n ? 
 
 
 
 
 
 
5.  
F o u n d it diffi c ult t o w al k b e c a u s e  
of t h e p ai n ?  
 
 
 
 
 
 
6.  
F o u n d it diffi c ult t o e x er ci s e or d o 
t h e l ei s ur e a cti viti e s y o u w o ul d li k e 
t o d o b e c a u s e of t h e p ai n ? 
 
 
 
 
 
 
 
Pl e a s e v erif y t h at y o u h a v e c h e c k e d o n e b o x f or e a c h q u e sti o n  
b ef or e m o vi n g o n t o t h e n e xt p a g e.  
 


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Effecti ve:  2 0 -M A R - 2 0 1 8 
M y o va nt Scie nces G m b H  
1 0 0 
C O N FI D E N TI A L  
D U RI N G T H E L A S T 4  W E E K S ,  
B E C A U S E O F Y O U R E N D O M E T RI O SI S , H O W O F T E N H A V E Y O U ... 
 
N e v er  
R ar el y  
S o m eti m e s  
Oft e n 
Al w a y s  
7.  
L o st y o ur a p p etit e a n d/ or b e e n 
u n a bl e t o e at b e c a u s e of t h e p ai n ?  
 
 
 
 
 
 
8.  
B e e n u n a bl e t o sl e e p pr o p erl y 
b e c a u s e of t h e p ai n ?  
 
 
 
 
 
 
9.  
H a d t o g o t o b e d/li e d o w n b e c a u s e 
of t h e p ai n ?  
 
 
 
 
 
 
1 0.  B e e n u n a bl e t o d o t h e t hi n g s y o u 
w a nt b e c a u s e of t h e p ai n ?  
 
 
 
 
 
 
1 1.  F elt u n a bl e t o c o p e wit h t h e p ai n ?  
 
 
 
 
 
 
1 2.  G e n er all y f elt u n w ell ?  
 
 
 
 
 
 
1 3.  F elt fr u str at e d b e c a u s e y o ur 
s y m pt o m s ar e n ot g etti n g b ett er ?  
 
 
 
 
 
 
1 4.  F elt fr u str at e d b e c a u s e y o u ar e n ot 
a bl e t o c o ntr ol y o ur s y m pt o m s ?  
 
 
 
 
 
 
 
Pl e a s e v erif y t h at y o u h a v e c h e c k e d o n e b o x f or e a c h q u e sti o n  
b ef or e m o vi n g o n t o t h e n e xt p a g e.  
 
 


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Effecti ve:  2 0 -M A R - 2 0 1 8 
M y o va nt Scie nces G m b H  
1 0 1 
C O N FI D E N TI A L  
D U RI N G T H E L A S T 4  W E E K S ,  
B E C A U S E O F Y O U R E N D O M E T RI O SI S , H O W O F T E N H A V E Y O U ... 
 
N e v er  
R ar el y  
S o m eti m e s  
Oft e n 
Al w a y s  
1 5.  F elt u n a bl e t o f or g et y o ur 
s y m pt o m s ?  
 
 
 
 
 
 
1 6.  F elt a s t h o u g h y o ur s y m pt o m s  
ar e r uli n g y o ur lif e ?  
 
 
 
 
 
 
1 7.  F elt y o ur s y m pt o m s ar e t a ki n g 
a w a y y o ur lif e ?  
 
 
 
 
 
 
1 8.  F elt d e pr e s s e d ?  
 
 
 
 
 
 
1 9.  F elt w e e p y/t e arf ul ?  
 
 
 
 
 
 
2 0.  F elt mi s er a bl e ?  
 
 
 
 
 
 
2 1.  H a d m o o d s wi n g s ?  
 
 
 
 
 
 
2 2.  F elt b a d -t e m p er e d or s h ort -
t e m p er e d ? 
 
 
 
 
 
 
 
Pl e a s e v erif y t h at y o u h a v e c h e c k e d o n e b o x f or e a c h q u e sti o n  
b ef or e m o vi n g o n t o t h e n e xt p a g e.  
 
 


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3  
 
Effecti ve:  2 0 -M A R - 2 0 1 8 
M y o va nt Scie nces G m b H  
1 0 2 
C O N FI D E N TI A L  
D U RI N G T H E L A S T 4  W E E K S ,  
B E C A U S E O F Y O U R E N D O M E T RI O SI S , H O W O F T E N H A V E Y O U ... 
 
N e v er  
R ar el y  
S o m eti m e s  
Oft e n 
Al w a y s  
2 3.  F elt vi ol e nt or a g gr e s si v e ?  
 
 
 
 
 
 
2 4.  F elt u n a bl e t o t ell ot h er s h o w  
y o u f e el ?  
 
 
 
 
 
 
2 5.  F elt ot h er s d o n ot u n d er st a n d  
w h at y o u ar e g oi n g t hr o u g h ?  
 
 
 
 
 
 
2 6.  F elt a s t h o u g h ot h er s t hi n k  
y o u ar e w hi ni n g ?  
 
 
 
 
 
 
2 7.  F elt al o n e ?  
 
 
 
 
 
 
2 8.  
F elt fr u str at e d t h at y o u c a n n ot 
al w a y s w e ar t h e cl ot h e s y o u  
w o ul d c h o o s e ?  
 
 
 
 
 
 
2 9.  F elt y o ur a p p e ar a n c e h a s b e e n 
aff e c t e d ? 
 
 
 
 
 
 
3 0.  L a c k e d c o nfi d e n c e ?  
 
 
 
 
 
 
 
Pl e a s e v erif y t h at y o u h a v e c h e c k e d o n e b o x f or e a c h q u e sti o n . 
 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
103 
CONFIDENTIAL 
 
European Quality of Life Five-Dimension Five-Level Scale 
Appendix 4.
 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
104 
CONFIDENTIAL 
 
Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 




Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
106 
CONFIDENTIAL 
Patient Global Assessment (for pain) 
How would you rate your pelvic pain right now? 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly button 
Absent 
Mild 
Moderate 
Severe 
Very Severe 
Patient Global Assessment (for function) 
How much were your daily activities limited by endometriosis over the last 4 weeks?  
Not at all 
Minimally 
Moderately 
Significantly  
Very significantly 
Note: PGA for function is administered via a paper questionnaire. 


Clinical Study Protocol:  MVT-601-3103 
 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
107 
CONFIDENTIAL 
 
Endometriosis Health Profile - Work Domain 
Appendix 6.
 
Note: EHP Work Domain is administered via a paper questionnaire. 
 


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Clinical Study Protocol:  MVT-601-3103 
Effective:  20-MAR-2018 
Myovant Sciences GmbH 
109 
CONFIDENTIAL 
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;
•
CBC 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;
•
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or
gastroenterologist).
CBC, complete blood count; 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.


1 
CLINICAL STUDY PROTOCOL 
Study Title: 
Investigational Product: 
Protocol Number: 
Indication: 
Sponsor: 
Regulatory Identifiers: 
Version and 
Effective Date: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Relugolix 
MVT-601-3103 
Treatment of Endometriosis-Associated Pain 
Myovant Sciences GmbH 
Viaduktstrasse 8              
4051 Basel 
Switzerland 
IND# 076642 
EudraCT # 2017-004066-10 
Original:  06-NOV-2017 
Amendment 1: 20-MAR-2018 
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. 


Clinical Study Protocol:  MVT-601-3103 
 
Amendment 1, Effective:  20-MAR-2018 
Myovant Sciences GmbH 
2 
CONFIDENTIAL 
AMENDMENT 1:  SUMMARY OF CHANGES 
The main purpose of the amendment was to align the protocols with changes made to the parent 
protocols MVT-601-3101 and MVT-601-3102 in Amendment 1. A detailed list of changes is 
described below.  Note that corrections of typos, administrative changes, minor clarifications and 
minor wording changes to improve readability and understanding, and version and signatory 
updates are not included in this table.  
 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Synopsis: Study 
Objectives and 
Endpoints 
Section 3.0 
Section 9.4 
 
N/A 
Secondary endpoint responder analyses for 
EHP-30 pain domain added at Week 52. 
“Proportion of responders at Week 52/EOT 
based on their EHP-30 Pain Domain score.” 
 
 
To support the 
key secondary 
objective related 
to function, to 
define a 
responder for 
this endpoint, 
and to align with 
Amendment 1 
update to the 
parent studies. 
Section 3.0 
Section 9.4 
 
 
For endpoint of proportion of responders at 
Week 52/EOT based on EHP-30 Pain Domain 
scores, a responder is defined using the same 
within-patient score change threshold 
determined from the parent studies.  
 
Synopsis: 
Inclusion and 
Exclusion 
Criteria 
Section 4.3.1 
EC #1 
“Has had 
gynecologic surgery 
or other surgical 
procedures for 
treatment of 
endometriosis at any 
time during the 
parent study (MVT-
601-3101 or MVT-
601-3102).” 
EC #1 
“Has had a surgical procedure for treatment of 
endometriosis at any time during the parent 
study (MVT-601-3101 or MVT-601-3102).” 
 
 
To simplify 
wording to 
improve clarity 
and to align with 
Amendment 1 
update to the 
parent studies. 
Section 4.6 
None 
Clarification that “throughout the study” also 
included the 30 days following the last dose of 
study drug. 
 
“. . . including through 30 days following the 
To clarify 
duration of 
required 
contraception to 
align with 


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Clinical Study Protocol:  MVT-601-3103 
 
Amendment 1, Effective:  20-MAR-2018 
Myovant Sciences GmbH 
4 
CONFIDENTIAL 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
footnotes x and y 
Section 6.2 
 
visit were specified. 
 
Amendment 1 
update to the 
parent studies. 
Synopsis Study 
Design 
Schedule of 
Activities 
footnote r 
Section 4.1 
Section 6.5.2.6 
 
Follow-up DXA to be 
done for patients not 
continuing into the 
extension if BMD 
loss is >3% at the 
Week 52/ET visit. 
Follow-up DXA to be done for patients if BMD 
loss is >3% at the Week 52/ET visit or most 
recent study scan. 
 
 
To clarify 
procedure to be 
followed for 
patients who 
terminated early 
but did not 
undergo an ET 
visit and to align 
with Amendment 
1 update to the 
parent studies. 
Section 7.6 
Safety Report Forms 
to be submitted to 
PRA Safety & Risk 
Management 
Safety Report Forms to be submitted to IQVIA 
RDS Inc. 
To reflect a 
change in the 
safety vendor. 
Section 1.o  
Section 9.2 
Section 9.4 
ITT analysis 
Modified ITT analysis (mITT) 
 
The term “ITT” 
was updated to 
“modified ITT” 
to better reflect 
that planned 
analysis The 
planned analysis 
was not changed. 
Section 5.6 
Section 10.1.7 
Kit numbers to be 
maintained during 
drug accountability 
Lot numbers to be maintained during drug 
accountability. 
To reflect the fact 
that study drug 
kits contain lot 
numbers. 
Section 10.2.1 
None 
Statement added that sponsor safety reporting 
will comply with global regulatory guidance. 
 
To clarify that 
safety reporting 
will be in 
accordance with 
US and non-US 
health authority 
requirements and 
to align with 
Amendment 1 
update to the 
parent studies. 
Section 10.2.2 
None 
Statement added that all protocol modifications 
will be submitted to the appropriate IRB or IEC 
for information and approval in accordance with 
local requirements and to the appropriate Health 
Authority, if required. 
To clarify that 
protocol 
modifications 
will be in 
accordance with 
US and non-US 


Clinical Study Protocol:  MVT-601-3103 
 
Amendment 1, Effective:  20-MAR-2018 
Myovant Sciences GmbH 
5 
CONFIDENTIAL 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
 
health authority 
requirements and 
to align with 
Amendment 1 
update to the 
parent studies. 
Appendix 1 
List of Tier 1 and 
Tier 2 study-specified 
medications by 
country 
Updated to specify Tier 1 and Tier 2 study-
specified analgesic examples and prescribing 
procedures. 
 
 
 
To align with 
Amendment 1 
update to the 
parent studies. 
 


 
 
1 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3103 
Indication: 
Treatment of Endometriosis-Associated Pain  
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Regulatory Identifiers: 
IND No.  076642 
EudraCT No.  2017-004066-10 
Version and 
Effective Date: 
Original:  06 NOV 2017 
Amendment 1: 20 MAR 2018 
Amendment 2: 11 Dec 2018 
 
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. 


II O E G 2ol f' 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Clinical Study Protocol:  MVT-601-3103 
Amendment 2, 11 Dec 2018 
Myovant Sciences GmbH 
3 
CONFIDENTIAL 
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 
 
 
 


Clinical Study Protocol:  MVT-601-3103 
Amendment 2, 11 Dec 2018 
Myovant Sciences GmbH 
4 
CONFIDENTIAL 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SPONSOR SIGNATURE PAGE ..................................................................................................2 
INVESTIGATOR STATEMENT ................................................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
LIST OF ABBREVIATIONS .......................................................................................................8 
1. 
PROTOCOL SYNOPSIS .........................................................................................10 
1.1. 
Schedule of Activities .................................................................................................19 
2. 
INTRODUCTION ....................................................................................................24 
2.1. 
Endometriosis-Associated Pain ..................................................................................24 
2.2. 
Relugolix .....................................................................................................................25 
2.2.1. 
Indication ....................................................................................................................25 
2.2.2. 
Pharmacology .............................................................................................................26 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................27 
4. 
INVESTIGATIONAL PLAN ..................................................................................31 
4.1. 
Overall Study Design ..................................................................................................31 
4.2. 
Discussion of Study Design, Including Dosing ..........................................................33 
4.3. 
Selection of Study Population ....................................................................................35 
4.3.1. 
Inclusion/Exclusion Criteria .......................................................................................35 
4.4. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number .......................................................................................................................38 
4.5. 
Removal of Patients from Therapy .............................................................................38 
4.6. 
Contraception/Pregnancy Avoidance .........................................................................39 
5. 
TREATMENTS ........................................................................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Identity of Investigational Product .............................................................................41 
5.2.1. 
Product Characteristics ...............................................................................................41 
5.3. 
Randomization and Stratification ...............................................................................42 
5.4. 
Directions for Administration .....................................................................................42 
5.5. 
Dose Reduction/Dose Administration ........................................................................42 


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5.6. 
Storage, Packaging, and Labeling ..............................................................................42 
5.7. 
Rescue Analgesic Medications ...................................................................................43 
5.8. 
Blinding ......................................................................................................................44 
5.9. 
Study Drug Accountability and Treatment Compliance ............................................44 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ..................................44 
5.10.1. 
Prohibited Medications ...............................................................................................44 
5.10.2. 
Permitted Medications ................................................................................................47 
5.10.3. 
Prohibited Non-Drug Therapies .................................................................................48 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................49 
6.1. 
Schedule of Observations and Procedures ..................................................................49 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 104) ..............................49 
6.3. 
Early Termination Visit and Follow-up Visit .............................................................51 
6.4. 
Unscheduled Visits .....................................................................................................51 
6.5. 
Study Procedures ........................................................................................................52 
6.5.1. 
Efficacy-Related Procedures ......................................................................................52 
6.5.2. 
Safety-Related Procedures ..........................................................................................53 
7. 
SAFETY CONSIDERATIONS ...............................................................................57 
7.1. 
Adverse Event Definitions ..........................................................................................57 
7.1.1. 
Adverse Event .............................................................................................................57 
7.1.2. 
Serious Adverse Event ................................................................................................58 
7.2. 
Adverse Event Reporting ............................................................................................59 
7.2.1. 
Adverse Event Reporting Period ................................................................................60 
7.3. 
Assigning Causal Relationship to Study Drug ...........................................................60 
7.4. 
Assigning Severity Rating for Adverse Events ..........................................................60 
7.5. 
Adverse Events of Clinical Interest Reporting ...........................................................61 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities ......................................................................................................61 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities ............................................................................................62 
7.6. 
Serious Adverse Event Reporting ...............................................................................62 
7.7. 
Study Drug Overdose Management ............................................................................63 
7.8. 
Pregnancy Reporting ..................................................................................................64 


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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures ........................................64 
7.10. 
Benefit/Risk Assessment ............................................................................................64 
8. 
DATA QUALITY ASSURANCE ............................................................................67 
8.1. 
Clinical Procedures .....................................................................................................67 
8.2. 
Monitoring ..................................................................................................................67 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ........................68 
9.1. 
Randomization Methods .............................................................................................68 
9.2. 
Analysis Populations ..................................................................................................68 
9.3. 
Sample Size Justification ............................................................................................68 
9.4. 
Efficacy Analyses .......................................................................................................68 
9.5. 
Safety Analyses ..........................................................................................................70 
9.6. 
Pharmacodynamics Analyses .....................................................................................71 
9.7. 
Exploratory Analyses ..................................................................................................72 
9.8. 
Interim Analyses .........................................................................................................72 
9.9. 
Steering Committee ....................................................................................................72 
10. 
RESPONSIBILITIES ...............................................................................................73 
10.1. 
Investigator Responsibilities .......................................................................................73 
10.1.1. 
Good Clinical Practice ................................................................................................73 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................73 
10.1.3. 
Informed Consent .......................................................................................................73 
10.1.4. 
Confidentiality ............................................................................................................74 
10.1.5. 
Study Files and Retention of Records ........................................................................74 
10.1.6. 
Electronic Case Report Forms ....................................................................................75 
10.1.7. 
Investigational Product Accountability ......................................................................76 
10.1.8. 
Inspections ..................................................................................................................76 
10.1.9. 
Protocol Compliance ..................................................................................................76 
10.2. 
Sponsor Responsibilities .............................................................................................76 
10.2.1. 
Safety Reporting .........................................................................................................76 
10.2.2. 
Protocol Modifications ...............................................................................................76 
10.2.3. 
Study Report ...............................................................................................................77 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers ......................77 
10.3. 
Joint Investigator/Sponsor Responsibilities ................................................................77 


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10.3.1. 
Access to Information Monitoring..............................................................................77 
10.3.2. 
Access to Information for Auditing or Inspections ....................................................77 
10.3.3. 
Study Discontinuation ................................................................................................78 
10.3.4. 
Publications .................................................................................................................78 
11. 
REFERENCES .........................................................................................................79 
12. 
APPENDICES ...........................................................................................................81 
 Protocol-Specified Rescue Analgesics ...................................................................81 
 Daily eDiary ...........................................................................................................82 
 Endometriosis Health Profile-30 ..........................................................................106 
 European Quality of Life Five-Dimension Five-Level Scale...............................110 
 Patient Global Impression of Change and Patient Global Assessments ...............112 
 Endometriosis Health Profile - Work Domain .....................................................114 
 Assessment of Abnormal Liver Function Tests ...................................................115 
 
LIST OF TABLES 
Table 1-1 Schedule of Activities for Study MVT-601-3103 ......................................................19 
Table 5-1 Description of MVT-601-3003 Study Drugs ..............................................................41 
Table 5-2 Prohibited Medications ...............................................................................................44 
Table 6-1 Clinical Laboratory Tests ...........................................................................................54 
Table 7-1 Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................61 
Table 7-2 Protocol Risk Assessment and Mitigation Strategies .................................................65 
Appendix Table 1 Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .........115 
Appendix Table 2 Investigations of Alternative Causes for Abnormal Liver Tests .................116 
 
LIST OF FIGURES 
Figure 4-1 MVT-601-3103 Study Schematic ...............................................................................33 
 
 
 


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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dehydroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EHP 
Endometriosis Health Profile 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
EU 
European Union 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HR 
heart rate 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NMPP 
nonmenstrual pelvic pain 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 
PLD 
phospholipidosis 
QTc 
corrected QT (interval) 


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Term 
Explanation 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
SNRI 
serotonin and norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TCA  
tricyclic antidepressant 
ULN 
upper limit of normal 
US 
United States 
W 
Week 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced  


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1. 
PROTOCOL SYNOPSIS 
Study Title 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Safety and Efficacy Extension Study to Evaluate Relugolix Co-Administered 
with Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain 
Protocol Number 
MVT-601-3103 
Location 
Multinational, including North and South America, Europe, Africa, 
New Zealand, and Australia 
Study Centers 
Approximately 320 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with endometriosis-associated pain 
Number of Patients 
Planned 
Approximately 800 
Study Objectives 
In women with endometriosis-associated pain, the study objectives are as 
follows: 
Primary Efficacy Objectives 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated pain. 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 104 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated pain. 
 
Secondary Efficacy Objectives 
To be assessed at Week 52 and Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate, 
among patients who previously completed a 24-week treatment period in 
one of the parent studies (MVT-601-3101 or MVT-601-3102), on the 
following: 
o 
Function, as measured by the Endometriosis Health Profile (EHP)-30 
Pain Domain; 
o 
Dysmenorrhea, as measured by the Numerical Rating Scale (NRS) for 
dysmenorrhea; 
o 
Patient Global Impression of Change (PGIC) for dysmenorrhea; 
o 
Nonmenstrual pelvic pain (NMPP), as measured by the NRS for 
NMPP; 


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o 
PGIC for NMPP; 
o 
Dyspareunia, as measured by the NRS; 
o 
PGIC for dyspareunia; 
o 
Dyspareunia-related functional effects (Subject Modified Biberoglu 
and Behrman [sB&B]); 
o 
To determine the benefit of relugolix 40 mg once daily co-
administered with 24 weeks of low-dose estradiol and norethindrone 
acetate compared with placebo on function measured by the EHP-30 
Pain Domain; 
o 
Patient Global Assessment (PGA) for pain; 
o 
PGA for function; 
o 
Endometriosis-associated quality of life, as measured by the EHP-30 
Control and Powerlessness, Social Support, Emotional Well-Being, 
and Self-Image domains; 
o 
Dysmenorrhea-related functional effects (sB&B); 
o 
NMPP-related functional effects (sB&B). 
 
Safety Objectives 
• 
To evaluate the safety of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate for up to 104 weeks, 
among patients who previously completed a 24-week treatment period in 
one of the parent studies (MVT-601-3101 or MVT-601-3102), including: 
o Adverse events; 
o Changes in bone mineral density. 
 
Pharmacodynamic Objective 
• 
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 104 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
 
Exploratory Objective 
• 
To evaluate the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate on endometriosis-
associated quality of life (EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life outcomes (European 
Quality of Life Five-Dimension Five-Level Scale [EQ-5D-5L]) for up to 
104 weeks among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102). 
Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term efficacy 
and safety study that will enroll eligible patients who have completed their participation in one of the 
phase 3 randomized, double-blind, placebo-controlled parent studies (MVT-601-3101 or 
MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg once daily co-administered 
with low-dose- estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 80 weeks.  Approximately 
800 women with endometriosis-associated pain will be enrolled.  The objectives of the study are to 


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evaluate long-term efficacy and safety through up to 104 weeks of treatment (including treatment 
during the parent study) of relugolix co-administered with low-dose estradiol/norethindrone acetate.  
Eligible patients will have completed participation in one of the parent studies and consented to 
participate in this extension study.  Baseline procedures will be done at the same visit for this extension 
study (referred to as the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit 
from the parent study and will be defined as the date of completion of the last Week 24 procedure in 
the parent study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent study have 
been completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 24/Baseline 
visit.  No MVT-601-3103 study procedures will be performed until the consent form for this extension 
study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  Therefore, results of testing required for eligibility must be available on or prior 
to the Week 24/Baseline visit.  The administration of the first dose of study drug for MVT-601-3103 
will define enrollment into this study.  Study participants will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once 
daily for 80 weeks.  If necessary for logistical reasons (eg, delayed availability of study drug supply on 
site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  
If the first dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients will 
continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, analgesic 
use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  Only study-
specific rescue analgesic medications should be used starting with the Week 24/Baseline visit and 
through the Follow-Up visit and these medications will be taken for control of pain and not 
prophylactically.  Health-related quality of life questionnaires; PGIC for dysmenorrhea, NMPP, and 
dyspareunia; and PGA for pain and function will be completed during the visits on an electronic tablet 
or on paper, according to the Schedule of Activities (Section 1.1). 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via dual-energy x-ray absorptiometry (DXA).   
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, and bone mineral density with 
DXA. 
Determination of bone mineral density by DXA at Early Termination and follow-up of findings will 
proceed according to the following rules: 
• 
For Early Termination occurring between Week 24 and Week 52: 
− 
For Early Termination occurring before Week 36, DXA is not required at Early Termination 
visit unless it will aid in the assessment of an adverse event. 
Follow-up DXA required at 6 months (± 1 month) if most recent DXA bone mineral density 
loss at lumbar spine (L1-L4) or total hip was > 2% relative to the parent study baseline. 
− 
For Early Termination occurring after Week 36, DXA is required at Early Termination unless a 


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DXA result is available from within six weeks prior to Early Termination. 
Follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan was at Week 
24 and bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 2%, relative to 
the parent study baseline. 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral 
density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to the parent study 
baseline. 
• 
For Early Termination occurring between Week 52 and Week 104: 
− 
DXA is required at Early Termination unless a DXA result is available from within six weeks 
prior to Early Termination. 
− 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral 
density loss at the lumbar spine (L1-L4) or total hip was > 7%, relative to parent study 
baseline. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption 
(eg, medical procedure or medications) will be contacted again by telephone 3 (+0.5) months after the 
Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 
visit, then the Follow-up visit and the follow-up procedures performed under this protocol, including 
the follow-up bone densitometry scan at 6 (±1) months and status of menstruation recovery, may be 
waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1. 
Completed 24 weeks of study drug treatment and study participation in either MVT-601-3101 
or MVT-601-3102; 
2. 
Has voluntarily signed and dated the informed consent form prior to initiation of any study-
specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures 
for this study will be done under the informed consent for the parent study. 
3. 
Is not expected to undergo gynecological surgery or other surgical procedures for treatment of 
endometriosis (including ablation, shaving, or excision) during the study, including during the 
Follow-Up Period, and the patient does not desire such treatment during this time frame; 
4. 
Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. 
Has agreed to continue to use only study-specified analgesic medications during the study and 
is not known to be intolerant to these; 
6. 
Agrees to continue to use acceptable non-hormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days after 
the last dose of study drug.  However, the patient is not required to use the specified non-
hormonal contraceptive methods if she: 
a. 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 


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b. 
Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), 
at least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
c. 
Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. 
Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as noted above; 
e. 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study. 
1. 
Has had a surgical procedure for treatment of endometriosis at any time during the parent study 
(MVT-601-3101 or MVT-601-3102); 
2. 
Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is 
treated with opioids or requires analgesics for ≥ 7 days per month; 
3. 
Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, bilateral 
hip replacement, spinal hardware in the lumbar spine); 
4. 
Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study 
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA 
assessment of bone mineral density; 
5. 
Anticipated to use any prohibited medications as detailed in Section 5.10.1; 
6. 
Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. 
Known, suspected, or history of breast cancer; 
b. 
Known or suspected estrogen-dependent neoplasia; 
c. 
Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to 
the Week 24/Baseline visit; 
d. 
History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. 
Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. 
Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
g. 
Migraine with aura; 
h. 
History of porphyria; 
7. 
Has current active liver disease from any cause; 
8. 
Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
syndromes, etc); psoriasis not requiring or anticipated to require systemic therapy is permitted; 
9. 
Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, 
if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. 
Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of 
normal (ULN); or 


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b. 
Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome 
or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 1 month after the last dose of study drug, or plans to donate ova during the study period 
or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 
90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the parent 
study Baseline visit; or 
b. 
The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 
12. Is inappropriate for participation in this study because of conditions that may interfere with 
interpretation of study results or prevent the patient from complying with study requirements, 
as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 80 weeks (Open-Label 
Treatment Period). 
Concomitant Medicinal Products Systematically Prescribed for All Study 
Patients 
Two protocol-specified analgesics include a first-line non-steroidal anti-
inflammatory drug and a second-line opioid or opioid/acetaminophen or 
opioid/paracetamol combination for endometriosis-related pain relief as 
required.  The specific analgesic drugs offered may differ for different 
countries or regions.  The analgesics for each patient will be the same as those 
prescribed for her during the parent study. 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made 
between the parent study Baseline and Week 52, and between the parent study 
Baseline and the end of the extension study (Week 104) for the following 
parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg 
norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate 
in the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this 
extension study for all change from baseline-related endpoints.  The pain 
scores during the Baseline Pain Assessment Period of the parent study will 


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establish the patient’s baseline for both the parent study and the extension 
study. 
 
Primary Efficacy Endpoints 
Week 52 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their NMPP NRS scores. 
Week 104 
• 
Proportion of women who respond or maintain response at 
Week 104/Early Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at 
Week 104/Early Termination, based on their NMPP NRS scores. 
 
Secondary Efficacy Endpoints 
To be assessed at Week 52 and Week 104, unless otherwise specified 
• 
Change from the parent study Baseline in the EHP-30 Pain Domain 
scores; 
• 
Change from the parent study Baseline in the mean dysmenorrhea NRS 
score; 
• 
Proportion of patients who are better or much better on the PGIC for 
dysmenorrhea (at Week 52 only); 
• 
Change from the parent study Baseline in the mean NMPP NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for 
NMPP (at Week 52 only); 
• 
Change from the parent study Baseline in the mean dyspareunia NRS 
scores; 
• 
Proportion of patients who are better or much better on the PGIC for 
dyspareunia (at Week 52 only);; 
• 
Change from the parent study Baseline in the mean dyspareunia 
functional impairment on the sB&B scale; 
• 
Change from the parent study Baseline in severity scores on the PGA for 
pain; 
• 
Proportion of responders based on their EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline in function impairment on the 
PGA for function; 
• 
Change from the parent study Baseline in each of the non-pain EHP-30 
domains (Control and Powerlessness, Social Support, Emotional Well-
Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period in 
dysmenorrhea-related functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period in NMPP-
related functional effects (sB&B). 
 
Safety Endpoints 


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To be assessed at Week 52 and Week 104 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline in bone mineral density at 
the lumbar spine (L1-L4), femoral neck, and total hip as assessed by 
DXA. 
 
Pharmacodynamic Endpoint 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose concentrations of serum 
estradiol. 
 
Exploratory Endpoints 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale total score; 
• 
Change from Baseline in the EHP Work Domain score; 
• 
Change from parent study Baseline in the EQ-5D-5L. 
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
There will be two analyses: one at Week 52 and one at Week 104.  A clinical study report will be 
generated from each analysis. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Parent Study Groups A, B, and C) for the modified Intent-to-Treat Population.  The analyses 
methods for efficacy endpoints are similar to those used for the parent studies, unless otherwise 
specified in the statistical analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic medications, 
proportion of responders based on NMPP scores and use of rescue analgesic medications) will be 
calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with DXA.  Safety data 
analyses will use data from all patients from the parent studies who receive any amount of study drug 
(ie, from parent study Baseline to Week 52 or Week 104). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, high 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.  Laboratory values will be classified 
by toxicity grade based on the National Cancer Institute CTCAE.  Laboratory shift tables of the parent 
study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early Termination visits.  The 


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absolute change and percent change from parent study Baseline and Z-scores will be summarized by 
visit and parent study treatment group. 
The mean percentage change from parent study Baseline to Week 52 in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3101 
or MVT-601-3102) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, 
bone mineral density loss for the relugolix add-back treatment will be considered insignificant.  The 
95% CI for mean percentage change at Week 104 from parent study Baseline in bone mineral density 
lumbar spine (L1-L4) will be provided along with descriptive statistics for bone mineral density loss at 
Week 104 as supportive analyses. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3101 or MVT-601-3102) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 


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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3103 
 
PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
 and  
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 91 
Week 
104a/ 
Early 
Termin
ation 
Un-
scheduledb 
Follow-Upc 
(~30 days after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
 
X 
 
 
X 
 
X 
 
X 
Xh 
 
Complete Physical 
Examination 
Xg 
 
 
 
 
Xi 
 
 
 
Xi 
Xh 
 
Visual Acuityj 
Xg 
 
 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-
Directed Physical 
Examinationk 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xh 
X 
12-Lead ECGl 
Xg 
 
 
 
 
X 
 
 
 
 
Xh 
 
Clinical Laboratory 
Testsm 
Xg,n 
X 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
Xh 
X 
Pharmacodynamics 
Sampleo 
Xg,n 
 
 
 
 
Xn 
 
 
 
Xn 
Xh,n 
 


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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
 and  
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 91 
Week 
104a/ 
Early 
Termin
ation 
Un-
scheduledb 
Follow-Upc 
(~30 days after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Urinalysis 
Xg 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Daily eDiaryp 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Site Review of eDiary 
Data 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Bone Densitometryq 
Xg 
 
X 
 
 
Xr,s 
 
 
 
Xr,s 
Xh 
 
Endometrial Biopsy 
Xg,t 
 
 
 
 
X 
 
 
 
Xt 
Xh 
 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Dispense or Prescribe 
Protocol-Specified 
Analgesic Drugsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose 
in Clinic 
Xv 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Daily Self-
Administration of Study 
Treatmentw 
 
X -------------------------------------- X 
 
 
 
Take Protocol-Specified 
Rescue Analgesics as 
Neededx 
 
X ------------------------------------------------------------------------------------------------- X 
 
 
EHP-30 Questionnairey 
Xg 
 
X 
 
X 
X 
 
X 
 
X 
Xh 
 


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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
 and  
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 91 
Week 
104a/ 
Early 
Termin
ation 
Un-
scheduledb 
Follow-Upc 
(~30 days after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Patient Global 
Assessment for Painy 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
[on paper] Patient 
Global Assessment for 
Functionz 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xn 
X 
Xh 
 
Patient Global 
Impression of Changey 
Xg 
 
X 
 
 
X 
 
 
 
 
Xh 
 
[on paper] EHP Work 
Domainz 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
EQ-5D-5L 
Questionnairey 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
Adverse Event 
Collectionaa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
Xbb 
Telephone Contactcc 
 
 
 
 
 
X 
(W57) 
X 
(W71) 
X 
(W85) 
X 
(W98) 
 
 
 
BP = blood pressure; DXA = dual-energy x-ray absorptiometry; ECG = electrocardiogram; eDiary = electronic diary; EHP = Endometriosis Health Profile; EQ-5D-5L = European 
Quality of Life Five-Dimension Five-Level Scale; HR = heart rate; NRS = Numerical Rating Scale; PGA = Patient Global Assessment; sB&B = Subject Modified Biberoglu and 
Behrman; W = week. 
a The Week 52 visit should occur on or after the 1-year anniversary of Baseline Day 1 of the parent study, and the Week 104 visit should occur on or after the 
2-year anniversary of Baseline Day 1 of the parent study. 
b Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents. 
c The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 visit. 
d May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3103 is defined by 
administration of the first dose of MVT-601-3103 study drug. 
e Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up Period.  Concomitant 
medications with start date prior to the first dose of study drug for MVT-601-3103 should be reported as concomitant medications in the parent study 


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(MVT-601-3101 or MVT-601-3102).  If concomitant medication is ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case 
Report Form Completion Guidelines for instructions for recording the follow-up status. 
f Concomitant medications are recorded both for the parent study and for MVT-601-3103 at the Week 24/Baseline visit.  (See footnote e for further details). 
g This is a parent study (MVT-601-3101 or MVT-601-3102) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3103 and is 
covered under the informed consent for the parent study. 
h The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal 
laboratory test). 
i The Week 52 and Week 104 physical examinations will include a breast examination. 
j See parent study protocols (MVT-601-3101 or MVT-601-3102) for instructions on testing visual acuity. 
k The examination may include a gynecologic examination, if indicated based on signs and symptoms. 
l The 12-lead ECGs will be submitted for central reading. 
m Clinical chemistries will be collected at each visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, Week 52, Week 65, 
Week 78, Week 91, and Week 104.  At the Week 24/Baseline visit, Week 52 visit, and Week 104 visit, additional tests will include the following:  fasting (at 
least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
n Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period. 
o For Week 24/Baseline samples, see the parent protocol (MVT-601-3101 or MVT-601-3102).  At Week 104/Early Termination, collect a sample for analysis of 
estradiol concentrations only.  On days when pharmacodynamics samples are collected, administer the study treatment after the pharmacodynamics sample 
collections are collected. 
p All women enrolled in the study will continue to use the patient eDiary dispensed in the parent study.  Patients will complete daily eDiary entries, including 
NRS pain scores, menstruation information, analgesic drug use, date and time of study drug administration, and sB&B scale scores until Week 52.  After 
Week 52, eDiary scores will be entered over four eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 
visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
q Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
r This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier or within 4 weeks 
after completion of the Wek 36 or Week 52 scan. However, the procedure may be done if it will aid in the evaluation of an ongoing adverse event.  
s Determination of bone mineral density by DXA at Early Termination and follow-up of findings will proceed based on the timing of the Early Termination visit.  
For Early Termination occurring after Week 24 and before Week 36, DXA is not required at Early Termination visit unless it will aid in the assessment of an 
adverse event, and follow-up DXA required at 6 months (± 1 month) if most recent DXA bone mineral density loss at lumbar spine (L1-L4) or total hip was 
> 2% relative to the parent study baseline.  For Early Termination occurring after Week 36 and before Week 52, DXA is required at Early Termination unless a 
DXA result is available from within six weeks prior to Early Termination, and follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan 
was at Week 24 and bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 2% or most recent DXA result was after Week 24 and bone 
mineral density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to the parent study baseline.  For Early Termination occurring between Week 
52 and Week 104, DXA is required at Early Termination unless a DXA result is available from within six weeks prior to Early Termination, and follow-up 
DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 7%, relative to 
parent study baseline. 
t Endometrial biopsies are to be done per instructions in the parent study.  Procedures for handling and shipping biopsy samples to the central laboratory for 
analysis are described in the Investigator Site File.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who 
participated in MVT-601-3101 only (see MVT-601-3101 protocol for details), at Week 52 for all patients.  All patients are eligible for a biopsy at Week 104; 
however, patients will have the option to opt out. 


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u Please see Appendix 1 for list of protocol-specified analgesics and see the Investigator Site File for information on where and how to obtain protocol-specified 
analgesic medications by country.  At the Week 104 visit, patients who will not be proceeding to another extension study will be re-dispensed or prescribed 
protocol-specified analgesic drugs, if needed, to ensure sufficient supply until the Follow-Up visit.  For patients proceeding to another extension study, refer to 
the protocol for that next study. 
v Pregnancy test must be negative before the study drug dose is administered.  For patients whose Baseline Day 1 visit is conducted on a different day than the 
parent study Week 24 visit, perform an unscheduled pregnancy test at Baseline Day 1 prior to administering the first dose of study drug. 
w Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  If necessary for logistical 
reasons (eg, delayed availability of study drug supply on site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not given during this up 
to 10-day interval, the parent study follow-up procedures should be followed (ie, adverse event reporting, eDiary completion, etc.).  The first dose of study drug 
for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed.  Therefore, results of testing 
required for eligibility (eg, DXA) must be available on or prior to the Week 24/Baseline visit.  The last dose of study drug will be taken in the clinic during the 
Week 104/Early Termination visit. 
x Patients may only take their study-specified analgesics for pain.  Analgesics should not be taken prophylactically (ie, in anticipation of pain). 
y The patient will enter her response(s) into an electronic tablet device at the site. On visits when both tablet and paper questionnaires are being performed at the 
site, the patient should complete the tablet questionnaires before the paper questionnaires. 
z The patient will enter her response onto a paper questionnaire at the site.  Paper questionnaires should be done in the following order:  PGA for function, EHP 
Work Domain. 
aa Collect adverse events from the time that the first dose of study drug for MVT-601-3103 is administered.  Adverse events with onset prior to the first dose of 
study drug for MVT-601-3103 should be reported as an adverse event in the parent study (MVT-601-3101 or MVT-601-3102).  If events originating in the 
parent study are ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report Form Completion Guidelines for instructions 
for recording the follow-up status. 
bb Patients whose menses have not resumed as of the Follow-up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted again by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and questioned about factors 
that may affect resumption of menses. 
cc A telephone call will be performed at Weeks 57, 71, 85, and 98.  The following activities should be completed: a concomitant medication review, evaluation of 
adverse events, a reminder of compliance with non-hormonal contraception requirements and the need to call the investigator if pregnancy is suspected, and a 
review of eDiary and study medication compliance. 
 


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2. 
INTRODUCTION 
2.1. 
Endometriosis-Associated Pain 
Endometriosis is a common chronic condition occurring primarily in women of reproductive age.  
It is one of the most common gynecologic disorders, evident in 70 to 90% of women with pelvic 
pain symptoms [Practice Committee of the American Society for Reproductive Medicine, 2014].  
The exact prevalence of endometriosis is unknown but estimates range from 2 to 10% of women 
of reproductive age [Dunselman, 2014].  Symptoms range from minimal to severely debilitating. 
The pathogenesis of endometriosis is the presence of endometrial glands and stroma outside the 
uterine cavity.  Although the ectopic endometriotic lesions are most commonly found in the 
pelvis, they may also be located in the bowel, in the pleural cavity, and elsewhere.  Women with 
endometriosis have an increased risk of abdominopelvic pain, dysmenorrhea, and dyspareunia 
compared with controls without endometriosis [Practice Committee of the American Society for 
Reproductive Medicine, 2014].  In a study of 940 women with endometriosis, the most common 
symptom leading to diagnosis was dysmenorrhea in approximately 90%, pelvic pain in 
approximately 80%, and dyspareunia in approximately 45%, with 34% of women diagnosed on 
the basis of all three symptoms [Sinaii, 2008].  Presenting symptoms of infertility (25%) and 
endometrioma (ovarian mass) (20%) were also common [Sinaii, 2008]. 
The mechanisms of pain in endometriosis are generally postulated to involve production of 
substances such as growth factors and cytokines, the direct and indirect effects of active bleeding 
from endometriotic implants, and irritation of pelvic floor nerves or direct invasion of those 
nerves by infiltrating endometriotic implants [Practice Committee of the American Society for 
Reproductive Medicine, 2014]. 
According to the American Society for Reproductive Medicine Practice Committee, 
“Endometriosis is a chronic disease that requires a lifelong management plan with the goal of 
maximizing the use of medical treatment and avoiding repeated surgical procedures” [Practice 
Committee of the American Society for Reproductive Medicine, 2014]. 
Although hysterectomy with bilateral salpingo-oophorectomy is a definitive treatment of 
endometriosis, the American Society of Reproductive Medicine recommends that this option be 
reserved as a last resort for women with debilitating endometriosis symptoms who have 
completed childbearing and have failed to respond to alternative treatments [Practice Committee 
of the American Society for Reproductive Medicine, 2014].  Other surgical options for treatment 
of endometriosis include uterosacral nerve ablation, presacral neurectomy, and laparoscopic 
resection.  Rates of recurrent dysmenorrhea 1 and 3 years after laparoscopic surgery with 
uterosacral nerve ablation were not better than with laparoscopic surgery without nerve ablation 
in a large randomized trial.  Presacral neurectomy, which involves interrupting the sympathetic 
innervation to the uterus, improves pain but is a technically challenging procedure associated 
with significant risk of bleeding from the adjacent venous plexus.  Patients may also experience 
constipation and/or urinary retention postoperatively.  Laparoscopic treatment of endometriosis 
was found to be more effective at reducing pain than diagnostic laparoscopy in a meta-analysis 
of 5 randomized controlled studies.  While laparoscopic treatment is effective, pain can recur, 
and the option of performing multiple surgeries is limited by risks that include the development 


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of pelvic pain from adhesions and decreased ovarian reserve, resulting in reduced fertility.  In 
one retrospective study, subsequent surgery was performed after laparoscopic treatment in 21%, 
47%, and 45% of women after 2, 5, and 7 years, respectively [Practice Committee of the 
American Society for Reproductive Medicine, 2014]. 
Medical management of endometriosis includes analgesics and treatments aimed at 
decidualization followed by atrophy of endometrial tissue with reduction or antagonism of 
estrogen production and induction of amenorrhea.  Compared to normal endometrium, 
endometriotic implants are characterized by overproduction of prostaglandins and local 
production of estrogens and cytokines, which synergize the activities of each other and promote 
implantation of ectopic endometrium.  In addition, the implants have upregulated estrogen 
synthesis pathways [Practice Committee of the American Society for Reproductive Medicine, 
2014].  Interventions that reduce ovarian estrogen production reduce this synergistic process, 
thereby reducing or eliminating endometriosis-associated pain. 
Medical hormonal options include hormonal contraceptives, progestins, gonadotropin-releasing 
hormone (GnRH) agonists, danazol, and aromatase inhibitors.  Because of lack of data 
supporting use of one treatment over another, the treatment choice is based upon symptom 
severity, patient preferences, side effects, efficacy, contraceptive needs, costs, and availability 
[Dunselman, 2014].  The main adverse effects of GnRH agonists relate to induction of a 
hypoestrogenic state (eg, bone mineral density loss and vasomotor symptoms) whereas danazol 
produces androgenic adverse effects such as hirsutism, weight gain, and deepening of the voice.  
Some patients treated with GnRH agonists also experience an initial “flare effect” (increased 
pain and bleeding), and this can result in premature discontinuation of treatment.  Side effects of 
progestin treatment can include irregular uterine bleeding, weight gain, mood changes such as 
depression, and bone mineral density loss with long-term use of certain agents. 
The goal of the relugolix phase 3 development plan is to demonstrate that relugolix can decrease 
dysmenorrhea and nonmenstrual pelvic pain (NMPP) in women with endometriosis safely 
through 12 months of therapy and to evaluate effects on pain-related quality of life and function.  
By enhancing the safety and tolerability of the active treatment arm with the co-administration of 
low-dose hormonal add-back therapy, the program ultimately aims to bring to women suffering 
endometriosis-associated pain a long-term oral medical therapy that significantly reduces pain 
and improves quality of life and provides an alternative to invasive procedures. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix Investigator Brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once-daily oral medication for the treatment of endometriosis-associated pain.  The proposed 
dose of relugolix is 40 mg administered orally once daily and the proposed doses of estradiol and 
norethindrone acetate are 1.0 mg and 0.5 mg once daily, respectively. 


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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 gonadotropin-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 
luteinizing hormone and follicle-stimulating hormone fall rapidly, followed by a decline over a 
few days in estradiol and progesterone levels.  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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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Descriptive assessments of long-term efficacy and safety will be made between the parent study 
Baseline and Week 52, and between the parent study Baseline the end of the extension study 
(Week 104) for the following parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily followed 
by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg estradiol and 
0.5 mg norethindrone acetate in the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this extension study for all 
change from baseline-related endpoints.  The pain scores during the Baseline Pain Assessment 
Period of the parent study will establish the patient’s baseline for both the parent study and the 
extension study. 
In women with endometriosis-associated pain, the study objectives and corresponding endpoints 
are as follows: 
 
 


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Objectives 
Endpoints 
Primary Efficacy 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 104 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
To be assessed at Week 52 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
Numerical Rating Scale (NRS) scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
 
To be assessed at Week 104 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their dysmenorrhea 
NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their NMPP NRS 
scores. 
 
Secondary Efficacy 
To be assessed at Week 52 and Week 104 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on the 
following: 
 
 
 
 
 
To be assessed at Week 52 and Week 104, unless 
otherwise specified 
 
• 
Function, as measured by the Endometriosis 
Health Profile (EHP)-30 Pain Domain; 
• 
Change from the parent study Baseline in the 
EHP-30 Pain Domain scores; 
• 
Dysmenorrhea, as measured by the NRS for 
dysmenorrhea; 
• 
Change from the parent study Baseline in the 
mean dysmenorrhea NRS score; 
• 
Patient Global Impression of Change (PGIC) 
for dysmenorrhea; 
• 
Proportion of patients who are better or much 
better on the PGIC for dysmenorrhea (at 
Week 52 only); 
• 
NMPP, as measured by the NRS for NMPP; 
 
• 
Change from the parent study Baseline in the 
mean NMPP NRS score; 


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Objectives 
Endpoints 
• 
PGIC for NMPP; 
 
• 
Proportion of patients who are better or much 
better on the PGIC for NMPP (at Week 52 
only); 
• 
Dyspareunia, as measured by the NRS; 
• 
Change from the parent study Baseline in the 
mean dyspareunia NRS scores; 
• 
PGIC for dyspareunia; 
• 
Proportion of patients who are better or much 
better on the PGIC for dyspareunia (at 
Week 52 only); 
• 
Dyspareunia-related functional effects 
(Subject Modified Biberoglu and Behrman 
[sB&B]); 
• 
Change from the parent study Baseline in the 
mean dyspareunia functional impairment on 
the sB&B scale; 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with 24 weeks of 
low-dose estradiol and norethindrone acetate 
compared with placebo on function measured 
by the EHP-30 Pain Domain; 
• 
Proportion of responders based on EHP-30 
Pain Domain scores; 
• 
Patient Global Assessment (PGA) for pain; 
• 
Change from the parent study Baseline in 
severity scores on the PGA for pain; 
• 
PGA for function; 
• 
Change from the parent study Baseline in 
function impairment on the PGA for function; 
• 
Endometriosis-associated quality of life, as 
measured by the EHP-30 Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image domains; 
• 
Change from the parent study in each of the 
non-pain EHP-30 domains (Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image); 
• 
Dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline pain 
assessment period in NMPP-related 
functional effects (sB&B). 
Safety 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including: 
 
 
 
 
 
To be assessed at Week 52 and Week 104 
• 
Adverse events; 
• 
Incidence of adverse events; 
• 
Changes in bone mineral density. 
• 
Percent change from the parent study Baseline 
in bone mineral density at the lumbar spine 
(L1-L4), femoral neck, and total hip as 
assessed by dual-energy x-ray absorptiometry 
(DXA). 


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Objectives 
Endpoints 
Pharmacodynamic 
 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 104 weeks, among patients 
who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
estradiol. 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose 
concentrations of serum estradiol. 
Exploratory 
 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life 
(EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life 
outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) for 
up to 104 weeks among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102). 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• 
Change from parent study Baseline in the 
EQ-5D-5L. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety study that will enroll eligible patients who have completed their participation 
in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3101 or MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg 
once daily co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for 
up to 80 weeks.  Approximately 800 women with endometriosis-associated pain will be enrolled.  
The objectives of the study are to evaluate long-term efficacy and safety through up to 
104 weeks of treatment (including treatment during the parent study) of relugolix 
co-administered with low-dose estradiol/norethindrone acetate.  Eligible patients will have 
completed participation in one of the parent studies and consented to participate in this extension 
study.  Baseline procedures will be done at the same visit for this extension study (referred to as 
the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit from the parent 
study and will be defined as the date of completion of the last Week 24 procedure in the parent 
study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent 
study have been completed, the investigator will assess patient eligibility for participation in the 
open-label extension study.  The eligibility assessment will be based on data available at the 
Week 24/Baseline visit.  No MVT-601-3103 study procedures will be performed until the 
consent form for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Therefore, results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline visit.  The administration of the first dose of study 
drug for MVT-601-3103 will define enrollment into this study.  Study participants will then take 
the open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 80 weeks.  If necessary for logistical reasons 
(eg, delayed availability of study drug supply on site, others), and with sponsor/designee 
approval, the first dose of open-label study drug for MVT-601-3103 may be administered up to 
10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not 
given during this up to 10-day interval, the parent study follow-up procedures should be 
followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  
Only study-specific rescue analgesic medications should be used starting with the 
Week 24/Baseline visit and through the Follow-Up visit and these medications will be taken for 
control of pain and not prophylactically.  Health-related quality of life questionnaires; PGIC for 
dysmenorrhea, NMPP, and dyspareunia; and PGA for pain and function will be completed 


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during the visits on an electronic tablet or on paper, according to the Schedule of Activities 
(Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, and bone mineral density 
with DXA. 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via DXA.  Follow-up of bone densitometry findings will 
proceed according to the rules described in Section 6.5.2.6. 
 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted again by telephone 3 
(+ 0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 1-1. 


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Figure 1-1 
MVT-601-3103 Study Schematic 
 
4.2. 
Discussion of Study Design, Including Dosing 
The SPIRIT EXTENSION study (MVT-601-3103) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3101 and MVT-601-3102) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with endometriosis-associated pain.  This 
80-week extension study provides additional efficacy and safety data up to 104 weeks to 
demonstrate the benefit and safety of relugolix co-administered with low-dose estradiol (1 mg) 
and norethindrone acetate (0.5 mg).  The primary objectives of the study are to assess long-term 
efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks on dysmenorrhea and NMPP, common and 
burdensome symptoms of endometriosis.  The study will also evaluate safety of relugolix 40 mg 
once daily co-administered with low-dose estradiol and norethindrone acetate for up to 
104 weeks, among patients who previously completed a 24-week treatment period in one of the 
parent studies (MVT-601-3101 or MVT-601-3102), including adverse events and change in bone 
mineral density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily suppressed estradiol levels 
to below 20 pg/mL in the majority of women, and results were similar to those in the group of 
women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the relugolix 
40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary endpoint of 


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the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 
demonstrated the 40-mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from endometriosis-associated pain to move forward into phase 3 clinical 
development and, based on the DXA data from the phase 2 study, are not expected to prevent 
bone mineral density loss in a significant majority of women over 104 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 104 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in dysmenorrhea and NMPP.  It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2017; Lee, 2016; Franke, 2000] or endometriosis-associated 
pain [Wu, 2014].  The estradiol/norethindrone acetate combination proposed for evaluation in 
this phase 3 study is currently approved in the United States (US) as long-term hormone 
replacement therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal 
women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 


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lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Activella US Prescribing Information, 2013]) would not provide sufficient serum estradiol 
concentrations to protect against the loss of bone mineral density resulting from the 
hypoestrogenic state induced by once daily administration of relugolix 40 mg. 
The doses of estradiol and norethindrone acetate used in this study (1.0 mg and 0.5 mg, 
respectively) were used in the parent studies (MVT-601-3101 and MVT-601-3102) and represent 
less than one fifth the estrogenic effects of an oral contraceptive pill containing 30 µg of ethinyl 
estradiol.  Therefore, this low-dose hormonal add-back therapy is added solely to improve the 
safety of relugolix therapy, and it is expected to have either a neutral or a marginal detrimental 
effect on efficacy, while mitigating the side effects of relugolix on bone mineral density loss and 
vasomotor symptoms. 
In summary, relugolix at a dose of 40 mg once daily resulted in a significant decrease in 
endometriosis-associated pain in a well-designed large phase 2 study.  However, its 
administration was associated with a degree of bone mineral density loss unacceptable for 
long-term treatment.  This phase 3 study extension study will assess long-term efficacy and 
safety of relugolix 40 mg co-administered with low-dose estradiol and norethindrone acetate to 
decrease dysmenorrhea and NMPP and to prevent the bone mineral density loss and ameliorate 
some of the other side effects of a hypoestrogenic state such as hot flushes. 
This open-label extension study will allow for a description of long-term efficacy data and safety 
for an additional 80 weeks of treatment, providing approximately 1 year of efficacy and safety 
data from the women originally randomized to relugolix in studies (MVT-601-3101 and 
MVT-601-3102).  This study design will allow eligible patients with endometriosis-associated 
pain, including those randomized to placebo in the parent study, to receive relugolix 
co-administered with low-dose hormonal add-back therapy during the extension. 
4.3. 
Selection of Study Population 
The study population will include approximately 800 premenopausal women aged 18 to 51 years 
with endometriosis-associated pain. 
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. 
4.3.1. 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization): 
1. Completed 24 weeks of study drug treatment and study participation in either 
MVT-601-3101 or MVT-601-3102; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
study-specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline 
procedures for this study will be done under the informed consent for the parent study. 


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3. Is not expected to undergo gynecological surgery or other surgical procedures for 
treatment of endometriosis (including ablation, shaving, or excision) during the study, 
including during the Follow-Up Period, and the patient does not desire such treatment 
during this time frame; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Has agreed to continue to use only study-specified analgesic medications during the study 
and is not known to be intolerant to these; 
6. Agrees to continue to use acceptable non-hormonal contraceptive methods as described 
in Section 4.6 consistently during the Open-Label Treatment Period and for at least 
30 days after the last dose of study drug.  However, the patient is not required to use the 
specified non-hormonal contraceptive methods if she: 
a. 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 6 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
c. 
Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of non-hormonal contraception as noted above; 
e. 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria 
1. Has had a surgical procedure for treatment of endometriosis at any time during the parent 
study (MVT-601-3101 or MVT-601-3102); 
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, 
that is treated with opioids or requires analgesics for ≥ 7 days per month; 
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, 
bilateral hip replacement, spinal hardware in the lumbar spine); 
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent 
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study 
Week 24 DXA assessment of bone mineral density; 
5. Anticipated to use any prohibited medications as detailed in Section 5.10.1; 


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6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. 
Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. 
Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. 
Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. 
Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc); psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the 
upper limit of normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 
90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the 
parent study Baseline visit; or 
b. The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 


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12. Is inappropriate for participation in this study because of conditions that may interfere 
with interpretation of study results or prevent the patient from complying with study 
requirements, as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
4.4. 
Method of Assigning Patients to Treatment Group and Patient 
Identification Number 
Eligible patients who sign consent will be identified with the same Patient Identification (ID) 
Number assigned to the patient during the parent study.  This extension study is a single-arm, 
open-label study, and thus all eligible patients are assigned to the same treatment group of 
relugolix 40 mg co-administered with low-dose of estradiol and norethindrone acetate (see 
Section 5.1 for treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 104 visit defines completion of the study.  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 Early Termination visit (see the Week 104 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication).  When patients complete the study or early terminate from the study, they 
must be deactivated from the study in the interactive voice response system/interactive web 
response system (IVRS/IWRS), eDiary, and tablet device. 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• 
Any adverse event that is intolerable to the patient and 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; 
• 
If it is discovered after enrollment that a patient failed to meet protocol entry criteria and 
continued participation poses an unacceptable risk to the patient’s health; 
• 
If the following 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): 
− 
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 
international normalized ratio (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%); 


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• 
QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec read by 
a cardiologist; 
• 
Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial biopsy; 
• 
If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or femoral 
neck compared with the parent study Baseline; 
• 
If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  Gross noncompliance includes < 75% 
compliance with the study drug over > 2 consecutive months; missing multiple study visits; 
and persistent (> 2 consecutive months) noncompliance (< 50% of the required number of 
days) with eDiary completion up to Week 52 or persistent (≥ 2 eDiary collection cycles) 
noncompliance (< 50% of the required number of days) with eDiary completion from 
Week 52 to Week 104.  Investigators will follow up with the patient and encourage 
compliance with study drug or eDiary prior to discontinuing her from the study; 
• 
If the patient becomes pregnant at any time after providing a signed informed consent form, 
the patient must be withdrawn immediately (see Section 7.8 for information on pregnancy 
reporting). 
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 noncompliance.  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 three 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.” 
4.6. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones for contraception are excluded, and 
patients must agree to use non-hormonal contraception throughout the study including through 
30 days following the last dose of study drug, unless any of the following apply: 
• 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
• 
Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure) at 
least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
• 
Has a non-hormonal intrauterine device (eg, Paragard) placed in the uterus; 
• 
Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as described below; 


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• 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods do 
not apply are: 
• 
Condom (male or female condom) with or without spermicide (cream, spray, foam, gel, 
suppository, or polymer film); 
• 
Diaphragm with spermicide (condom may or may not be used); 
• 
Cervical cap with spermicide (condom may or may not be used); or 
• 
Vaginal sponge impregnated with spermicide used with a condom. 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed according to the Schedule of Activities (Table 1-1; 
including just prior to receiving the first dose of study drug), and patients will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures.  Patients 
should call the investigator immediately if they suspect they may be pregnant. Patients who 
become pregnant during the study will be withdrawn from the study and followed for pregnancy 
outcome (see Section 7.8). 


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5. 
TREATMENTS 
5.1. 
Treatments Administered 
In this extension study, all patients will receive the following open-label oral study treatment: 
• 
80 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol and 
0.5 mg norethindrone acetate. 
Each patient will be instructed to take one tablet and one capsule per day. 
Table 1-2 
Description of MVT-601-3003 Study Drugs 
Name of Investigational 
Product 
Relugolix 
Estradiol / Norethindrone 
Acetate 
Formulation Description 
Round film-coated pink tablet 
A Swedish orange, over-
encapsulated round film-coated 
white tablet with back-fill 
material 
Dosage Form 
Tablet 
Capsule 
Unit Dose Strength 
40 mg 
Estradiol 1.0 mg / norethindrone 
acetate 0.5 mg 
Route of Administration/ 
Duration 
Oral once daily/ 
80 weeks 
Oral once daily/ 
80 weeks 
Two protocol-specified analgesics include a first-line non-steroidal anti-inflammatory drug 
(NSAID) and a second-line opioid or opioid/acetaminophen (or paracetamol) combination for 
endometriosis-related pain relief as required.  The specific analgesic drugs offered may differ for 
different countries or regions.  A list of study-specified analgesics is provided in Appendix 1. For 
directions on prescribing rescue analgesic medications, see Section 5.7. 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name 1-(4-{1-[(2,6-difluorophenyl)methyl]-5-
[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl}phenyl)-3-methoxyurea. 
Estradiol (1.0 mg) and norethindrone acetate (0.5 mg) is a fixed-dose combination product. 
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 common 
excipients. 


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The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing 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. 
On Week 24/Baseline 1, Week 52, and Week 104 clinic visit days, study drug will be 
administered in the clinic rather than at home (see Schedule of Activities in Section 1.1). 
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 cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location at room 
temperature.  Follow storage conditions described on the drug labeling.  Study drug should be 
stored protected from light.  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.  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. 
Study drug will be labeled with the study protocol number, medication or lot/batch number, 
contents, directions for use, storage directions, clinical study statement, and any other labeling 
required by regulatory bodies in the study locations and will list Myovant Sciences GmbH as the 
sponsor.  Patients will be instructed to store study drug at room temperature out of the reach of 
children. 


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All labels for relugolix and the estradiol/norethindrone acetate combination to be distributed will 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices:  Manufacture of investigational medicinal products (July 
2010) and/or other local regulations as applicable. 
Please see Appendix 1 for a list of protocol-specified analgesics.  Further details on analgesic 
medication are provided in the Investigator Site File. 
5.7. 
Rescue Analgesic Medications 
Management of endometriosis-associated pain often requires treatment with analgesics and some 
patients require treatment with opioid drugs. Two tiers of pain medications are specified for this 
trial.  The study-specified pain medications for each patient will be the same as for the parent 
study.  Only study-specific Tier 1 and Tier 2 analgesic medications (see Appendix 1) should be 
taken starting with the Baseline/Week 24 visit and subsequently.  Analgesic medications will be 
taken for control of pain and not prophylactically. 
If a patient develops uncontrolled endometriosis-associated pain during the study despite use of 
the study-specified analgesics or an intolerance to a study-specified analgesic, please contact the 
medical monitor. 
Short-term use of non-study specified analgesics for the treatment of an intercurrent event (eg, 
injury or surgery) is allowed, if required.  Such events should be reported as adverse events when 
appropriate. 
Investigators must instruct the patient on the use of ibuprofen 200 mg tablets (ie, number of 
tablets per dose, dosing frequency, maximum number of tablets per day).  For patients who may 
need the Tier 2 analgesic medication, a prescription should also be written for this at the time of 
enrollment into this study.  This is to ensure that patients do not endure unnecessary pain during 
the conduct of the study. 
Quantities of opioids prescribed should be based on the patient’s expected usage until the next 
study visit.  Prescriptions for Tier 1 and Tier 2 rescue analgesic medications should be in 
accordance with their full prescribing information (ie, the local product labeling) and 
prescriptions for opioids should not provide for any refills.  Patients should be counseled on the 
safe use of opioids. 
Patients who are not prescribed the Tier 2 medication at the time of enrollment in this study, for 
example, because requirement for analgesics beyond the Tier 1 medication is not expected (eg, 
based on pain level and/or recent analgesic requirements) should be advised to contact the 
investigator if pain is inadequately controlled with the Tier 1 medication alone.  To avoid 
experiencing extended periods of uncontrolled pain, patients who require the Tier 2 medication 
should get a prescription from the investigator and initiate treatment with the Tier 2 medication 
as soon as feasible. 
Use of protocol-specified rescue analgesic medications and any other analgesics taken for any 
type of pain, must be recorded by the patient in the e-Diary. 


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5.8. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and should bring all unused and used 
(including partially used) study drug kits to each study visit.  At the Week 24/Baseline visit and 
Week 104/Early Termination visit, all used, partially used, and unused study drug kits should be 
retained at the site.  At all other visits, only fully used study drug kits should be retained at the 
site.  New study drug should be dispensed as described in Section 1.1 (Schedule of Activities). 
Study drug accountability will be conducted and results will be recorded.  If a patient is 
persistently noncompliant with the study treatment, it may be appropriate to withdraw the patient 
from the study (see Section 4.5).  All patients should be reinstructed about the dosing 
requirement during study contacts.  The authorized study personnel conducting the re-education 
must document the process in the patient’s source records. 
Because of the importance to both safety and efficacy evaluation, patients who are grossly 
noncompliant with eDiary completion must undergo an Unscheduled visit to evaluate reasons for 
noncompliance and to develop a plan to improve compliance.  Failure to improve compliance 
may result in the sponsor withdrawing the patient from further study treatment (including study 
analgesics) and/or discontinuation from the study (see Section 4.5 for details). 
All patients should be reinstructed about the dosing requirement and eDiary 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 1-3 provides examples of prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Drugs and drug classes in Table 1-3 are prohibited at any time 
during the study through the Follow-Up visit, except as noted in the table.  Consult the medical 
monitor if there is any uncertainty regarding patient use of a particular drug or drug class. 
Table 1-3 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zoledronic acid 
 
GnRH analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
 
Anti-androgens 
danazol 
 


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Drug Class 
Examples 
Comments 
Anticonvulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
Note: All other anticonvulsants are 
allowed 
Aromatase inhibitors 
anastrozole 
letrozole 
 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
Hormonal contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
NuvaRing 
 
Selective estrogen 
receptor modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
 
Selective progesterone 
receptor modulators  
mifepristone 
ulipristal acetate 
 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
 
Intrauterine devices 
levonorgestrel 
copper 
 
Bone agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 


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Drug Class 
Examples 
Comments 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use of systemic 
glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study.   
Note:  topical, inhaled, intranasal, 
otic, ophthalmic, intraarticular, or 
intralesional subcutaneous are 
permitted without restriction. 
Short duration (< 21 days) higher-
dose glucocorticoids required for 
acute events are permitted during 
the study. 
P-glycoprotein inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavirf 
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 and strong 
P-glycoprotein- inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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. 


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Drug Class 
Examples 
Comments 
Analgesic drugs other 
than those specified for 
use during the studyh 
Acetaminophen/paracetamol (other 
than any included in a 
study-specified analgesic) 
aspirin > 325 mg/day 
NSAIDs (other than study-specified 
NSAIDs) 
gabapentin 
pregabalin 
carbamazepine 
metamizole 
cannabinoids 
Note:  Aspirin ≤ 325 mg per day is 
allowed 
Antidepressants 
New treatment or 
changed doses of SSRI, 
SNRI, or TCA 
antidepressants 
SNRI examples: 
duloxetine 
venlafaxine 
desvenlafaxine 
SSRI examples: 
citalopram 
fluoxetine 
paroxetine 
fluvoxamine 
TCA examples: 
amitriptyline 
doxepin 
desipramine 
nortriptyline 
SSRI, SNRI, or TCA allowed if 
given at the same dose as used 
during the 3 months prior to the 
Run-In Period of MVT-601-3101 or 
MVT-601-3102. 
New start, dose change or 
discontinuation of these drugs is not 
allowed during the study.  Changes 
made for safety reasons are allowed 
with approval of the medical 
monitor. 
DHEA = dihydroepiandrosterone; GnRH = gonadotropin-releasing hormone; NSAID = nonsteroidal anti-
inflammatory drug; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake 
inhibitor; TCA = tricyclic antidepressant. 
 
a. 
Roxithromycin is allowed. 
b. 
All other angiotensin converting enzyme inhibitors are allowed. 
c. 
Tacrolimus is allowed. 
d. 
Amlodipine and nifedipine are allowed. 
e. 
Fluconazole is allowed. 
f. 
Integrase inhibitors are allowed. 
g. 
Clopidogrel is allowed. 
h. 
For situations where non-study analgesics may be allowed, see Section 5.7. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded in the electronic Case Report 
Forms (eCRFs), including the drug generic name, dose amount, route of administration, start 
date, and stop date. 
5.10.2.1. 
Analgesics 
All analgesics will be collected in the eDiary and recorded in the eCRFs. 


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5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of endometriosis is prohibited from the Week 24/Baseline visit until the 
patient’s final study visit unless urgently needed for patient safety. 


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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 6.5.  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 2 periods:  Open-Label Treatment 
Period and Safety Follow-Up Period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 104) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3101 or MVT-601-3102 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week 24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• 
Informed consent (unless signed previously); 
• 
Record concomitant medications; 
• 
Update the patient’s status in the IVRS/IWRS as being in the MVT-601-3103 and receive the 
lot numbers for study drug allocation; 
• 
Dispense study treatment; 
• 
Dispense or prescribe protocol-specified analgesic drugs; 
• 
Transition the patient within her eDiary from the parent study to MVT-601-3103 
• 
Take study drug dose in clinic; and 
• 
Record adverse events, if any. 
The Week 24 visit date in the parent study is defined as the date that the last procedures for the 
Week 24 visit were completed, acknowledging that the Week 24 visit procedures may be 
completed on different dates.  Patients will have received their last dose of study drug in the 
parent study on the day prior to the Week 24/Baseline visit and will receive their first dose of 
study drug for this extension study in the clinic after the patient is determined to be eligible for 
this extension study and has provided informed consent to participate.  Therefore, results of 
testing required for eligibility must be available on or prior to the Week 24/Baseline visit.  If 


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necessary for logistical reasons (eg, delayed availability of study drug supply on site, others), and 
with sponsor/designee approval, the first dose of open label study drug for MVT-601-3103 may 
be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first 
dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, eDiary completion, etc.). 
Patients will continue recording data in their eDiary daily and taking protocol-specified 
analgesics as needed until Week 52.  After Week 52, the eDiary will be collected on the 
following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 visit, Week 85 to 
the Week 91 visit, and Week 98 to the Week 104 visit.  Following the Week 24/Baseline visit, 
on-treatment study visits will occur at Weeks 28, 32, 36, 40, 44, 48, 52, 65, 78, 91, and 104.  
Sites will monitor diary completion using the Trial Manager web portal throughout the study. 
A telephone call will be performed at Weeks 57, 71, 85 and 98.  The following activities should 
be completed: a concomitant medication review, an evaluation of adverse events, a review of 
study medication compliance, a reminder of compliance with non-hormonal contraception 
requirements and the need to call the investigator if pregnancy is suspected, and a reminder to 
the patient to start recording in the eDiary daily. 
Accountability for study drug will be performed at each visit.  Instructions for analgesic 
medication usage will be reinforced at each visit. 
Questionnaires are administered on the electronic tablet and on paper at each visit.  These 
procedures should occur before any other types of study procedures are performed.  When both 
electronic tablet and paper questionnaires are required at a visit, the electronic questionnaires 
should be done first.  The order in which the electronic tablet and paper questionnaires should be 
administered are as follows: 
• 
Electronic tablet questionnaires (in the order they appear in the tablet) 
• 
Paper questionnaires 
− 
PGA for function 
− 
EHP Work Domain [Week24/Baseline, Week 52, Week 78, and Week 104 only] 
Patients will bring their eDiary, analgesic medications, and study drug to each visit.  The site 
must document the start and stop dates of the patient’s menses. 
An endometrial biopsy will have been performed at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 (see MVT-601-3101 protocol for details), at 
Week 52 for all subjects.  All patients will be eligible for the Week 104 biopsy; however, 
patients will have the option to opt out.  Safety monitoring for this study includes physical 
examination, clinical laboratory tests, pregnancy tests, and adverse event collection at each visit.  
Clinical chemistries will be collected at each visit.  A complete blood count will be collected at 
Week 24/Baseline, Week 28, Week 36, Week 52, Week 65, Week 78 and Week 104.  At the 
Week 24/Baseline visit, Week 52 visit, and Week 104 visit, additional tests include fasting (at 
least 8 hours, other than water) glucose, lipid profile, and hemoglobin A1c. 
Electrocardiograms will be performed at the Week 24/Baseline and the Week 52 visits. 


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Bone densitometry will occur at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early 
Termination visits.  Follow-up of bone densitometry findings will proceed according to the rules 
described in Section 6.5.2.6. 
Bone densitometry and ECGs will be submitted for central reading. 
Study drug compliance will be reviewed at each visit.  Fasting (other than water) for at least 
8 hours is required prior to blood sampling on Week 24/Baseline and Week 52/Early 
Termination visits and for 1 hour after administration of the study drug in the clinic.  Laboratory 
requisitions must indicate whether or not the patient was not fasted for their chemistry and lipid 
testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment Period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 104.  Bone 
densitometry may be performed at the investigator’s discretion, if it aids in follow-up of an 
ongoing adverse event(s).  Follow-up bone densitometry findings for patients who terminate 
from the study early will proceed according to the rules provided in 6.5.2.6. 
Patients (including those who complete the Week 104 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
endometriosis, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 104 visit, the Follow-up visit may be 
waived. 
The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the Follow-
up visit. 
Follow-up of bone densitometry findings for patients who terminate from the study early will 
proceed according to the rules provided in Section 6.5.2.6. 
6.4. 
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 source 
documentation.  The following activities should be completed at Unscheduled visits:  recording 
of reason for the visit, concomitant medication review, and evaluation of adverse events.  In 
addition, procedures such as vital signs, weight, complete physical examination, sign- and 
symptom-directed physical examination, clinical laboratory assessment, urinalysis, urine 
pregnancy testing, pharmacodynamic sampling, 12-lead ECG, study drug compliance and 


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dispensation, eDiary review, dispensation or prescription of protocol-specified analgesics, etc, 
may be conducted as needed.  See the Schedule of Activities (Section 1.1) for tests that may be 
performed, as indicated at an Unscheduled visit.  The investigator should consult with the 
medical monitor, if needed, to discuss Unscheduled visit testing.  The investigator should obtain 
approval from the sponsor to perform an unscheduled endometrial biopsy or DXA, unless 
urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Pharmacodynamics Sample Collection 
A blood sample for the pharmacodynamic analysis of serum estradiol will be collected predose at 
the visits indicated in the study Schedule of Activities (see Section 1.1), other than at the 
Week 104 or the Early Termination visit, when no dose is administered.  These 
pharmacodynamic samples will be analyzed at a central laboratory.  These results will not be 
shared with the sites at any time. 
6.5.1.2. 
Patient eDiary 
All women enrolled in the study will continue to use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete daily eDiary entries, including NRS pain scores, 
menstruation information, analgesic drug use, date and time of study drug administration, and 
sB&B scale scores until Week 52.  After Week 52, eDiary scores will be entered over four 
eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to 
the Week 78 visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
The site should review the eDiary data at every visit. 
6.5.1.3. 
Endometriosis Health Profile-30 
The EHP-30 is used to evaluate the functional impact and the quality of life of patients with 
endometriosis (see Appendix 3).  Patients will complete the EHP-30 questionnaire at the site at 
visits indicated in Section 1.1 before other types of study procedures, such as blood draws and 
physical examinations, are performed.  The EHP-30 will be completed on a tablet device at the 
study site. 
6.5.1.4. 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes (see 
Appendix 4).  Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are 
each assessed on a 5-level categorical scale. 
Patients will complete the EQ-5D-5L questionnaire at the site at visits indicated in Section 1.1 
before other types of study procedures, such as blood draws and physical examinations, are 
performed.  The EQ-5D-5L will be completed on a tablet device at the study site. 


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6.5.1.5. 
Patient Global Assessment and Patient Global Impression of Change 
These simple questions are used by the patient to qualitatively describe severity of pain or effects 
on function (PGA) or impression of change in pain severity (PGIC) (see Appendix 5) on a 
schedule described in the Schedule of Activities (Section 1.1).  Patients should answer these 
questions before other types of study procedures, such as blood draws and physical 
examinations, are performed.  The PGA for pain severity and the PGIC will be completed on a 
tablet device at the study site.  The PGA for function will be completed on a paper questionnaire 
at the study site. 
6.5.1.6. 
Endometriosis Health Profile Work Domain 
This 5-question paper questionnaire will be completed by the patient to describe the effects of 
endometriosis on their work (Appendix 6).  Patients will complete the EHP Work Domain 
questionnaire at visits indicated in Section 1.1 before other types of study procedures, such as 
blood draws and physical examinations, are performed.  The EHP Work Domain will be 
completed on a paper questionnaire at the study site. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 
6.5.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest. 
6.5.2.3. 
Physical Examinations 
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.  The physical 
examinations at Week 52 and Week 104 will include a breast examination. 
6.5.2.4. 
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. 


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The samples collected for clinical laboratory tests are listed in Table 1-4. 
Table 1-4 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatine kinase 
Hemoglobin A1c 
Bilirubin total 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Alkaline phosphatase 
White blood cell count 
White blood cell differential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelet count 
Red blood cell morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and clarity 
pH 
Leucocyte esterase 
Ketones 
Nitrite 
Specific gravity 
Urine microscopy (reflex 
testing based on abnormal 
urine analysis) 
Hormones 
Lipids 
Pregnancy 
Estradiol 
Total cholesterol 
Low-density lipoprotein 
High-density lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
serum hormone levels.  Each study site will conduct urine pregnancy tests locally. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal values, determined to 
be clinically significant, should be reported as adverse events. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 
6.5.2.5. 
Electrocardiograms 
Electrocardiograms (12-lead) will be obtained at the time points described in the Schedule of 
Activities (Section 1.1).  Electrocardiograms will be measured using standardized equipment 
provided by the central core laboratory with the patient in a semi-supine or supine position after 


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5 minutes of rest.  The ECGs will be assessed by central review and a report provided to the site.  
The investigator or sub-investigator (or a qualified individual at the investigational site) will 
interpret the ECG report provided by the central reviewer using one of the following categories:  
normal or abnormal.  The investigator or sub-investigator will judge if any of the findings are 
clinically significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3, and L4), total hip, and femoral neck (same leg within each patient) at the time 
points described in the Schedule of Activities (Section 1.1).  The scans will be read by the central 
imaging laboratory in accordance with the imaging charter.  Training, quality review, and 
readings will be done by a central radiology laboratory as described in the central radiology 
charter for bone mineral density. 
Throughout the study, the same DXA apparatus will used at each site and operated in the same 
scan mode for all scans for an individual patient and should be the same as used for the patient 
during the parent study (MVT-601-3101 and MVT-601-3102).  The central core imaging 
laboratory will collect and evaluate all DXA scans for acceptability.  Bone mineral density 
changes for individual patients will be monitored by the central imaging laboratory over the 
course of the study. 
Determination of bone mineral density by DXA at Early Termination and follow-up of findings 
will proceed according to the following rules: 
• 
For Early Termination occurring between Week 24 and Week 52: 
− 
For Early Termination occurring before Week 36, DXA is not required at Early 
Termination visit unless it will aid in the assessment of an adverse event. 
Follow-up DXA required at 6 months (± 1 month) if most recent DXA bone mineral 
density loss at lumbar spine (L1-L4) or total hip was > 2% relative to the parent study 
baseline. 
− 
For Early Termination occurring after Week 36, DXA is required at Early Termination 
unless a DXA result is available from within six weeks prior to Early Termination. 
Follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan was at 
Week 24 and bone mineral density loss at the lumbar spine (L1-L4) or total hip was 
> 2%, relative to the parent study baseline. 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone 
mineral density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to the 
parent study baseline. 
• 
For Early Termination occurring between Week 52 and Week 104: 
− 
DXA is required at Early Termination unless a DXA result is available from within six 
weeks prior to Early Termination. 


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• 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone 
mineral density loss at the lumbar spine (L1-L4) or total hip was > 7%, relative to parent 
study baseline. 
The follow-up bone densitometry will be submitted for central reading. 
 
Patients who experience a bone mineral density loss from the parent study Baseline of ≥ 7% at 
any of the anatomical sites assessed will be discontinued from the extension study and will 
undergo another bone densitometry scan as described above.  Patients should be assessed for 
secondary causes of bone loss and followed up further if not improving on the 6-month 
follow-up scan, unless an alternative etiology has been identified. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, then the follow-up bone densitometry scan at 6 (±1) months conducted under 
this protocol may be waived. 
6.5.2.1. 
Endometrial Biopsy 
For patients in parent study MVT-601-3101, an endometrial biopsy is performed at the Week 24 
visit.  If the required Week 24 biopsy is inadequate for diagnosis, it should be repeated, and a 
sample submitted to the central laboratory.  If the second sample is inadequate, ensure an 
endometrial thickness has been reported from the Week 24 transvaginal ultrasound and contact 
the medical monitor to review the findings.  Patients who have endometrial hyperplasia or 
endometrial carcinoma will be withdrawn from study drug treatment and followed per 
instructions in the parent study protocol. 
Additional assessment of the effects of relugolix co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will be performed at Week 52 for all patients.  At 
Week 104, all patients will be eligible for an additional endometrial biopsy; however, patients 
will have the option to opt out.  Patient participation in the Week 104 endometrial biopsy is 
voluntary and refusal to participate will not preclude entry into the study or indicate withdrawal 
from the study. 
The Week 52 and Week 104 endometrial biopsy samples will be submitted to the central 
laboratory.  If the Week 52 or Week 104 biopsy specimen is inadequate, a transvaginal 
ultrasound for endometrial thickness should be obtained and read locally.  The transvaginal 
ultrasound findings will be used to determine if further action is required: 
• 
Endometrial thickness ≤ 5 mm – no further action required. 
• 
Endometrial thickness > 5 mm at any location or any other endometrial abnormality – 
repeat endometrial sampling.  Contact medical monitor if second specimen is 
inadequate for diagnosis. 
Unscheduled endometrial biopsies may also be performed when medically indicated and as 
deemed necessary by the investigator.  The investigator should obtain approval from the sponsor 
to perform an unscheduled endometrial biopsy, unless urgently indicated.  Additional consent is 
not required in this circumstance. 


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6.5.2.2. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted again by 
telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and will 
be asked about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, ECGs, and bone mineral density assessments. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
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: 
− 
Induces clinical signs or symptoms; 
− 
Requires active intervention; 
− 
Requires interruption or discontinuation of study drug. 


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Events that do not meet the definition of an adverse event include: 
• 
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event; 
• 
Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• 
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); 
• 
Endometriosis-associated pain is not considered an adverse event in this study because it is 
being quantitatively measured as the primary efficacy endpoint. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE).  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. 
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 participant 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 admitted to a hospital, 
independent of the duration of that hospitalization.  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) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 


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e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events which 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 Institutional Review Board (IRB) or Independent Ethics Committee 
(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 eDiary entries, including bleeding and answers to the other patient-reported 
outcome measures, 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 the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 


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7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for endometriosis, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  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. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
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 
following definitions are to be used for the relationship of the adverse event to study drug: 
• 
Probably related:  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 
(rechallenge) or withdrawal (dechallenge). 
• 
Possibly related:  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.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 


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Table 7-1 
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 
CTCAE = Common Terminology Criteria for Adverse Events. 
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 Open-Label 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 7. 
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 the 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%). 


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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; 
− 
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 Safety Reporting 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. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest (defined in Section 7.5), and events of overdose is available on the Serious Adverse 
Event report form and is as follows: 


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3 
A me n d me nt 2, 1 1 Dec 2 0 1 8 
M y o va nt Scie nces G m b H  
6 3 
C O N FI D E N TI A L  
Se n d c o m p lete d S af et y Re p ort F or ms t o I Q VI A R D S I nc. (f or merl y Q ui ntilesI M S): 
Site L oc ati o n 
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber 
( Sec o n d ar y re p orti n g met h o d) 
All st u d y sites  
 
 
F or q uesti o ns o n Seri o us A d verse E ve nt/ A d vers e E ve nt of Cli nic al I nterest  re p orti n g, 
ple ase c all:  
•  N ort h/ S o ut h A merica:  
 
•  E ur o pe, Asia- Pacific, a n d Africa:  see re gi o n -s pecific p h o ne n u m bers acc o m pa n yi n g t he 
Safet y R e p orti n g F or m 
T he i nitial re p ort s h o ul d i ncl u de: 
•  St u d y n u m b er ( M V T- 6 0 1- 3 1 0 3); 
•  Site a d dress a n d n u m ber; 
•  I n v esti gat or na me; 
•  Patie nt I D n u m ber, se x, a n d a ge; 
•  Details of st u d y dr u g a d mi nistrati o n ; 
•  T he date of t h e re p ort ; 
•  A descri pti o n of t he seri o us a d verse e ve nt (e ve nt t er m, seri o us ness of t h e e ve nt, date of o nset, 
i nte nsit y); 
•  Ca usal relati o ns hi p t o t he st u d y dr u g. 
If t he patie nt die d, t he re p ort s h o ul d i ncl u de t he ca use of deat h as t he e v e nt ter m ( wit h deat h as 
o utc o me) a n d w h et her or n ot t he e ve nt lea di n g t o deat h was relate d t o st u d y dr u g treat me nt, as 
well as t he a ut o ps y fi n di n gs if a v aila ble.  
D o n ot dela y re p orti n g a s us pecte d seri o us a d vers e e ve nt i n or der t o o btai n a d diti o nal 
i nf or mati o n.  A n y a d diti o nal i nf or mati o n, if c ollect e d, ca n b e re p orte d as a f oll o w- u p t o t he 
i nitial re p ort.  All seri o us a d verse e ve nts will be f oll o we d u ntil res ol uti o n, u ntil t he e ve nt has 
sta bilize d, a n d/ or reac h e d a ne w bas eli ne.  All seri o us a d verse e ve nts c o nti n ui n g at t he 
c o m pleti o n of t he st u d y m ust be assesse d or f oll o we d t o deter mi ne o utc o m e. 
7. 7.  
St u d y Dr u g  O ve r d ose M a n a ge me nt 
T he m e dical m o nit or m ust be c o ntacte d i n t he e ve nt of a n y st u d y dr u g o ver d ose. 
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of st u d y dr u g, t o or b y 
a st u d y p atie n t, at a d ose a b o ve t hat assi g ne d t o t h at i n di vi d ual patie n t acc or di n g t o t he st u d y 
pr ot oc ol. 
P P D
P P D
P P D


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For this study, any dose of relugolix > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 x the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose. 
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 according to Section 7.6, whether or not the overdose is 
associated with an adverse event; 
• 
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 any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  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 
form, 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. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.5.2 details the requirements for measurement of safety parameters including vital 
signs, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on endometriosis-associated pain.  Low-dose hormonal 
add-back therapy with estradiol and norethindrone acetate will be evaluated for maintenance of 
bone mineral density during treatment with relugolix. 


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Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 
reproductive toxicity, and metabolic and cardiovascular changes (insulin resistance, 
dyslipidemia, increased weight) with an increased risk of diabetes mellitus and possible 
increased risk of cardiovascular disease.  Additionally, there are potential risks associated with 
the addition of estradiol/norethindrone acetate.  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 strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
Week 52, and 
Week 104/Early Termination 
visits with specified 
discontinuation and follow-
up criteria and all fractures 
will be reported as adverse 
events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52visits, and as 
clinically applicable; 
withdrawal for QTcF 
> 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
Period will be reported 
within 24 hours of study 
personnel awareness. 


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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
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, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
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. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each visit. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; QTc = corrected QT 
interval; QTcF = QT interval by the Fridericia correction; PLD = phospholipidosis; 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 (GCP) 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 GCP.  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 (WHO-DDE), 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. 


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9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  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. 
There will be two analyses: one at Week 52 and one at Week 104.  A clinical study report will be 
generated from each analysis. 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 80 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the modified Intent-to-Treat (mITT) Population, 
defined as all patients who were randomized in a parent study (MVT-601-3101 or 
MVT-601-3102) and who have received any amount of randomized study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of randomized study drug. 
The analysis methods for safety and efficacy endpoints are the same as those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Justification 
Because this is an extension study, the sample size will be determined by the number of patients 
who have completed a parent study and who are eligible and willing to participate in the 
extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 
9.4. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the mITT Population.  
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
The point estimates and 2-sided 95% confidence intervals (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic 


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medications, proportion of responders based on NMPP scores and use of rescue analgesic 
medications) will be calculated. 
A responder at a given time point and for a specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that type of pain from Baseline in the parent study 
greater than or equal to a pre-determined threshold and who did not have an increase in the use 
of rescue analgesic medications for endometriosis-associated pain compared with the use at 
Baseline. Patients who had a pain reduction less than the pre-determined threshold or who had an 
increase in the use of analgesics for endometriosis-associated pain will be considered non-
responders.  The pain reduction thresholds will be determined for NMPP and dysmenorrhea 
separately (see the SAP for details) for the parent studies and these same thresholds will be 
applied to this study. 
Baseline values are calculated using the Baseline pain assessment period, which is defined as the 
period from the date of the first dose of placebo in the parent study Run-In Period through the 
day prior to the first dose of randomized study drug.  Patients’ average NRS pain scores and use 
of rescue analgesic medications for endometriosis-associated pain (dysmenorrhea or NMPP) will 
be compared between a given visit-specific pain assessment period (eg, Week 28, Week 32, etc.) 
and the Baseline pain assessment period.  The visit-specific pain assessment period is defined as 
the last 35 calendar days immediately prior to and including the last dose of study drug treatment 
received prior to the visit date. 
For any pain assessment period (Baseline or visit-specific), the average NRS scores will be 
calculated for dysmenorrhea and NMPP separately.  An average NRS score for dysmenorrhea is 
calculated as the average NRS score over the days with menses during a given pain assessment 
period.  An average NRS score for NMPP is calculated as the average NRS score over the days 
without menses during a given pain assessment period.  The analgesic use for a given pain 
assessment period is summarized by total dose count defined as the average daily dose count 
taken during the given pain assessment period multiplied by 35.  Additional details on 
calculating dose counts and on the precise definition of an increase in analgesic use will be 
provided in the SAP. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies at Week 52 and Week 104. 
• 
Change from the parent study Baseline in the EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline to in the mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for dysmenorrhea; 
• 
Change from the parent study Baseline in the mean NMPP NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for NMPP; 
• 
Change from the parent study Baseline in the mean dyspareunia NRS scores; 
• 
Proportion of patients who are better or much better on the PGIC for dyspareunia; 
• 
Change from the parent study Baseline in the mean dyspareunia functional impairment on the 
sB&B scale; 
• 
Change from the parent study Baseline in severity scores on the PGA for pain; 


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• 
Proportion of responders based on EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline in function impairment on the PGA for function; 
• 
Change from the parent study Baseline in each of the non-pain EHP-30 domains (Control and 
Powerlessness, Social Support, Emotional Well-Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period in NMPP-related functional 
effects (sB&B). 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
For endpoint of proportion of responders based on EHP-30 Pain Domain scores, a responder is 
defined using the same within-patient score change threshold determined from the parent studies.  
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with 
DXA.  Safety summaries by treatment group will be performed using treatment groups defined 
based on the actual randomized treatment received in the parent study. 
The treatment-emergent period will be defined as the period of time from the first dose date and 
time of randomized study drug in the parent study through 30 days after the last dose of study 
drug, or the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for endometriosis, whichever occurs 
first.  Safety will be assessed through summaries of adverse events, the frequency of treatment 
discontinuations due to adverse events, laboratory evaluations, and bone densitometry results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute CTCAE.  All adverse events will be coded to preferred term, high level term, 
and system organ class using MedDRA 20.0 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 to do the 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 
parent study Baseline versus post-baseline results.  All data will be listed and summarized by 


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visit.  The change from parent study Baseline to each post-baseline study visit will be presented 
by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  Electrocardiograms will also 
be read centrally.  The distributions of QTc interval will be summarized at each visit.  All data 
will be listed and summarized by visit.  The change from parent study Baseline to each post-
baseline study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for percent change at 
Week 52 from parent study Baseline in bone mineral density will be provided based on mixed 
effects model (assumed missing at random) for each parent study treatment group.  The 95% CI 
for mean percentage change at Week 104 from parent study Baseline in bone mineral density 
lumbar spine (L1-L4) will be provided along with descriptive statistics for bone mineral density 
loss at Week 104 as supportive analyses. 
All data will be listed and summarized by visit.  The absolute change and percent change from 
parent study Baseline to Weeks 36, 52, and 104 and associated 95% CIs will be presented by the 
parent study treatment group for each bone mineral density parameter.  The number and 
percentage of patients meeting a bone mineral density decline of at least 4%, 5%, 6%, or 7% by 
body area (lumbar spine, total hip, or femoral neck) will be estimated with 95% CIs by the parent 
study treatment group. 
Additional analyses will be performed to examine the correlation between bone mineral density 
loss with demographic and baseline characteristics and with treatment exposure.  Details will be 
provided in the SAP. 
9.6. 
Pharmacodynamics Analyses 
The change from the parent study Baseline to Week 52 and to Week 104 in predose 
concentrations of serum estradiol will be summarized.  Percentage of patients with 
concentrations of serum estradiol levels < 10 pg/mL and < 20 pg/mL will be provided. 


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9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed at Week 52 and Week 104: 
• 
Change from Baseline in the EHP-30 scale total score; 
• 
Change from Baseline in the EHP Work Domain score; 
• 
Change from parent study Baseline in the EQ-5D-5L. 
9.8. 
Interim Analyses 
An interim analysis will be conducted at Week 52 in which all efficacy and safety endpoints will 
be assessed as described above.  A clinical study report will be generated based on these data to 
support submission of one-year data. 
9.9. 
Steering Committee 
The study will be overseen by a Steering Committee consisting of experts in the field of 
women’s health and staff members of Myovant Sciences GmbH.  The Steering Committee will 
participate in the design, conduct, analyses, and publication of the study. 


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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 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, 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, 1998, 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 1 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 
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 


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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. 
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. 
10.1.5. 
Study Files and Retention of Records 
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 two 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; 


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− 
Results of efficacy parameters, as required by the protocol; 
− 
Start and end date (including dose regimen) of study drug (drug dispensing, return, 
and accountability 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 indication; and 
− 
Date of study completion and reason for early termination, 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, decoding procedures for blinded studies, 
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. 
10.1.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed as specified in the Investigator Site File.  
The eCRF casebook for each study patient will be signed by the investigator or sub-investigator 
(as appropriate) listed on the 1572 and/or other appropriate local health authority documents.  
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. 


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10.1.7. 
Investigational Product Accountability 
The investigator or investigator’s designee (eg, pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, accountability, 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 once the study monitor has reviewed 
and returned used and unused study drug for accountability purposes.  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. 
10.1.8. 
Inspections 
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. 
10.1.9. 
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. 
Safety Reporting 
The sponsor will comply with safety reporting requirements consistent with US FDA, European 
Union (EU) National competent authority, and Health Canada Guidance 2.8.4, Health Canada 
Food and Drugs Act and Regulations, Division 5, Part C.05.014, and applicable ICH and 
regional regulatory safety reporting requirements. 
10.2.2. 
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 appropriate IRB or IEC 
for information and approval in accordance with local requirements and to the appropriate Health 
Authority (eg, FDA, Health Canada, EU National competent authority), if required.  All protocol 
modifications must be submitted to the IRB or IEC in accordance with local requirements.  


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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. 
10.2.3. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies) at Week 52 
and a second clinical study report will be prepared at the end of the study (Week 104).  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).  An abbreviated report may be prepared in 
certain cases. 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
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 GCP 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.  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. 
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). 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
study must be submitted to Myovant for corporate review.  The Clinical Study Agreement 
among the institution, principal investigator, and Myovant will detail the procedures for, and 
timing of, Myovant’s review of publications. 


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11. 
REFERENCES 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 02 October 2017. 
Archer DF, Chwalisz K, Feldman R, et al.  Elagolix for the management of heavy menstrual 
bleeding (HMB) associated with uterine fibroids (UF): Results from a phase 2A proof-of-
concept study. Fertil Steril. 2017 Jul;108(1);152-60.e4. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J 
Obstet Gynec.1992 Feb;166(2):740-5. 
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for 
add-back therapy with gonadotropin-releasing hormone agonists in women with 
endometriosis. Reprod Sci. 2012 Mar;19(6):563-71. 
Dunselman GA, Vermeulen N, Becker Cet al. European Society of Human Reproduction and 
Embryology. ESHRE guideline: management of women with endometriosis. Hum 
Reprod. 2014 Mar;29(3):400-12. 
Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. US Dept. of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research, Center for Biologics 
Evaluation and Research. July 2009. 
Franke HR, van de Weijer PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist 
plus add-back’ hormone replacement therapy for treatment of endometriosis: a 
prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000 
Sep;74(3):534-9. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstet Gynecol. 1998 Jan;91(1):16-24. 
Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on hypoestrogenic 
problems by postoperative gonadotropin-releasing hormone agonist treatment in 
endometriosis. Obstet Gynecol Sci. 2016 Jan;59(1):32-8. 
Morris EP, Rymer J, Robinson J, Fogelman I. Efficacy of tibolone as add-back therapy’ in 
conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine 
fibroids. Fertil Steril. 2008 Feb;89(2):421-8. 
Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic 
pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reprod Health. 2015 Mar;21(1):16-23. 
Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P. Differences in 
characteristics among 1,000 women with endometriosis based on extent of disease. Fertil 
Steril. 2008 Mar;89(3):538-45. 


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Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
therapy in treatment of endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014 
Sep;290(3):513-23. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
in the treatment of endometriosis-associated pain. Fertil Steril. 2004 Nov;82(5):1303-8. 
 


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12. 
APPENDICES 
 
Protocol-Specified Rescue Analgesics 
The medications below are listed based on their dose strength. The prescription (or instructions 
for use) for these medications may allow for use of more than one tablet at any given time. 
Analgesics should be prescribed in accordance with the respective country’s approved product 
labeling.  The subject’s historical use of opioid analgesics should be taken into consideration 
when prescribing these drugs.  
Only one Tier 2 medication should be selected for a given patient to be used throughout the 
study.  
Study-specified analgesics include: 
• 
Tier 1 
− 
ibuprofen (200 mg dose strength)1 
• 
Tier 2 
− 
tramadol (37.5 mg) / paracetamol (325 mg) 
− 
tramadol (50 mg) 
− 
codeine (30 mg) 
− 
codeine (30 mg) / paracetamol (300 mg) 
− 
codeine (30 mg) / paracetamol (500 mg) 
− 
codeine 15 mg/ paracetamol (500 mg) 
− 
hydrocodone (5 mg) / acetaminophen 325 mg 
 
Please consult your site-specific instructions for study-specified analgesics for your country. 
 
 
 
 
 
1All second-tier drugs that contain acetaminophen or paracetamol are fixed-dose combination 
products (eg, single tablet containing both drugs). 
 


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Daily eDiary 
 


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Endometriosis Health Profile-30 
ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. 
Ben unable to go to social events 
because of the pain? 
 
 
 
 
 
 
 
2. 
Ben unable to do jobs around the 
house because of the pain? 
 
 
 
 
 
 
3. 
Found it dificult to stand because 
of the pain?
 
 
 
 
 
 
 
4. 
Found it dificult to sit because 
 
of the pain?
 
 
 
 
 
 
 
5. 
Found it dificult to walk because 
 
of the pain?
 
 
 
 
 
 
 
6. 
Found it dificult to exercise or do 
the leisure activities you would like 
to do because of the pain? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question 
 
before moving on to the next page. 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
7. 
Lost your apetite and/or ben 
unable to eat because of the pain? 
 
 
 
 
 
 
8. 
Ben unable to slep properly 
because of the pain?
 
 
 
 
 
 
 
9. 
Had to go to bed/lie down because 
of the pain?
 
 
 
 
 
 
 
10. Ben unable to do the things you 
want because of the pain? 
 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
 
12. Generaly felt unwel? 
 
 
 
 
 
 
13. Felt frustrated because your 
sympto
ms are not geting beter?
 
 
 
 
 
 
 
14. Felt frustrated because you are not 
able to control your symptoms?
 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question 
 
before moving on to the next page. 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
15. Felt unable to forget your 
symptoms?
 
 
 
 
 
 
 
16. Felt as though your symptoms 
 
are ruling your life?
 
 
 
 
 
 
 
17. Felt your symptoms are taking 
away 
your life?
 
 
 
 
 
 
 
18. Felt depresed?
 
 
 
 
 
 
 
19. Felt wepy/tearful? 
 
 
 
 
 
 
20. Felt miserable? 
 
 
 
 
 
 
21. Had mod swings? 
 
 
 
 
 
 
22. Felt bad-
tempered or short
-
tempered?
 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question 
 
before moving on to the next page. 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
23. Felt violent or agresive? 
 
 
 
 
 
 
24. Felt unable to tel others how 
 
you fel?
 
 
 
 
 
 
 
25. Felt others do not understand 
 
what you are going through?
 
 
 
 
 
 
 
26. Felt as though others think 
you are whining? 
 
 
 
 
 
 
27. Felt alone? 
 
 
 
 
 
 
28. 
Felt frustrated that you canot 
always wear the clothes you 
would chose? 
 
 
 
 
 
 
29. Felt your apearance has ben 
afec
ted?
 
 
 
 
 
 
 
30. Lacked confidence?
 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question
. 
 


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European Quality of Life Five-Dimension Five-Level Scale 
 


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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 




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Patient Global Assessment (for pain) 
How would you rate your pelvic pain right now? 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly button 
Absent 
Mild 
Moderate 
Severe 
Very Severe 
Patient Global Assessment (for function) 
How much were your daily activities limited by endometriosis over the last 4 weeks?  
Not at all 
Minimally 
Moderately 
Significantly  
Very significantly 
Note: PGA for function is administered via a paper questionnaire. 


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Endometriosis Health Profile - Work Domain 
 
Note: EHP Work Domain is administered via a paper questionnaire. 
 


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Assessment of Abnormal Liver Function Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) 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 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]), Alkaline Phosphatase, and INR Tests  
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities improve 
If ALT or AST ≥ 3 × 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 
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; 
• 
CBC 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; 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
CBC = complete blood count; 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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AMENDMENT 2:  SUMMARY OF CHANGES 
The MVT-601-3103 protocol has been amended as described in the table below.  The primary purpose of the 
amendment is to extend the study from 52 weeks of treatment to 104 weeks of treatment, inclusive of the 24 weeks 
of treatment in the parent study.  Additionally, the protocol is being amended to include an endometrial biopsy at 
Week 52 and an optional endometrial biopsy at Week 104. 
A detailed list of changes is described below, where deleted text is indicated by strikethrough and new text is 
indicated with bold formatting.  Note that the correction of typos, minor clarifications, and minor wording changes 
to improve readability, understanding, and consistency may not be included in this table. 
 


Cli nic al St u d y Pr ot oc ol:  M V T - 6 0 1- 3 1 0 3 
A me n d me nt 2:  1 1 Dec 2 0 1 8 
M y o va nt Scie nces G m b H  
2 
C O N FI D E N TI A L  
Secti o n  
Ite m 
Ori gi n al  
A me n d me nt 2  
R ati o n ale  
Title P a ge  
Versi o n a n d 
Effecti ve Date  
Ori gi nal:  0 6 -N O V -2 0 1 7  
A me n d me nt 1: 2 0 -M A R -2 0 1 8  
Ori gi nal:  0 6  N O V  2 0 1 7  
A me n d me nt 1: 2 0  M A R  2 0 1 8  
A me n d me nt 2: 1 1 Dec 2 0 1 8  
U p date d t he effecti ve date of 
t he c urre nt a me n d me nt. 
Hea der  
A me n d me nt 1, 2 0 -M A R -2 0 1 8  
A me n d me nt 2, 1 1 Dec 2 0 1 8  
U p date d effecti ve date of 
c urre nt a me n d me nt.  
S p o ns or Si g nat ure 
P a ge  
Pr ot oc ol N u m ber:  M V T -6 0 1 -3 1 0 3  
Pr ot oc ol N u m ber:  M V T -6 0 1 -3 1 0 3  
A me n d me nt  2 
U p date d t he c urre nt versi o n of 
t he pr ot oc ol. 
S p o ns or Si g nat ure 
P a ge  
 
 
 
 
U p date d si g nat ories. 
List of 
A b bre viati o ns  
E O T:  e n d of treat me nt  
B P:  bl o o d press ure  
C B C:  c o m plete bl o o d c o u nt  
E U:  E ur o pe a n U ni o n  
H R:  he art r ate  
I V R S:  i nter acti ve v oice res p o nse s yste m 
I W R S:  i nter acti ve w e b res p o nse s yste m 
S N RI:  ser ot o ni n a n d n ore pi ne p hri ne 
re u pt a ke i n hi bit or  
S S RI:  selecti ve ser ot o ni n re u pt a ke i n hi bit or  
T C A:  tric yclic a nti de press a nt  
W:  w ee k  
U p date d list of a b bre viati o ns t o 
reflect a b bre viati o ns i ncl u de d 
i n t he pr ot oc ol. 
S y n o psis  
St u d y O bj ecti ves  
Pri mar y Efficac y O bj ecti ve  
T o e val uate l o n g -ter m efficac y of rel u g oli x 4 0 
m g o nce dail y c o -a d mi nistere d wit h l o w-d ose 
estra di ol a n d n oret hi n dr o ne acetate f or u p t o 
5 2  wee ks, a m o n g patie nts w h o pre vi o usl y 
c o m plete d a 2 4 -wee k treat me nt peri o d i n o ne of 
t he pare nt st u dies ( M V T -6 0 1 -3 1 0 1 or 
M V T -6 0 1 -3 1 0 2), o n e n d o metri osis -ass ociate d 
pai n.  
Pri mar y Efficac y O bjecti ves  
T o be assesse d at Wee k 5 2  
•  T o e val uate l o n g -ter m efficac y of rel u g oli x 
4 0 m g o nce dail y c o -a d mi nist ere d wit h 
l o w-d ose estra di ol a n d n oret hi n dr o ne acetate 
f or u p t o 5 2 wee ks, a m o n g patie nts w h o 
pre vi o usl y c o m plete d a 2 4 -we e k treat me nt 
peri o d i n o ne of t he pare nt st u dies 
( M V T-6 0 1 -3 1 0 1 or M V T -6 0 1 -3 1 0 2), o n 
e n d o metri osis-ass ociate d pai n.  
U p date d pri mar y o bj ecti ve t o 
reflect e xte n di n g t he st u d y t o 
1 0 4 t otal wee ks of treat me nt  to 
e val uate t he l o n g -ter m efficac y 
a n d safet y of rel u g oli x 4 0 m g 
o nce dail y c o -a d mi nistere d wit h 
l o w-d ose E 2/ N E T A.  
A d diti o nall y, c ha n ges reflect 
t he pla n  to c o n d uct t w o 
a nal yses, t he first usi n g data 
c ollecte d t hr o u g h 5 2 wee ks of 
treat me nt, a n d t he sec o n d usi n g 
P P D
P P D
P P D


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Section 
Item 
Original 
Amendment 2 
Rationale 
To be assessed at Week 104 
• To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone 
acetate for up to 104 weeks, among 
patients who previously completed a 
24-week treatment period in one of the 
parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-
associated pain. 
data collected through 
104 weeks of treatment. 
Synopsis 
Study Objectives 
Secondary Efficacy Objectives 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102), on the following: 
 
Safety Objectives 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks, 
among patients who previously completed a 
24-week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102), 
including: 
Pharmacodynamic Objective 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for 
up to 52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
Secondary Efficacy Objectives 
To be assessed at Week 52 and Week 104 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on the 
following: 
• To determine the benefit of relugolix 
40 mg once daily co-administered with 
24 weeks of low-dose estradiol and 
norethindrone acetate compared with 
placebo on function measured by the 
EHP-30 Pain Domain; 
Safety Objectives 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 104 weeks, 
among patients who previously completed a 
24-week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102), 
including: 
Pharmacodynamic Objective 
Updated secondary objectives 
to reflect extending the study to 
104 total weeks of treatment 
and the intention to conduct 
analyses on data through 
Week 52 and Week 104. 
 
Additionally, secondary 
efficacy endpoint was added in 
the synopsis to match the 
endpoints listed in the body of 
the protocol. 


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Exploratory Objective 
To evaluate the benefit of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate on 
endometriosis-associated quality of life (EHP-30 
total score), work (EHP Work Domain), and 
patient-reported quality of life outcomes 
(European Quality of Life Five-Dimension 
Five-Level Scale [EQ-5D-5L]) for up to 52 
weeks among patients who previously completed 
a 24-week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102). 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for 
up to 104 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
Exploratory Objective 
To evaluate the benefit of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate on 
endometriosis-associated quality of life (EHP-30 
total score), work (EHP Work Domain), and 
patient-reported quality of life outcomes 
(European Quality of Life Five-Dimension 
Five-Level Scale [EQ-5D-5L]) for up to 
104 weeks among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102). 
Synopsis 
Study Design 
All patients will receive oral relugolix 40 mg 
once daily coadministered 
with -lowdose- estradiol 1.0 mg and 
norethindrone acetate 0.5 mg for up to 28 weeks.  
Approximately 800 women with endometriosis-
associated pain will be enrolled.  The objectives 
of the study are to evaluate long-term efficacy 
and safety through up to 52 weeks of treatment 
(including treatment during the parent study) of 
relugolix co-administered with low-dose 
estradiol/norethindrone acetate. 
All patients will receive open-label oral 
relugolix 40 mg once daily co-administered with 
low-dose- estradiol 1.0 mg and norethindrone 
acetate 0.5 mg for up to 80 weeks.  
Approximately 800 women with endometriosis-
associated pain will be enrolled.  The objectives 
of the study are to evaluate long-term efficacy 
and safety through up to 104 weeks of treatment 
(including treatment during the parent study) of 
relugolix co-administered with low-dose 
estradiol/norethindrone acetate. 
Added clarification on the 
open-label nature of the study 
and updated timing elements to 
reflect extension to 104 total 
weeks of treatment. 
Synopsis 
Study Design 
Patients will have received their last dose of 
study drug in the parent study on the day prior to 
the Week 24/Baseline visit and will receive their 
first dose of study drug for this extension study 
in the clinic after the patient is determined to be 
Patients will have received their last dose of 
study drug in the parent study on the day prior to 
the Week 24/Baseline visit and will receive their 
first dose of study drug for this extension study 
in the clinic after the patient is determined to be 
Added clarification that the first 
dose of study drug could be 
initiated up to 10 days after 
completion of the parent study 
to allow for logistical issues.   


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eligible for this extension study and has provided 
informed consent to participate.  Therefore, 
results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline 
visit.  The administration of the first dose of 
study drug for MVT-601-3103 will define 
enrollment into this study.  Study participants 
will then take the open-label study treatment 
(relugolix 40 mg coadministered- with estradiol 
1.0 mg and norethindrone acetate 0.5 mg) orally 
once daily for 28 weeks. 
eligible for this extension study and has provided 
informed consent to participate.  Therefore, 
results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline 
visit.  The administration of the first dose of 
study drug for MVT-601-3103 will define 
enrollment into this study.  Study participants 
will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 
1.0 mg and norethindrone acetate 0.5 mg) orally 
once daily for 80 weeks.  If necessary for 
logistical reasons (eg, delayed availability of 
study drug supply on site, others), and with 
sponsor/designee approval, the first dose of 
open label study drug for MVT-601-3103 may 
be administered up to 10 days following the 
parent study Week 24/Baseline visit.  If the 
first dose of study drug is not given during 
this up to 10-day interval, the parent study 
follow-up procedures should be followed (ie, 
adverse event reporting, electronic diary 
[eDiary] completion, etc.). 
Synopsis 
Study Design 
During the 28-week Open-Label Treatment 
Period and the ~30-day Follow-Up Period, 
patients will continue to record study treatment, 
assessment of pain using the NRS, menstrual 
bleeding, analgesic use, and the functional 
effects of endometriosis-associated pain (sB&B) 
in the electronic diary (eDiary). 
During the 80-week Open-Label Treatment 
Period and the ~30-day Follow-Up Period, 
patients will continue to record study treatment, 
assessment of pain using the NRS, menstrual 
bleeding, analgesic use, and the functional 
effects of endometriosis-associated pain (sB&B) 
in the electronic diary (eDiary). 
Updated duration of treatment 
to reflect extension of 
treatment. 
Synopsis 
Study Design 
At the Week 36 visit and Week 52/Early 
Termination visit, each patient will have an 
assessment of bone mineral density via 
dual-energy x-ray absorptiometry (DXA). 
At the Week 36, Week 52, and Week 104/Early 
Termination visits, each patient will have an 
assessment of bone mineral density via 
dual-energy x-ray absorptiometry (DXA). 
Updated timing of DXA scans 
to reflect extension of 
treatment. 
Synopsis 
Study Design 
Patients with a bone mineral density loss of > 3% 
at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit (or most recent 
Determination of bone mineral density by 
DXA at Early Termination and follow-up of 
Added clarification for when 
DXA scans would be 


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scan, if the Week 52/ET scan was not done)  
relative to the parent study Baseline 
measurement will undergo another bone 
densitometry scan at 6 (±1) months after the last 
dose of study medication. 
findings will proceed according to the 
following rules: 
• 
For Early Termination occurring between 
Week 24 and Week 52: 
− 
For Early Termination occurring 
before Week 36, DXA is not required 
at Early Termination visit unless it 
will aid in the assessment of an 
adverse event. 
Follow-up DXA required at 6 months 
(± 1 month) if most recent DXA bone 
mineral density loss at lumbar spine 
(L1-L4) or total hip was > 2% relative 
to the parent study baseline. 
− 
For Early Termination occurring 
after Week 36, DXA is required at 
Early Termination unless a DXA 
result is available from within six 
weeks prior to Early Termination. 
Follow-up DXA is required at 
6 months (± 1 month) if the most 
recent DXA scan was at Week 24 and 
bone mineral density loss at the 
lumbar spine (L1-L4) or total hip was 
> 2%, relative to the parent study 
baseline. 
Follow-up DXA is required at 
6 months (± 1 month) if on the most 
recent DXA, bone mineral density 
loss at the lumbar spine (L1-L4) or 
conducted and the follow-up 
rules for DXA results. 


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total hip was > 3%, relative to the 
parent study baseline. 
• 
For Early Termination occurring between 
Week 52 and Week 104: 
− 
DXA is required at Early 
Termination unless a DXA result is 
available from within six weeks prior 
to Early Termination. 
− 
Follow-up DXA is required at 
6 months (± 1 month) if on the most 
recent DXA, bone mineral density 
loss at the lumbar spine (L1-L4) or 
total hip was > 7%, relative to parent 
study baseline. 
Synopsis 
Study Design 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the 
follow-up procedures performed under this 
protocol, including the follow-up bone 
densitometry scan at 6 (±1) months and status of 
menstruation recovery, may be waived. 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 104 visit, then the Follow-up visit and the 
follow-up procedures performed under this 
protocol, including the follow-up bone 
densitometry scan at 6 (±1) months and status of 
menstruation recovery, may be waived. 
Updated study timing to reflect 
extension of treatment. 
Synopsis 
Exclusion Criteria 
The presenting visual acuity score has decreased 
by 10 or more points at the Week 24/Baseline 
visit relative to the parent study Baseline visit; 
11. Has a decline in presenting visual acuity 
score, as defined below (unless explained 
by refractive error or approved by the 
sponsor): 
a. 90 or lower and five or more points 
lower at Week 24/Baseline visit 
relative to the parent study Baseline 
visit; or 
b. The presenting visual acuity score has 
decreased by ten or more points at the 
Clarified visual acuity criteria. 


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Week 24/Baseline visit relative to the 
parent study Baseline visit. 
Synopsis 
Duration of 
Treatment 
Study treatment will be self-administered for 
28 weeks (Open-Label Treatment Period). 
Study treatment will be self-administered for 
80 weeks (Open-Label Treatment Period). 
Updated study timing to reflect 
extension of treatment. 
Synopsis 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy 
and safety will be made between the parent study 
Baseline and the end of the extension study 
(Week 52) for the following parent study 
treatment groups: 
Descriptive assessments of long-term efficacy 
and safety will be made between the parent study 
Baseline and Week 52, and between the parent 
study Baseline and the end of the extension 
study (Week 104) for the following parent study 
treatment groups: 
Updated to reflect extension of 
treatment. 
Synopsis 
Criteria for 
Evaluation 
Primary Efficacy Endpoints 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
Primary Efficacy Endpoints 
Week 52 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
Week 104 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their 
dysmenorrhea NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their NMPP NRS 
scores. 
Updated endpoints to reflect 
extension of treatment. 
Synopsis 
Criteria for 
Evaluation 
Secondary Efficacy Endpoints 
• 
Change from the parent study Baseline to 
Week 52 in the EHP-30 Pain Domain scores; 
Secondary Efficacy Endpoints 
Updated endpoints to reflect 
extension of treatment. 


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• 
Change from the parent study Baseline to 
Week 52/end of treatment (EOT) in the 
mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for dysmenorrhea 
at Week 52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean NMPP NRS 
score; 
• 
Proportion of patients who are better or 
much better on the PGIC for NMPP at Week 
52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean dyspareunia NRS 
scores; 
• 
Proportion of patients who are better or 
much better on the PGIC for dyspareunia at 
Week 52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean dyspareunia 
functional impairment on the sB&B scale; 
• 
Change from the parent study Baseline to 
/EOT in severity scores on the PGA for pain; 
• 
Proportion of responders at Week 52/EOT 
based on their EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline to 
Week 52/EOT in function impairment on the 
PGA for function; 
• 
Change from the parent study Baseline to 
Week 52/EOT in each of the non-pain EHP-
30 domains (Control and Powerlessness, 
Social Support, Emotional Well-Being, and 
Self-Image); 
To be assessed at Week 52 and Week 104, 
unless otherwise specified 
• 
Change from the parent study Baseline in the 
EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline in the 
mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for dysmenorrhea 
(at Week 52 only); 
• 
Change from the parent study Baseline in the 
mean NMPP NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for NMPP (at 
Week 52 only); 
• 
Change from the parent study Baseline in the 
mean dyspareunia NRS scores; 
• 
Proportion of patients who are better or 
much better on the PGIC for dyspareunia (at 
Week 52 only); 
• 
Change from the parent study Baseline in the 
mean dyspareunia functional impairment on 
the sB&B scale; 
• 
Change from the parent study Baseline in 
severity scores on the PGA for pain; 
• 
Proportion of responders based on their 
EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline in 
function impairment on the PGA for 
function; 
• 
Change from the parent study Baseline in 
each of the non-pain EHP-30 domains 
(Control and Powerlessness, Social Support, 
Emotional Well-Being, and Self-Image); 


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• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline pain 
assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
Change from the parent study Baseline pain 
assessment period in NMPP-related 
functional effects (sB&B). 
Synopsis 
Criteria for 
Evaluation 
Safety Endpoints 
• 
Incidence of adverse events; 
• 
Percent change from the parent study 
Baseline to Week 52 in bone mineral density 
at the lumbar spine (L1-L4), femoral neck, 
and total hip as assessed by DXA. 
Safety Endpoints 
To be assessed at Week 52 and Week 104 
• 
Incidence of adverse events; 
• 
Percent change from the parent study 
Baseline in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and 
total hip as assessed by DXA. 
Updated endpoints to reflect 
extension of treatment. 
Synopsis 
Criteria for 
Evaluation 
Pharmacodynamic Endpoint 
• 
Change from parent study Baseline to Week 
52 in pre-dose concentrations of serum 
estradiol. 
Exploratory Endpoints 
• 
Change from Baseline to Week 52/EOT in 
the EHP-30 scale total score; 
• 
Change from Baseline to Week 52/EOT in 
the EHP Work Domain score; 
• 
Change from parent study Baseline to Week 
52/EOT in the EQ-5D-5L. 
Pharmacodynamic Endpoint 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in 
predose concentrations of serum estradiol. 
Exploratory Endpoints 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• 
Change from parent study Baseline in the 
EQ-5D-5L. 
Updated endpoints to reflect 
extension of treatment. 
Synopsis 
Statistical Methods 
 
There will be two analyses: one at Week 52 
and one at Week 104.  A clinical study report 
will be generated from each analysis. 
Clarified plan to conduct two 
analyses (one with data through 
52 weeks of treatment and one 
with data through 104 weeks of 
treatment) and develop a 


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separate clinical study report 
for each analysis. 
Synopsis 
Statistical Methods 
Safety assessments will include treatment-
emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 
12-lead ECG, and bone mineral density with 
DXA.  Safety data analyses will use data from all 
patients from the parent studies who receive any 
amount of study drug (ie, from parent study 
Baseline to Week 52). 
Safety assessments will include treatment-
emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 
12-lead ECG, and bone mineral density with 
DXA.  Safety data analyses will use data from all 
patients from the parent studies who receive any 
amount of study drug (ie, from parent study 
Baseline to Week 52 or Week 104). 
Updated to reflect extension of 
treatment. 
Synopsis 
Statistical Methods 
Bone mineral density will be evaluated in all 
patients at the lumbar spine (L1-L4), femoral 
neck, and total hip at the Week 24/Baseline, 
Week 36, and Week 52/Early Termination visits.  
The absolute change and percent change from 
parent study Baseline and Z-scores will be 
summarized by visit and parent study treatment 
group. 
Bone mineral density will be evaluated in all 
patients at the lumbar spine (L1-L4), femoral 
neck, and total hip at the Week 24/Baseline, 
Week 36, Week 52, and Week 104/Early 
Termination visits.  The absolute change and 
percent change from parent study Baseline and 
Z-scores will be summarized by visit and parent 
study treatment group. 
Updated to reflect extension of 
treatment. 
Synopsis 
Statistical Methods 
The mean percentage change at Week 52 from 
parent study Baseline in bone mineral density 
and corresponding 95% CI will be provided for 
each treatment group.  For patients who were 
randomized to 24 weeks of treatment with 
relugolix and add-back in the parent studies 
(Group A in MVT-601-3101 or MVT-601-3102) 
and enrolled in the extension study, the lower 
bound of the 95% CI for mean percentage 
change at Week 52 from parent study Baseline in 
bone mineral density lumbar spine (L1-L4) will 
be compared with a pre-specified clinically 
acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 
52 weeks of treatment.  If the lower bound is 
> -2.2%, bone mineral density loss for the 
relugolix add-back treatment will be considered 
insignificant. 
The mean percentage change from parent study 
Baseline to Week 52 in bone mineral density and 
corresponding 95% CI will be provided for each 
treatment group.  For patients who were 
randomized to 24 weeks of treatment with 
relugolix and add-back in the parent studies 
(Group A in MVT-601-3101 or MVT-601-3102) 
and enrolled in the extension study, the lower 
bound of the 95% CI for mean percentage 
change at Week 52 from parent study Baseline in 
bone mineral density lumbar spine (L1L4) will 
be compared with a pre-specified clinically 
acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 
52 weeks of treatment.  If the lower bound is 
> 2.2%, bone mineral density loss for the 
relugolix add-back treatment will be considered 
insignificant.  The 95% CI for mean 
Updated to reflect extension of 
treatment, and to provide a 
description of analyses to be 
conducted on data from 
Week 104. 


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percentage change at Week 104 from parent 
study Baseline in bone mineral density lumbar 
spine (L1-L4) will be provided along with 
descriptive statistics for bone mineral density 
loss at Week 104 as supportive analyses. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
 
Note:  Week 65, Week 78, Week 91, and 
Week 104, along with corresponding 
assessments/activities were added to the 
Schedule of Activities.  Telephone contact at 
Week 57, Week 71, Week 85, and Week 98 was 
added (an ‘X’ was added to the nearest 
scheduled visit in the Schedule of Activities). 
Updated to reflect extension of 
treatment, add telephone 
contact at Weeks 57, 71, 85, 
and 98. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote a 
a The Week 52 visit should occur on or after the 
1-year anniversary of Study Day 1 of the 
parent study. 
a The Week 52 visit should occur on or after the 
1-year anniversary of Baseline Day 1 of the 
parent study, and the Week 104 visit should 
occur on or after the 2-year anniversary of 
Baseline Day 1 of the parent study. 
Updated to reflect extension of 
treatment. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote i 
Footnote i and subsequent footnotes were shifted 
by one to accommodate a new footnote. 
i The Week 52 and Week 104 physical 
examinations will include a breast 
examination. 
Clarified which physical 
examinations would include a 
breast examination. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote l 
l Clinical chemistries will be collected at each 
visit.  A complete blood count will be 
collected at Week 24/Baseline, Week 28, 
Week 36, and Week 52.  At the Week 
24/Baseline visit and Week 52 visit, additional 
tests include:  fasting (at least 8 hours) 
glucose, lipid profile, and hemoglobin A1c. 
m Clinical chemistries will be collected at each 
visit.  A complete blood count will be 
collected at Week 24/Baseline, Week 28, 
Week 36, Week 52, Week 65, Week 78, 
Week 91, and Week 104.  At the 
Week 24/Baseline visit, Week 52 visit, and 
Week 104 visit, additional tests will include 
the following:  fasting (at least 8 hours) 
glucose, lipid profile, and hemoglobin A1c. 
Updated to reflect extension of 
treatment. 
Table 1-1  
Schedule of 
Activities for Study 
n For Week 24/Baseline samples, see the parent 
protocol (MVT-601-3101 or MVT-601-3102).  
At Week 52/Early Termination, collect 
samples for analysis of estradiol 
o For Week 24/Baseline samples, see the parent 
protocol (MVT-601-3101 or MVT-601-3102).  
At Week 104/Early Termination, collect a 
sample for analysis of estradiol concentrations 
Updated to reflect extension of 
treatment. 


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MVT-601-3103 
Footnote n 
concentrations only.  On days when 
pharmacodynamics samples are collected, 
administer the study treatment after the 
pharmacodynamics sample collections are 
completed. 
only.  On days when pharmacodynamics 
samples are collected, administer the study 
treatment after the pharmacodynamics sample 
collections are collected. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote o 
o At the Week 24/Baseline visit, transition the 
patient within her eDiary from the parent 
study to MVT-601-3103.  The eDiary data 
collection will include NRS pain scores, 
menstruation information (including severity 
of bleeding), analgesic drug use, date and time 
of study drug administration, and sB&B scale 
scores. 
p All women enrolled in the study will 
continue to use the patient eDiary dispensed 
in the parent study.  Patients will complete 
daily eDiary entries, including NRS pain 
scores, menstruation information, analgesic 
drug use, date and time of study drug 
administration, and sB&B scale scores until 
Week 52.  After Week 52, eDiary scores will 
be entered over four eDiary collection 
cycles on the following schedule:  Week 57 
to the Week 65 visit, Week 71 to the 
Week 78 visit, Week 85 to the Week 91 
visit, and Week 98 to the Week 104 visit. 
Added clarification on the 
timing of eDiary entries. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote r 
r Patients with a bone mineral density loss of 
> 3% at their Week 52/Early Termination visit 
(or most recent scan if the Week 52/Early 
Termination visit was not done) relative to 
parent study Baseline measurement will 
undergo a follow-up bone densitometry scan 
at 6 (±1) months and will be contacted to 
question them about medications and 
conditions (eg, pregnancy) that might affect 
bone mineral density through the time of 
follow-up bone densitometry.  The follow-up 
bone densitometry will be submitted for 
central reading. 
s Determination of bone mineral density by 
DXA at Early Termination and follow-up 
of findings will proceed based on the timing 
of the Early Termination visit.  For Early 
Termination occurring after Week 24 and 
before Week 36, DXA is not required at 
Early Termination visit unless it will aid in 
the assessment of an adverse event, and 
follow-up DXA required at 6 months 
(± 1 month) if most recent DXA bone 
mineral density loss at lumbar spine 
(L1-L4) or total hip was > 2% relative to 
the parent study baseline.  For Early 
Termination occurring after Week 36 and 
before Week 52, DXA is required at Early 
Termination unless a DXA result is 
available from within six weeks prior to 
Early Termination, and follow-up DXA is 
Added clarification for when 
DXA scans would be 
conducted and the follow-up 
rules for DXA results. 


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required at 6 months (± 1 month) if the 
most recent DXA scan was at Week 24 and 
bone mineral density loss at the lumbar 
spine (L1-L4) or total hip was > 2% or most 
recent DXA result was after Week 24 and 
bone mineral density loss at the lumbar 
spine (L1-L4) or total hip was > 3%, 
relative to the parent study baseline.  For 
Early Termination occurring between 
Week 52 and Week 104, DXA is required at 
Early Termination unless a DXA result is 
available from within six weeks prior to 
Early Termination, and follow-up DXA is 
required at 6 months (± 1 month) if on the 
most recent DXA, bone mineral density loss 
at the lumbar spine (L1-L4) or total hip 
was > 7%, relative to parent study baseline. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote s 
s Endometrial biopsies are to be done per 
instructions in the parent study.  See the 
Laboratory Manual for guidance on handling 
and shipping the biopsy sample to the central 
laboratory for analysis.  An endometrial 
biopsy will have been performed at the parent 
study Week 24 visit for all patients who 
participated in MVT-601-3101 only (see 
MVT-601-3101 protocol for details). 
t Endometrial biopsies are to be done per 
instructions in the parent study.  Procedures 
for handling and shipping biopsy samples to 
the central laboratory for analysis are 
described in the Investigator Site File.  An 
endometrial biopsy will have been performed 
at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 
only (see MVT-601-3101 protocol for details), 
at Week 52 for all patients.  All patients are 
eligible for a biopsy at Week 104; however, 
patients will have the option to opt out. 
Updated to reflect extended 
duration of study and to update 
the referenced document.  
Additionally, added 
clarification for the addition of 
endometrial biopsies at 
Week 52 and Week 104. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote t 
t Please see Appendix 1 for list of protocol-
specified analgesics and see the Study 
Reference Manual for information on where 
and how to obtain protocol-specified analgesic 
medications by country.  At the Week 52 visit, 
patients who will not be proceeding to another 
extension study will be re-dispensed or 
u Please see Appendix 1 for list of protocol-
specified analgesics and see the Investigator 
Site File for information on where and how to 
obtain protocol-specified analgesic 
medications by country.  At the Week 104 
visit, patients who will not be proceeding to 
another extension study will be re-dispensed 
Updated to reflect extended 
duration of study and to update 
the referenced document. 


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prescribed protocol-specified analgesic drugs, 
if needed, to ensure sufficient supply until the 
Follow-Up visit.  For patients proceeding to 
another extension study, refer to the protocol 
for that next study. 
or prescribed protocol-specified analgesic 
drugs, if needed, to ensure sufficient supply 
until the Follow-Up visit.  For patients 
proceeding to another extension study, refer to 
the protocol for that next study. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote u 
u Pregnancy test must be negative before the 
study drug dose is administered. 
v Pregnancy test must be negative before the 
study drug dose is administered.  For patients 
whose Baseline Day 1 visit is conducted on 
a different day than the parent study Week 
24 visit, perform an unscheduled pregnancy 
test at Baseline Day 1 prior to 
administering the first dose of study drug. 
Updated to clarify pregnancy 
test procedures for patients 
whose parent study Week 24 
visit was different than the 
baseline visit for this study. 
Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote v 
v Patients will take the first dose of the study 
drug for this study once daily starting with the 
Week 24/Baseline visit (taken at the visit).  
The first dose of study drug for this extension 
study must not be taken until all parent study 
Week 24 procedures such as laboratory tests 
have been completed. Therefore, results of 
testing required for eligibility (eg, DXA) must 
be available on or prior to the Week 
24/Baseline visit.  The last dose of study drug 
will be taken in the clinic during the 
Week 52/Early Termination visit. 
w Patients will take the first dose of the study 
drug for this study once daily starting with the 
Week 24/Baseline visit (taken at the visit).  If 
necessary for logistical reasons (eg, delayed 
availability of study drug supply on site, 
others), and with sponsor/designee 
approval, the first dose of open label study 
drug for MVT-601-3103 may be 
administered up to 10 days following the 
parent study Week 24/Baseline visit.  If the 
first dose of study drug is not given during 
this up to 10-day interval, the parent study 
follow-up procedures should be followed 
(ie, adverse event reporting, eDiary 
completion, etc.).  The first dose of study 
drug for this extension study must not be 
taken until all parent study Week 24 
procedures such as laboratory tests have been 
completed.  Therefore, results of testing 
required for eligibility (eg, DXA) must be 
available on or prior to the Week 24/Baseline 
visit.  The last dose of study drug will be taken 
in the clinic during the Week 104/Early 
Termination visit. 
Added clarification that the first 
dose of study drug could be 
initiated up to 10 days after 
completion of the parent study 
to allow for logistical issues.  
Additionally, updated timing to 
reflect extension of study to 
104 weeks of treatment. 


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Table 1-1  
Schedule of 
Activities for Study 
MVT-601-3103 
Footnote cc 
 
cc A telephone call will be performed at 
Weeks 57, 71, 85, and 98.  The following 
activities should be completed: a 
concomitant medication review, evaluation 
of adverse events, a reminder of compliance 
with non-hormonal contraception 
requirements and the need to call the 
investigator if pregnancy is suspected, and 
a review of eDiary and study medication 
compliance. 
Added to clarify when 
telephone contact would be 
made and what would be 
reviewed during the telephone 
contact. 
Section 3 
Study Objectives 
and Endpoints 
Descriptive assessments of long-term efficacy 
and safety will be made between the parent study 
Baseline and the end of the extension study 
(Week 52) for the following parent study 
treatment groups: 
Descriptive assessments of long-term efficacy 
and safety will be made between the parent study 
Baseline and Week 52, and between the parent 
study Baseline the end of the extension study 
(Week 104) for the following parent study 
treatment groups: 
Updated to reflect extending 
the study to 104 total weeks of 
treatment to evaluate the 
long-term efficacy and safety of 
relugolix 40 mg once daily 
co-administered with low-dose 
E2/NETA.  Additionally, 
changes reflect the plan to 
conduct two analyses, the first 
using data collected through 
52 weeks of treatment, and the 
second using data collected 
through 104 weeks of 
treatment. 
Section 3 
Study Objectives 
and Endpoints 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated 
pain. 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
 
To be assessed at Week 104 
Updated secondary objectives 
to reflect extending the study to 
104 total weeks of treatment 
and the intention to conduct 
analyses on data through 
Week 52 and Week 104. 


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• 
To evaluate long-term efficacy of 
relugolix 40 mg once daily 
co-administered with low-dose estradiol 
and norethindrone acetate for up to 
104 weeks, among patients who 
previously completed a 24-week 
treatment period in one of the parent 
studies (MVT-601-3101 or 
MVT-601-3102), on 
endometriosis-associated pain. 
Section 3 
Study Objectives 
and Endpoints 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
Numerical Rating Scale (NRS) scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
To be assessed at Week 52 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
Numerical Rating Scale (NRS) scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
 
To be assessed at Week 104 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their 
dysmenorrhea NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their NMPP NRS 
scores. 
Updated objectives to reflect 
extending the study to 104 total 
weeks of treatment and the 
intention to conduct analyses 
on data through Week 52 and 
Week 104. 
Section 3 
Study Objectives 
and Endpoints 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
To be assessed at Week 52 and Week 104 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate, among 
patients who previously completed a 24-week 
Updated objectives to reflect 
extending the study to 104 total 
weeks of treatment and the 
intention to conduct analyses 


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the parent studies (MVT-601-3101 or 
MVT-601-3102), on the following: 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on the 
following: 
on data through Week 52 and 
Week 104. 
Section 3 
Study Objectives 
and Endpoints 
Secondary Efficacy Endpoints 
• 
Change from the parent study Baseline to 
Week 52 in the EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline to 
Week 52/end of treatment (EOT) in the 
mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for dysmenorrhea 
at Week 52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean NMPP NRS 
score; 
• 
Proportion of patients who are better or 
much better on the PGIC for NMPP at Week 
52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean dyspareunia NRS 
scores; 
• 
Proportion of patients who are better or 
much better on the PGIC for dyspareunia at 
Week 52/EOT; 
• 
Change from the parent study Baseline to 
Week 52/EOT in the mean dyspareunia 
functional impairment on the sB&B scale; 
• 
Change from the parent study Baseline to 
Week 52/EOT in severity scores on the PGA 
for pain; 
• 
Proportion of responders at Week 52/EOT 
based on their EHP-30 Pain Domain score; 
Secondary Efficacy Endpoints 
To be assessed at Week 52 and Week 104, 
unless otherwise specified 
• 
Change from the parent study Baseline in the 
EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline in the 
mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for dysmenorrhea 
(at Week 52 only); 
• 
Change from the parent study Baseline in the 
mean NMPP NRS score; 
• 
Proportion of patients who are better or 
much better on the PGIC for NMPP (at 
Week 52 only); 
• 
Change from the parent study Baseline in the 
mean dyspareunia NRS scores; 
• 
Proportion of patients who are better or 
much better on the PGIC for dyspareunia (at 
Week 52 only); 
• 
Change from the parent study Baseline in the 
mean dyspareunia functional impairment on 
the sB&B scale; 
• 
Change from the parent study Baseline in 
severity scores on the PGA for pain; 
• 
Proportion of responders based on their 
EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline in 
function impairment on the PGA for 
function; 
Updated endpoints to reflect 
extension of treatment. 


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• 
Change from the parent study Baseline to 
Week 52/EOT in function impairment on the 
PGA for function; 
• 
Change from the parent study Baseline to 
Week 52/EOT in each of the non-pain EHP-
30 domains (Control and Powerlessness, 
Social Support, Emotional Well-Being, and 
Self-Image); 
• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period to Week 52/EOT in 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline in 
each of the non-pain EHP-30 domains 
(Control and Powerlessness, Social Support, 
Emotional Well-Being, and Self-Image); 
• 
Change from the parent study Baseline pain 
assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
Change from the parent study Baseline pain 
assessment period in NMPP-related 
functional effects (sB&B). 
Section 3 
Study Objectives 
and Endpoints 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks, 
among patients who previously completed a 
24 week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102), 
including: 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 104 weeks, 
among patients who previously completed a 
24 week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102), 
including: 
Updated objectives to reflect 
extension of treatment. 
Section 3 
Study Objectives 
and Endpoints 
• 
Incidence of adverse events; 
• 
Percent change from the parent study 
Baseline to Week 52 in bone mineral density 
at the lumbar spine (L1-L4), femoral neck, 
and total hip as assessed by DXA. 
To be assessed at Week 52 and Week 104 
• 
Incidence of adverse events; 
• 
Percent change from the parent study 
Baseline in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and 
total hip as assessed by DXA. 
Updated endpoints to reflect 
extension of treatment. 
Section 3 
Study Objectives 
and Endpoints 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 52 weeks, among patients 
who previously completed a 24 week 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for 
up to 104 weeks, among patients who previously 
completed a 24-week treatment period in one of 
Updated objectives to reflect 
extension of treatment. 


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treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
estradiol. 
the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
Section 3 
Study Objectives 
and Endpoints 
• 
Change from parent study Baseline to 
Week 52 in pre-dose concentrations of 
serum estradiol. 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in 
predose concentrations of serum estradiol. 
Updated endpoints to reflect 
extension of treatment. 
Section 3 
Study Objectives 
and Endpoints 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life 
(EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life 
outcomes (European Quality of Life 
Five-Dimension Five-Level Scale 
[EQ-5D-5L]) for up to 52-weeks among 
patients who previously completed a 
24-week treatment period in one of the 
parent studies (MVT-601-3101 or 
MVT-601-3102). 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life 
(EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life 
outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) 
for up to 104 weeks among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102). 
Updated objectives to reflect 
extension of treatment. 
Section 3 
Study Objectives 
and Endpoints 
Exploratory Endpoints 
• 
Change from Baseline to Week 52/EOT in 
the EHP-30 scale total score; 
• 
Change from Baseline to Week 52/EOT in 
the EHP Work Domain score; 
• 
Change from parent study Baseline to 
Week 52/EOT in the EQ-5D-5L. 
Exploratory Endpoints 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• 
Change from parent study Baseline in the 
EQ-5D-5L. 
Updated endpoints to reflect 
extension of treatment. 
Section 4.1 
Overall Study 
Design 
All patients will receive oral relugolix 40 mg 
once daily co-administered with low-dose 
estradiol 1.0 mg and norethindrone acetate 0.5 
mg for up to 28 weeks.  Approximately 
800 women with endometriosis-associated pain 
will be enrolled.  The objectives of the study are 
to evaluate long-term efficacy and safety through 
All patients will receive open-label oral 
relugolix 40 mg once daily co-administered with 
low-dose estradiol 1.0 mg and norethindrone 
acetate 0.5 mg for up to 80 weeks.  
Approximately 800 women with endometriosis-
associated pain will be enrolled.  The objectives 
of the study are to evaluate long-term efficacy 
Added clarification on the 
open-label nature of the study 
and updated timing elements to 
reflect extension to 104 total 
weeks of treatment. 


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up to 52 weeks of treatment (including treatment 
during the parent study) of relugolix 
co-administered with low-dose 
estradiol/norethindrone acetate. 
and safety through up to 104 weeks of treatment 
(including treatment during the parent study) of 
relugolix co-administered with low-dose 
estradiol/norethindrone acetate. 
Section 4.1 
Overall Study 
Design 
Patients will have received their last dose of 
study drug in the parent study on the day prior to 
the Week 24/Baseline visit and will receive their 
first dose of study drug for this extension study 
in the clinic after the patient is determined to be 
eligible for this extension study and has provided 
informed consent to participate.  Therefore, 
results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline 
visit.  The administration of the first dose of 
study drug for MVT-601-3103 will define 
enrollment into this study.  Study participants 
will then take the open-label study treatment 
(relugolix 40 mg coadministered- with estradiol 
1.0 mg and norethindrone acetate 0.5 mg) orally 
once daily for 28 weeks. 
Patients will have received their last dose of 
study drug in the parent study on the day prior to 
the Week 24/Baseline visit and will receive their 
first dose of study drug for this extension study 
in the clinic after the patient is determined to be 
eligible for this extension study and has provided 
informed consent to participate.  Therefore, 
results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline 
visit.  The administration of the first dose of 
study drug for MVT-601-3103 will define 
enrollment into this study.  Study participants 
will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 
1.0 mg and norethindrone acetate 0.5 mg) orally 
once daily for 80 weeks.  If necessary for 
logistical reasons (eg, delayed availability of 
study drug supply on site, others), and with 
sponsor/designee approval, the first dose of 
open label study drug for MVT-601-3103 may 
be administered up to 10 days following the 
parent study Week 24/Baseline visit.  If the 
first dose of study drug is not given during 
this up to 10-day interval, the parent study 
follow-up procedures should be followed (ie, 
adverse event reporting, electronic diary 
[eDiary] completion, etc.). 
Added clarification that the first 
dose of study drug could be 
initiated up to 10 days after 
completion of the parent study 
to allow for logistical issues. 
Section 4.1 
Overall Study 
Design 
During the 28-week Open-Label Treatment 
Period and the ~30-day Follow-Up Period, 
patients will continue to record study treatment, 
assessment of pain using the NRS, menstrual 
bleeding, analgesic use, and the functional 
During the 80-week Open-Label Treatment 
Period and the ~30-day Follow-Up Period, 
patients will continue to record study treatment, 
assessment of pain using the NRS, menstrual 
bleeding, analgesic use, and the functional 
Updated timing elements to 
reflect extension to 80 weeks of 
treatment in this study. 


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effects of endometriosis-associated pain (sB&B) 
in the electronic diary (eDiary). 
effects of endometriosis-associated pain (sB&B) 
in the eDiary. 
Section 4.1 
Overall Study 
Design 
At the Week 36 visit and Week 52/Early 
Termination visit, each patient will have an 
assessment of bone mineral density via DXA. 
Safety will be assessed throughout the study by 
the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical 
laboratory tests, 12-lead ECGs, and bone mineral 
density with DXA. 
Patients with a bone mineral density loss of > 3% 
at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit (or most recent 
scan, if the Week 52/ET scan was not done) 
relative to the parent study Baseline 
measurement will undergo another bone 
densitometry scan at 6 (± 1) months after the last 
dose of study medication. 
Safety will be assessed throughout the study by 
the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical 
laboratory tests, 12-lead ECGs, and bone mineral 
density with DXA. 
At the Week 36, Week 52, and 
Week 104/Early Termination visits, each 
patient will have an assessment of bone 
mineral density via DXA.  Follow-up of bone 
densitometry findings will proceed according 
to the rules described in Section 6.5.2.6. 
Clarified when DXA scans 
were to be conducted and 
follow-up rules for changes in 
bone mineral density. 
Section 4.1 
Overall Study 
Design 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the 
follow-up procedures performed under this 
protocol, including the follow-up bone 
densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 104 visit, then the Follow-up visit and the 
follow-up procedures performed under this 
protocol, including the follow-up bone 
densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 4.1 
Overall Study 
Design 
Figure 4-1 was replaced to account for changes 
in study duration. 
Figure 4-1 was replaced to account for changes 
in study duration. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 4.2 
Discussion of 
Study Design, 
Including Dosing 
This 28-week extension study provides 
additional efficacy and safety data up to 
52 weeks to demonstrate the benefit and safety of 
relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate 
(0.5 mg).  The primary objectives of the study 
This 80-week extension study provides 
additional efficacy and safety data up to 
104 weeks to demonstrate the benefit and safety 
of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate 
(0.5 mg).  The primary objectives of the study 
Updated timing elements to 
reflect extension of treatment to 
80 weeks for this study 
(104 weeks total). 


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are to assess long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks on dysmenorrhea and NMPP, common 
and burdensome symptoms of endometriosis.  
The study will also evaluate safety of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or 
MVT-601-3102), including adverse events and 
change in bone mineral density. 
are to assess long-term efficacy of relugolix 
40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
104 weeks on dysmenorrhea and NMPP, 
common and burdensome symptoms of 
endometriosis.  The study will also evaluate 
safety of relugolix 40 mg once daily co-
administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks, 
among patients who previously completed a 
24-week treatment period in one of the parent 
studies (MVT-601-3101 or MVT-601-3102), 
including adverse events and change in bone 
mineral density. 
Section 4.2 
Discussion of 
Study Design, 
Including Dosing 
Data from a phase 2 study in women with 
endometriosis demonstrated relugolix 40 mg 
once daily (N = 101) suppressed estradiol levels 
to below 20 pg/mL in the majority of women, 
and results were similar to those in the group of 
women treated with leuprolide subcutaneous 
injection, 3.75 mg. 
Data from a phase 2 study in women with 
endometriosis demonstrated relugolix 40 mg 
once daily suppressed estradiol levels to below 
20 pg/mL in the majority of women, and results 
were similar to those in the group of women 
treated with leuprolide subcutaneous injection, 
3.75 mg. 
Omitted for readability. 
Section 4.2 
Discussion of 
Study Design, 
Including Dosing 
Although relugolix doses of 20 mg and 10 mg 
once daily had less bone mineral density loss, 
these doses did not provide adequate relief from 
endometriosis-associated pain to move forward 
into phase 3 clinical development and, based on 
the DXA data from the phase 2 study, are not 
expected to prevent bone mineral density loss in 
a significant majority of women over 52 weeks 
of treatment. 
The co-administration of hormonal add-back 
therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the 
adverse impact of the hypoestrogenic state on 
bone mineral density through 52 weeks of 
treatment, as well as on vasomotor symptoms 
Although relugolix doses of 20 mg and 10 mg 
once daily had less bone mineral density loss, 
these doses did not provide adequate relief from 
endometriosis-associated pain to move forward 
into phase 3 clinical development and, based on 
the DXA data from the phase 2 study, are not 
expected to prevent bone mineral density loss in 
a significant majority of women over 104 weeks 
of treatment. 
The co-administration of hormonal add-back 
therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the 
adverse impact of the hypoestrogenic state on 
bone mineral density through 104 weeks of 
treatment, as well as on vasomotor symptoms 
Updated to reflect extension of 
treatment to 104 weeks. 


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such as hot flushes, but without substantial effect 
on the beneficial decrease in dysmenorrhea and 
NMPP. 
such as hot flushes, but without substantial effect 
on the beneficial decrease in dysmenorrhea and 
NMPP. 
Section 4.2 
Discussion of 
Study Design, 
Including Dosing 
This open-label extension study will allow for a 
description of long-term efficacy data and safety 
for an additional 28 weeks of treatment, 
providing approximately 1 year of efficacy and 
safety data from the women originally 
randomized to relugolix in studies 
(MVT-601-3101 and MVT-601-3102). 
This open-label extension study will allow for a 
description of long-term efficacy data and safety 
for an additional 80 weeks of treatment, 
providing approximately 1 year of efficacy and 
safety data from the women originally 
randomized to relugolix in studies 
(MVT-601-3101 and MVT-601-3102). 
Updated timing elements to 
reflect extension to 80 weeks of 
treatment in this study. 
Section 4.3.1 
Exclusion Criteria 
The presenting visual acuity score has decreased 
by 10 or more points at the Week 24/Baseline 
visit relative to the parent study Baseline visit; 
11. Has a decline in presenting visual acuity 
score, as defined below (unless explained 
by refractive error or approved by the 
sponsor): 
a. 90 or lower and five or more points 
lower at Week 24/Baseline visit 
relative to the parent study Baseline 
visit; or 
b. The presenting visual acuity score has 
decreased by ten or more points at the 
Week 24/Baseline visit relative to the 
parent study Baseline visit. 
Clarified visual acuity criteria. 
Section 4.4 
Method of 
Assigning Patients 
to Treatment 
Group and Patient 
Identification 
Number 
This extension study is a single-arm study, and 
thus all eligible patients are assigned to the same 
treatment group of relugolix 40 mg 
co-administered with low-dose of estradiol and 
norethindrone acetate (see Section 5.1 for 
treatment details). 
This extension study is a single-arm, open-label 
study, and thus all eligible patients are assigned 
to the same treatment group of relugolix 40 mg 
co-administered with low-dose of estradiol and 
norethindrone acetate (see Section 5.1 for 
treatment details). 
Added clarification on the 
open-label nature of the study. 
Section 4.5 
Removal of 
Patients from 
Therapy 
Completion of the Week 52 visit defines 
completion of the study.  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 
Completion of the Week 104 visit defines 
completion of the study.  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 
Updated to reflect extension of 
treatment to 104 weeks. 


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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 Early Termination visit (see the Week 52 
visit on the Schedule of Activities, Section 1.1) 
and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study 
drug treatment (ie, after the patient’s last dose of 
study medication). 
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 Early Termination visit (see the Week 104 
visit on the Schedule of Activities, Section 1.1) 
and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study 
drug treatment (ie, after the patient’s last dose of 
study medication). 
Section 4.5 
Removal of 
Patients from 
Therapy 
• If the patient, in the opinion of the 
investigator or the medical monitor, is grossly 
noncompliant with the protocol’s 
requirements.  Gross noncompliance includes 
< 75% compliance with the study drug over 
> 2 consecutive months; missing multiple 
study visits; and persistent (> 2 consecutive 
months) with < 50% of the required number 
of days of eDiary completion.  Investigators 
will follow up with the patient and encourage 
compliance with study drug or eDiary prior to 
discontinuing her from the study; 
• If the patient, in the opinion of the 
investigator or the medical monitor, is 
grossly noncompliant with the protocol’s 
requirements.  Gross noncompliance includes 
< 75% compliance with the study drug over 
> 2 consecutive months; missing multiple 
study visits; and persistent (> 2 consecutive 
months) noncompliance (< 50% of the 
required number of days) with eDiary 
completion up to Week 52 or persistent 
(≥ 2 eDiary collection cycles) 
noncompliance (< 50% of the required 
number of days) with eDiary completion 
from Week 52 to Week 104.  Investigators 
will follow up with the patient and encourage 
compliance with study drug or eDiary prior 
to discontinuing her from the study; 
Added clarification on timing 
of eDiary collection. 
Section 4.6 
Contraception/ 
Pregnancy 
Avoidance 
Urine pregnancy tests will be performed at 
monthly intervals during the study (including just 
prior to receiving the first dose of study drug), 
and patients will receive continued guidance with 
respect to the avoidance of pregnancy as part of 
the study procedures. 
Urine pregnancy tests will be performed 
according to the Schedule of Activities 
(Table 1-1; including just prior to receiving the 
first dose of study drug), and patients will 
receive continued guidance with respect to the 
avoidance of pregnancy as part of the study 
procedures.  Patients should call the 
investigator immediately if they suspect they 
may be pregnant. 
Changed for consistency so that 
pregnancy tests would coincide 
with patient visits from 
Week 52 to Week 104. 


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Section 5.1 
Treatments 
Administered 
In this extension study, all patients will receive 
the following open-label oral study treatment: 
• 
28 weeks of relugolix 40 mg tablet plus a 
capsule containing a tablet of 1.0 mg 
estradiol and 0.5 mg norethindrone acetate. 
In this extension study, all patients will receive 
the following open-label oral study treatment: 
• 80 weeks of relugolix 40 mg tablet plus a 
capsule containing a tablet of 1.0 mg 
estradiol and 0.5 mg norethindrone acetate. 
Updated timing elements to 
reflect extension to 80 weeks of 
treatment in this study. 
Section 5.1 
Treatments 
Administered 
Table 5-1 
Relugolix:  Oral once daily/28 weeks 
E2/NETA:  Oral once daily/28 weeks 
Table 5-1 
Relugolix:  Oral once daily/80 weeks 
E2/NETA:  Oral once daily/80 weeks 
Updated timing elements to 
reflect extension to 80 weeks of 
treatment in this study. 
Section 5.4 
Directions for 
Administration 
On Week 24/Baseline 1 and Week 52 clinic visit 
days, study drug will be administered in the 
clinic rather than at home (see Schedule of 
Activities in Section 1.1). 
On Week 24/Baseline 1, Week 52, and 
Week 104 clinic visit days, study drug will be 
administered in the clinic rather than at home 
(see Schedule of Activities in Section 1.1). 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 5.6 
Storage, 
Packaging, and 
Labeling 
Further guidance and information for final 
disposition of unused study drug are provided in 
the Study Reference Manual and Pharmacy 
Manual. 
Further guidance and information for final 
disposition of unused study drug are provided in 
the Investigator Site File. 
Updated referenced document. 
Section 5.6 
Storage, 
Packaging, and 
Labeling 
Please see Appendix 1 for a list of protocol-
specified analgesics.  Further details on analgesic 
medication are provided in the Study Reference 
Manual. 
Please see Appendix 1 for a list of protocol-
specified analgesics.  Further details on analgesic 
medication are provided in the Investigator Site 
File. 
Updated reference document. 
Section 5.9 
Study Drug 
Accountability and 
Treatment 
Compliance 
Patients should complete their eDiary each day 
on study and should bring all unused and used 
study drug to each study visit.  At the Week 
24/Baseline visit and Week 52/ET visit, all used 
and unused study drug kits should be retained at 
the site. At all other visits, only used study drug 
kits should be retained at the site. 
Patients should complete their eDiary each day 
on study and should bring all unused and used 
(including partially used) study drug kits to 
each study visit.  At the Week 24/Baseline visit 
and Week 104/Early Termination visit, all 
used, partially used, and unused study drug kits 
should be retained at the site.  At all other visits, 
only fully used study drug kits should be retained 
at the site. 
Clarified study drug 
accountability language and 
updated timing elements to 
reflect extension of study 
treatment to 104 total weeks of 
treatment. 
Section 5.10.1 
Prohibited 
Medications 
 
Table 5-2 
Analgesics:  Cannabinoids 
Clarification that cannabinoids 
are prohibited during this study. 


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Section 5.10.2 
Permitted 
Medications 
All concomitant medications used during the 
study will be recorded, including the drug 
generic name, dose amount, route of 
administration, start date, and stop date. 
All concomitant medications used during the 
study will be recorded in the electronic Case 
Report Forms (eCRFs), including the drug 
generic name, dose amount, route of 
administration, start date, and stop date. 
Clarified where concomitant 
medications should be 
recorded. 
Section 6.1 
Schedule of 
Observations and 
Procedures 
Further details of the procedures are provided in 
the Study Reference Manual. 
Further details of the procedures are provided in 
the Investigator Site File. 
Updated referenced document. 
Section 6.2 
Open-Label 
Treatment Period 
Open-Label Treatment Period 
(Week 24/Baseline to Week 52) 
Open-Label Treatment Period 
(Week 24/Baseline to Week 104) 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 6.2 
Open-Label 
Treatment Period 
 
If necessary for logistical reasons (eg, delayed 
availability of study drug supply on site, 
others), and with sponsor/designee approval, 
the first dose of open label study drug for 
MVT-601-3103 may be administered up to 
10 days following the parent study 
Week 24/Baseline visit.  If the first dose of 
study drug is not given during this up to 
10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse 
event reporting, eDiary completion, etc.). 
Added clarification that the first 
dose of study drug could be 
initiated up to 10 days after 
completion of the parent study 
to allow for logistical issues. 
Section 6.2 
Open-Label 
Treatment Period 
Patients will continue recording data in their 
eDiary daily and taking protocol-specified 
analgesics as needed.  Following the 
Week 24/Baseline visit, on-treatment study visits 
will occur at Weeks 28, 32, 36, 40, 44, 48, 
and 52.  Sites will monitor diary completion 
using the Trial Manager web portal throughout 
the study. 
Patients will continue recording data in their 
eDiary daily and taking protocol-specified 
analgesics as needed until Week 52.  After 
Week 52, the eDiary will be collected on the 
following schedule:  Week 57 to the Week 65 
visit, Week 71 to the Week 78 visit, Week 85 
to the Week 91 visit, and Week 98 to the 
Week 104 visit.  Following the 
Week 24/Baseline visit, on-treatment study visits 
will occur at Weeks 28, 32, 36, 40, 44, 48, 52, 
65, 78, 91, and 104.  Sites will monitor diary 
Updated to reflect extension of 
treatment to 104 weeks. 


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completion using the Trial Manager web portal 
throughout the study. 
A telephone call will be performed at 
Weeks 57, 71, 85 and 98.  The following 
activities should be completed: a concomitant 
medication review, an evaluation of adverse 
events, a review of study medication 
compliance, a reminder of compliance with 
non-hormonal contraception requirements 
and the need to call the investigator if 
pregnancy is suspected, and a reminder to the 
patient to start recording in the eDiary daily. 
Section 6.2 
Open-Label 
Treatment Period 
• 
Paper questionnaires 
− 
PGA for function 
− 
EHP Work Domain [Week24/Baseline 
and Week 52 only] 
• 
Paper questionnaires 
− 
PGA for function 
− 
EHP Work Domain [Week24/Baseline, 
Week 52, Week 78, and Week 104 
only] 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 6.2 
Open-Label 
Treatment Period 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see MVT-
601-3101 protocol for details.  Safety monitoring 
for this study includes physical examination, 
clinical laboratory tests, pregnancy tests, and 
adverse event collection at each visit.  Clinical 
chemistries will be collected at each visit.  A 
complete blood count will be collected at Week 
24/Baseline, Week 28, Week 36, and Week 52.  
At the Week 24/Baseline visit and Week 52 visit, 
additional tests include fasting (at least 8 hours, 
other than water) glucose, lipid profile, and 
hemoglobin A1c. 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see 
MVT-601-3101 protocol for details), at 
Week 52 for all subjects.  All patients will be 
eligible for the Week 104 biopsy; however, 
patients will have the option to opt out.  Safety 
monitoring for this study includes physical 
examination, clinical laboratory tests, pregnancy 
tests, and adverse event collection at each visit.  
Clinical chemistries will be collected at each 
visit.  A complete blood count will be collected 
at Week 24/Baseline, Week 28, Week 36, 
Week 52, Week 65, Week 78, and Week 104.  
At the Week 24/Baseline visit, Week 52 visit, 
and Week 104 visit, additional tests include 
fasting (at least 8 hours, other than water) 
glucose, lipid profile, and hemoglobin A1c. 
Updated to include an 
endometrial biopsy at Week 52 
and an optional endometrial 
biopsy at Week 104 in order to 
evaluate endometrial changes 
over the entire course of the 
study. 


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Section 6.2 
Open-Label 
Treatment Period 
Electrocardiograms will be done at the Week 
24/Baseline and at the Week 52/Early 
Termination visits. 
Electrocardiograms will be performed at the 
Week 24/Baseline and the Week 52visits. 
Updated to reflect that the last 
scheduled ECG for the study is 
planned for the Week 52 visit. 
Section 6.2 
Open-Label 
Treatment Period 
 
Bone densitometry will occur at the Week 
24/Baseline, Week 36, Week 52, and 
Week 104/Early Termination visits.  Follow-up 
of bone densitometry findings will proceed 
according to the rules described in 
Section 6.5.2.6. 
 
Added language regarding the 
assessment of bone 
densitometry and follow-up 
procedures. 
Section 6.3 
Early Termination 
and Follow-up 
Visit 
All patients withdrawing from the study prior to 
Week 52 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 52; however, for 
patients whose last dose of study drug is during 
Week 32 or earlier or within 4 weeks after 
completion of the Week 36 or Week 52 scan, the 
bone densitometry does not need to be 
performed.  This procedure may be performed, 
however, at the investigator’s discretion, if it aids 
in follow-up of an ongoing adverse event(s). 
All patients withdrawing from the study prior to 
Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 104.  Bone 
densitometry may be performed, at the 
investigator’s discretion, if it aids in follow-up of 
an ongoing adverse event(s). 
Follow-up of bone densitometry findings for 
patients who terminate from the study early 
will proceed according to the rules provided 
in Section 6.5.2.6. 
Clarified bone densitometry 
assessment at the early 
termination visit. 
Section 6.3 
Early Termination 
and Follow-up 
Visit 
Patients (including those who complete the 
Week 52 visit and those who withdraw early 
from this study) will have a Follow-up visit 
approximately 30 days after the last dose of 
study drug, or prior to the date of initiation of 
another investigational agent or hormonal 
therapy affecting the hypothalamic-pituitary-
gonadal axis or surgical intervention or other 
invasive procedure for endometriosis, whichever 
occurs first.  However, for patients who enroll 
directly into another relugolix clinical study upon 
completion of the Week 52 visit, the Follow-up 
visit may be waived. 
Patients (including those who complete the 
Week 104 visit and those who withdraw early 
from this study) will have a Follow-up visit 
approximately 30 days after the last dose of 
study drug, or prior to the date of initiation of 
another investigational agent or hormonal 
therapy affecting the hypothalamic-pituitary-
gonadal axis or surgical intervention or other 
invasive procedure for endometriosis, whichever 
occurs first.  However, for patients who enroll 
directly into another relugolix clinical study upon 
completion of the Week 104 visit, the Follow-up 
visit may be waived. 
Updated to reflect extension of 
treatment to 104 weeks. 


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Section 6.4 
Unscheduled Visits 
In addition, procedures such as vital signs, 
weight, symptom-directed brief physical 
examination, central safety laboratory 
assessment, urine pregnancy testing, 
pharmacodynamic sampling, 12-lead ECG, study 
drug compliance and dispensation, eDiary 
review, dispensation or prescription of protocol-
specified analgesics, etc, may be conducted as 
needed. 
In addition, procedures such as vital signs, 
weight, complete physical examination, sign- 
and symptom-directed physical examination, 
clinical laboratory assessment, urinalysis, urine 
pregnancy testing, pharmacodynamic sampling, 
12-lead ECG, study drug compliance and 
dispensation, eDiary review, dispensation or 
prescription of protocol-specified analgesics, etc, 
may be conducted as needed. 
Clarified safety assessments 
that could be performed at 
unscheduled visits. 
Section 6.5.1.1 
Pharmacodynamics 
Sample Collection 
A blood sample for the pharmacodynamic 
analysis of serum estradiol will be collected 
predose at the visits indicated in the study 
Schedule of Activities (see Section 1.1), other 
than at the Week 52 or the Early Termination 
visit, when no dose is administered. 
A blood sample for the pharmacodynamic 
analysis of serum estradiol will be collected 
predose at the visits indicated in the study 
Schedule of Activities (see Section 1.1), other 
than at the Week 104 or the Early Termination 
visit, when no dose is administered. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 6.5.1.2 
Patient eDiary 
All women enrolled in the study will continue to 
use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete 
daily eDiary entries including NRS pain scores, 
menstruation information, analgesic drug use, 
date and time of study drug administration, and 
sB&B scale scores. 
All women enrolled in the study will continue to 
use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete 
daily eDiary entries including NRS pain scores, 
menstruation information, analgesic drug use, 
date and time of study drug administration, and 
sB&B scale scores until Week 52.  After Week 
52, the eDiary scores will be entered over four 
eDiary collection cycles on the following 
schedule:  Week 57 to the Week 65 visit, Week 
71 to the Week 78 visit, Week 85 to the 
Week 91 visit, and Week 98 to the Week 104 
visit. 
Clarified timing of patient 
eDiary completion. 
Section 6.5.2.3 
Physical 
Examinations 
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 
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.  The 
Clarified which physical 
examinations will include a 
breast examination. 


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the patient to assess for clinically significant 
changes from the Baseline assessment. 
physical examinations at Week 52 and 
Week 104 will include a breast examination. 
Section 6.5.2.4 
Clinical Laboratory 
Samples 
All protocol-required laboratory assessments 
must be conducted in accordance with the Study 
Laboratory Manual and the protocol Schedule of 
Activities (see Section 1.1). 
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). 
Updated referenced document. 
Section 6.5.2.6 
Bone Mineral 
Density 
Patients with a bone mineral density loss of > 3% 
at lumbar spine or total hip at their 
Week 52/Early Termination visit (or most recent 
scan if the Week 52/ET scan was not done) 
relative to parent study Baseline measurement 
will undergo another bone densitometry scan at 
6 (± 1) months and will be contacted to obtain 
information about medications and conditions 
(eg, pregnancy) that might affect bone mineral 
density through the time of the follow-up bone 
densitometry.  The follow-up bone densitometry 
will be submitted for central reading. 
Determination of bone mineral density by 
DXA at Early Termination and follow-up of 
findings will proceed according to the 
following rules: 
• 
For Early Termination occurring between 
Week 24 and Week 52: 
− 
For Early Termination occurring 
before Week 36, DXA is not required 
at Early Termination visit unless it 
will aid in the assessment of an 
adverse event. 
Follow-up DXA required at 6 months 
(± 1 month) if most recent DXA bone 
mineral density loss at lumbar spine 
(L1-L4) or total hip was > 2% 
relative to the parent study baseline. 
− 
For Early Termination occurring 
after Week 36, DXA is required at 
Early Termination unless a DXA 
result is available from within six 
weeks prior to Early Termination. 
Follow-up DXA is required at 
6 months (± 1 month) if the most 
recent DXA scan was at Week 24 and 
bone mineral density loss at the 
lumbar spine (L1-L4) or total hip was 
Added clarification for when 
DXA scans would be 
conducted and the follow-up 
rules for DXA results. 


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> 2%, relative to the parent study 
baseline. 
Follow-up DXA is required at 6 
months (± 1 month) if on the most 
recent DXA, bone mineral density 
loss at the lumbar spine (L1-L4) or 
total hip was > 3%, relative to the 
parent study baseline. 
• 
For Early Termination occurring between 
Week 52 and Week 104: 
− 
DXA is required at Early 
Termination unless a DXA result is 
available from within six weeks prior 
to Early Termination. 
• 
Follow-up DXA is required at 6 months 
(± 1 month) if on the most recent DXA, 
bone mineral density loss at the lumbar 
spine (L1-L4) or total hip was > 7%, 
relative to parent study baseline. 
The follow-up bone densitometry will be 
submitted for central reading. 
Section 6.5.2.6 
Bone Mineral 
Density 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 52 visit, then the follow-up bone 
densitometry scan at 6 (±1) months conducted 
under this protocol may be waived. 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 104 visit, then the follow-up bone 
densitometry scan at 6 (±1) months conducted 
under this protocol may be waived. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 6.5.2.7 
Endometrial 
Biopsy 
 
For patients in parent study MVT-601-3101, 
an endometrial biopsy is performed at the 
Week 24 visit.  If the required Week 24 biopsy 
is inadequate for diagnosis, it should be 
repeated, and a sample submitted to the 
central laboratory.  If the second sample is 
inadequate, ensure an endometrial thickness 
With the addition of an 
endometrial biopsy at Week 52 
and optional endometrial 
biopsy at Week 104, details on 
endometrial biopsy were added. 


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has been reported from the Week 24 
transvaginal ultrasound and contact the 
medical monitor to review the findings.  
Patients who have endometrial hyperplasia or 
endometrial carcinoma will be withdrawn 
from study drug treatment and followed per 
instructions in the parent study protocol. 
Additional assessment of the effects of 
relugolix co-administered with low-dose 
estradiol and norethindrone acetate on the 
endometrium will be performed at Week 52 
for all patients.  At Week 104, all patients will 
be eligible for an additional endometrial 
biopsy; however, patients will have the option 
to opt out.  Patient participation in the 
Week 104 endometrial biopsy is voluntary and 
refusal to participate will not preclude entry 
into the study or indicate withdrawal from the 
study. 
The Week 52 and Week 104 endometrial 
biopsy samples will be submitted to the 
central laboratory.  If the Week 52 or 
Week 104 biopsy specimen is inadequate, a 
transvaginal ultrasound for endometrial 
thickness should be obtained and read locally.  
The transvaginal ultrasound findings will be 
used to determine if further action is 
required: 
• Endometrial thickness ≤ 5 mm – no 
further action required. 
• Endometrial thickness > 5 mm at any 
location or any other endometrial 
abnormality – repeat endometrial 
sampling.  Contact medical monitor if 
second specimen is inadequate for 
diagnosis. 


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Unscheduled endometrial biopsies may also be 
performed when medically indicated and as 
deemed necessary by the investigator.  The 
investigator should obtain approval from the 
sponsor to perform an unscheduled 
endometrial biopsy, unless urgently indicated.  
Additional consent is not required in this 
circumstance. 
Section 6.5.2.8 
Status of 
Menstruation 
Recovery 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 52 visit, follow-up under this protocol to 
determine the status of menstruation recovery 
may not be required. 
If the patient enrolls directly into another 
relugolix clinical study upon completion of the 
Week 104 visit, follow-up under this protocol to 
determine the status of menstruation recovery 
may not be required. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 7.7 
Study Drug 
Overdose 
Management 
If possible, obtain a plasma sample for 
pharmacokinetic 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); 
 
Originally included in error.  
Pharmacokinetic samples are 
not being collected for this 
study. 
Section 7.10 
Benefit/Risk 
Assessment 
Table 7-2 
Bone mineral density will be monitored at the 
Week 24/Baseline, Week 36, and Week 52/Early 
Termination visits with specified discontinuation 
and follow-up criteria and all fractures will be 
reported as adverse events. 
 
12-lead ECG at the Week 24/Baseline and 
Week 52/Early Termination visits, and as 
clinically applicable; withdrawal for QTcF 
> 500 msec. 
Table 7-2 
Bone mineral density will be monitored at the 
Week 24/Baseline, Week 36, Week 52, and 
Week 104/Early Termination visits with 
specified discontinuation and follow-up criteria 
and all fractures will be reported as adverse 
events. 
 
12-lead ECG at the Week 24/Baseline and 
Week 52/Early Termination visits, and as 
clinically applicable; withdrawal for QTcF 
> 500 msec. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 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 
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 
Updated referenced document. 


Clinical Study Protocol:  MVT-601-3103 
Amendment 2:  11 Dec 2018 
Myovant Sciences GmbH 
35 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 2 
Rationale 
requirements, reporting of serious adverse 
events, and to ensure a full understanding of the 
Study Reference Manual with the site personnel. 
requirements, reporting of serious adverse 
events, and to ensure a full understanding of the 
Investigator Site File with the site personnel. 
Section 9 
Statistical 
Considerations and 
Data Analyses 
 
There will be two analyses: one at Week 52 
and one at Week 104.  A clinical study report 
will be generated from each analysis. 
Clarified plan to conduct two 
analyses (one with data through 
52 weeks of treatment and one 
with data through 104 weeks of 
treatment) and develop a 
separate clinical study report 
for each analysis. 
Section 9.1 
Randomization 
Methods 
This is a single-arm, open-label extension study; 
patients are not randomized.  All patients who 
have entered the extension study will be treated 
with open-label relugolix and low-dose hormonal 
add-back therapy for 28 weeks. 
This is a single-arm, open-label extension study; 
patients are not randomized.  All patients who 
have entered the extension study will be treated 
with open-label relugolix and low-dose hormonal 
add-back therapy for 80 weeks. 
Updated timing elements to 
reflect extension to 80 weeks of 
treatment in this study. 
Section 9.4 
Efficacy Analyses 
A responder at a given time point and for a 
specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that 
type of pain from Baseline greater than or equal 
to a pre-determined threshold and who did not 
have an increase in the use of rescue analgesic 
medications for endometriosis-associated pain 
compared with the use at Baseline. 
A responder at a given time point and for a 
specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that 
type of pain from Baseline in the parent study 
greater than or equal to a pre-determined 
threshold and who did not have an increase in the 
use of rescue analgesic medications for 
endometriosis-associated pain compared with the 
use at Baseline. 
Clarified which baseline visit is 
being referred to. 
Section 9.4 
Efficacy Analyses 
Descriptive statistics will be provided for 
efficacy endpoints (listed below) similar to those 
used for the parent studies. 
• 
Change from the parent study Baseline to 
Week 52 in the EHP-30 Pain Domain scores; 
Note:  ‘Week 52/EOT’ were deleted from all 
subsequent endpoints listed. 
Descriptive statistics will be provided for 
efficacy endpoints (listed below) similar to those 
used for the parent studies at Week 52 and 
Week 104. 
• Change from the parent study Baseline to 
Week 52 in the EHP-30 Pain Domain scores; 
Note:  ‘Week 52/EOT’ were deleted from all 
subsequent endpoints listed. 
Clarified timepoints to be used 
in efficacy analyses. 
Section 9.5 
Safety Analyses 
For the relugolix add-back treatment Group A, 
the lower bound of the 95% CI for (arithmetic) 
For the relugolix add-back treatment Group A, 
the lower bound of the 95% CI for (arithmetic) 
Updated to reflect extension of 
treatment, and to provide a 


Clinical Study Protocol:  MVT-601-3103 
Amendment 2:  11 Dec 2018 
Myovant Sciences GmbH 
36 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 2 
Rationale 
mean percentage change at Week 52 from parent 
study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-
specified clinically acceptable threshold of -2.2% 
to evaluate magnitude of bone mineral density 
loss after 52 weeks of treatment.  If the lower 
bound is > -2.2%, the bone mineral density loss 
for the relugolix add-back treatment will be 
considered insignificant.  As supportive analysis, 
least square means and 95% CI for percent 
change at Week 52 from parent study Baseline in 
bone mineral density will be provided based on 
mixed effects model (assumed missing at 
random) for each parent study treatment group. 
mean percentage change at Week 52 from parent 
study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-
specified clinically acceptable threshold of -2.2% 
to evaluate magnitude of bone mineral density 
loss after 52 weeks of treatment.  If the lower 
bound is > -2.2%, the bone mineral density loss 
for the relugolix add-back treatment will be 
considered insignificant.  As supportive analysis, 
least square means and 95% CI for percent 
change at Week 52 from parent study Baseline in 
bone mineral density will be provided based on 
mixed effects model (assumed missing at 
random) for each parent study treatment group.  
The 95% CI for mean percentage change at 
Week 104 from parent study Baseline in bone 
mineral density lumbar spine (L1-L4) will be 
provided along with descriptive statistics for 
bone mineral density loss at Week 104 as 
supportive analyses. 
description of analyses to be 
conducted on data from 
Week 104. 
Section 9.5 
Safety Analyses 
All data will be listed and summarized by visit.  
The absolute change and percent change from 
parent study Baseline to Weeks 36 and 52 and 
associated 95% CIs will be presented by the 
parent study treatment group for each bone 
mineral density parameter. 
All data will be listed and summarized by visit.  
The absolute change and percent change from 
parent study Baseline to Weeks 36, 52, and 104 
and associated 95% CIs will be presented by the 
parent study treatment group for each bone 
mineral density parameter. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 9.6 
Pharmacodynamics 
Analyses 
The change from the parent study Baseline to 
Week 52 in pre-dose concentrations of serum 
estradiol will be summarized.  Percentage of 
patients with concentrations of serum estradiol 
levels < 10 pg/mL and < 20 pg/mL will be 
provided. 
The change from the parent study Baseline to 
Week 52 and to Week 104 in predose 
concentrations of serum estradiol will be 
summarized.  Percentage of patients with 
concentrations of serum estradiol levels 
< 10 pg/mL and < 20 pg/mL will be provided. 
Updated to reflect extension of 
treatment to 104 weeks. 
Section 9.7 
Exploratory 
Analyses 
Descriptive summaries by treatment group and 
between treatment group comparisons (when 
applicable) will be provided for the following 
exploratory endpoints.  Details on the endpoint 
Descriptive summaries by treatment group and 
between treatment group comparisons (when 
applicable) will be provided for the following 
exploratory endpoints.  Details on the endpoint 
Updated to reflect extension of 
treatment to 104 weeks. 


Clinical Study Protocol:  MVT-601-3103 
Amendment 2:  11 Dec 2018 
Myovant Sciences GmbH 
37 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 2 
Rationale 
analyses including deviations, handling of 
missing data, and statistical methods will be 
provided in the SAP.  The following exploratory 
endpoints will be assessed: 
• 
Change from Baseline to Week 52/EOT in 
the EHP-30 scale total score; 
• 
Change from Baseline to Week 52/EOT in 
the EHP Work Domain score; 
• 
Change from parent study Baseline to 
Week 52/EOT in the EQ-5D-5L. 
analyses including deviations, handling of 
missing data, and statistical methods will be 
provided in the SAP.  The following exploratory 
endpoints will be assessed at Week 52 and 
Week 104: 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• Change from parent study Baseline in the 
EQ-5D-5L. 
Section 9.8 
Interim Analyses 
There are no planned interim efficacy analyses. 
 
An interim analysis will be conducted at 
Week 52 in which all efficacy and safety 
endpoints will be assessed as described above.  
A clinical study report will be generated based 
on these data to support submission of 1-year 
data. 
Clarified plan to conduct two 
analyses (one with data through 
52 weeks of treatment and one 
with data through 104 weeks of 
treatment) and develop a 
separate clinical study report 
for each analysis. 
Section 10.1.6 
Electronic Case 
Report Forms 
For each patient enrolled, an eCRF must be 
completed as specified in the Study Reference 
Manual. 
For each patient enrolled, an eCRF must be 
completed as specified in the Investigator Site 
File. 
Updated referenced document. 
Section 10.2.3 
Study Report 
A clinical study report will be prepared and 
provided to the regulatory authority(ies). 
A clinical study report will be prepared and 
provided to the regulatory authority(ies) at 
Week 52 and a second clinical study report 
will be prepared at the end of the study 
(Week 104). 
Clarified plan to conduct two 
analyses (one with data through 
52 weeks of treatment and one 
with data through 104 weeks of 
treatment) and develop a 
separate clinical study report 
for each analysis. 
 


1 
CLINICAL STUDY PROTOCOL 
Study Title: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3103 
Indication: 
Treatment of Endometriosis-Associated Pain 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Regulatory Identifiers: 
IND No.  076642 
EudraCT No.  2017-004066-10 
Version and 
Effective Date: 
Original:  06 NOV 2017 
Amendment 1: 20 MAR 2018 
Amendment 2: 11 Dec 2018 
Amendment 3: 01 JUL 2020 
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. 


Cli nic al St u d y Pr ot oc ol:  M V T- 6 0 1- 3 1 0 3 
A me n d me nt 3, 0 1  J ul 2 0 2 0 
M y o va nt Scie nces G m b H 
2 
C O N FI D E N TI A L 
S P O N S O R SI G N A T U R E P A G E 
S PI RI T E X T E N SI O N:  A n I nter nati o nal P hase 3 O pe n- La bel, Si n gle- Ar m, Safet y a n d Efficac y 
E xte nsi o n St u d y t o E val uate Rel u g oli x C o- A d mi nistere d wit h L o w- D ose Estra di ol a n d 
N oret hi n dr o ne Acetate i n W o me n wit h E n d o metri osis- Ass ociate d Pai n 
Pr ot oc ol N u m ber:  M V T- 6 0 1- 3 1 0 3 A me n d me nt 3 
T his pr ot oc ol has bee n a p pr o ve d b y M y o va nt Scie nces G m b H.  T he f oll o wi n g si g nat ures d oc u me nt 
t his a p pr o val. 
Date 
Date 
Date 
D o c u Si g n E n v el o p e I D: 8 3 D 6 0 8 3 3- 7 6 C 0- 4 D 3 E- B 1 4 8- 1 C A F 7 1 9 9 C 6 3 4
3 0-J u n- 2 0 2 0 | 6: 2 9 P M P D T
0 1-J ul- 2 0 2 0 | 2: 3 1 P M P D T
0 1-J ul- 2 0 2 0 | 1 2: 1 9 P M P D T
P P D


Clinical Study Protocol:  MVT-601-3103 
Amendment 3, 01 Jul 2020 
Myovant Sciences GmbH 
3 
CONFIDENTIAL 
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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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
novel coronavirus 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dehydroepiandrosterone 
DTP 
direct-to-patient 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EHP 
Endometriosis Health Profile 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
EU 
European Union 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HR 
heart rate 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NMPP 
nonmenstrual pelvic pain 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 


Clinical Study Protocol:  MVT-601-3103 
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Term 
Explanation 
PLD 
phospholipidosis 
QTc 
corrected QT (interval) 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
SDV 
source data verification 
SNRI 
serotonin and norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TCA  
tricyclic antidepressant 
ULN 
upper limit of normal 
US 
United States 
W 
Week 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced  


Clinical Study Protocol:  MVT-601-3103 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Safety and Efficacy Extension Study to Evaluate Relugolix Co-Administered 
with Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain 
Protocol Number 
MVT-601-3103 
Location 
Multinational, including North and South America, Europe, Africa, 
New Zealand, and Australia 
Study Centers 
Approximately 320 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with endometriosis-associated pain 
Number of Patients 
Planned 
Approximately 800 
Study Objectives 
In women with endometriosis-associated pain, the study objectives are as 
follows: 
Primary Efficacy Objectives 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated pain. 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 104 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on endometriosis-associated pain. 
 
Secondary Efficacy Objectives 
To be assessed at Week 52 and Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate, 
among patients who previously completed a 24-week treatment period in 
one of the parent studies (MVT-601-3101 or MVT-601-3102), on the 
following: 
o 
Function, as measured by the Endometriosis Health Profile (EHP)-30 
Pain Domain; 
o 
Dysmenorrhea, as measured by the Numerical Rating Scale (NRS) for 
dysmenorrhea; 
o 
Patient Global Impression of Change (PGIC) for dysmenorrhea; 
o 
Nonmenstrual pelvic pain (NMPP), as measured by the NRS for 
NMPP; 
o 
Overall pelvic pain, as measured by the NRS; 


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o 
Analgesic use; 
o 
PGIC for NMPP; 
o 
Dyspareunia, as measured by the NRS; 
o 
PGIC for dyspareunia; 
o 
Dyspareunia-related functional effects (Subject Modified Biberoglu 
and Behrman [sB&B]); 
o 
To determine the benefit of relugolix 40 mg once daily co-
administered with 24 weeks of low-dose estradiol and norethindrone 
acetate compared with placebo on function measured by the EHP-30 
Pain Domain; 
o 
Patient Global Assessment (PGA) for pain; 
o 
PGA for function; 
o 
Endometriosis-associated quality of life, as measured by the EHP-30 
Control and Powerlessness, Social Support, Emotional Well-Being, 
and Self-Image domains; 
o 
Dysmenorrhea-related functional effects (sB&B); 
o 
NMPP-related functional effects (sB&B). 
 
Safety Objectives 
• 
To evaluate the safety of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate for up to 104 weeks, 
among patients who previously completed a 24-week treatment period in 
one of the parent studies (MVT-601-3101 or MVT-601-3102), including: 
o Adverse events; 
o Changes in bone mineral density. 
 
Pharmacodynamic Objective 
• 
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 104 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
 
Exploratory Objective 
• 
To evaluate the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate on endometriosis-
associated quality of life (EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life outcomes (European 
Quality of Life Five-Dimension Five-Level Scale [EQ-5D-5L]) for up to 
104 weeks among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102). 
Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term efficacy 
and safety study that will enroll eligible patients who have completed their participation in one of the 
phase 3 randomized, double-blind, placebo-controlled parent studies (MVT-601-3101 or 
MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg once daily co-administered 
with low-dose- estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 80 weeks.  Approximately 


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800 women with endometriosis-associated pain will be enrolled.  The objectives of the study are to 
evaluate long-term efficacy and safety through up to 104 weeks of treatment (including treatment 
during the parent study) of relugolix co-administered with low-dose estradiol/norethindrone acetate.  
Eligible patients will have completed participation in one of the parent studies and consented to 
participate in this extension study.  Baseline procedures will be done at the same visit for this extension 
study (referred to as the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit 
from the parent study and will be defined as the date of completion of the last Week 24 procedure in 
the parent study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent study have 
been completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 24/Baseline 
visit.  No MVT-601-3103 study procedures will be performed until the consent form for this extension 
study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  Therefore, results of testing required for eligibility must be available on or prior 
to the Week 24/Baseline visit.  The administration of the first dose of study drug for MVT-601-3103 
will define enrollment into this study.  Study participants will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once 
daily for 80 weeks.  If necessary for logistical reasons (eg, delayed availability of study drug supply on 
site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  
If the first dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients will 
continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, analgesic 
use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  Only study-
specific rescue analgesic medications should be used starting with the Week 24/Baseline visit and 
through the Follow-Up visit and these medications will be taken for control of pain and not 
prophylactically.  Health-related quality of life questionnaires; PGIC for dysmenorrhea, NMPP, and 
dyspareunia; and PGA for pain and function will be completed during the visits on an electronic tablet 
or on paper, according to the Schedule of Activities (Section 1.1). 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via dual-energy x-ray absorptiometry (DXA).   
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, mammograms (for women 
≥ 40 years of age), endometrial biopsies, and bone mineral density with DXA. 
Determination of bone mineral density by DXA at Early Termination and follow-up of findings will 
proceed according to the following rules: 
• 
For Early Termination occurring between Week 24 and Week 52: 
− 
For Early Termination occurring before Week 36, DXA is not required at Early Termination 
visit unless it will aid in the assessment of an adverse event. 
− 
Follow-up DXA required at 6 months (± 1 month) if most recent DXA bone mineral density 
loss at lumbar spine (L1-L4) or total hip was > 2% relative to the parent study baseline. 
− 
For Early Termination occurring after Week 36, DXA is required at Early Termination unless a 


Clinical Study Protocol:  MVT-601-3103 
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DXA result is available from within six weeks prior to Early Termination. 
− 
Follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan was at Week 
24 and bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 2%, relative to 
the parent study baseline. 
− 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral 
density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to the parent study 
baseline. 
• 
For Early Termination occurring between Week 52 and Week 104: 
− 
DXA is required at Early Termination unless a DXA result is available from within six weeks 
prior to Early Termination. 
− 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral 
density loss at the lumbar spine (L1-L4) or total hip was > 7%, relative to parent study 
baseline. 
• 
If patients have 6-month post-treatment follow-up scans that show bone loss of > 1.5% at the 
lumbar spine and/or > 2.5% at total hip compared with parent study baseline, patients are strongly 
encouraged to come back to the clinic for an additional post-treatment follow-up scan 12 months 
from the date of the last dose of the study drug. 
• 
If patients have 12-month post-treatment follow-up scans that show bone loss of ≥ 3% at the 
lumbar spine and/or total hip compared with parent study baseline, patients are referred to and 
strongly encouraged to see a bone specialist for further evaluation of the bone loss. 
Note:  When a patient is referred to a bone specialist for evaluation and management, 
Myovant will provide a Bone Consultation Letter to the investigator for this additional 
bone consult and will request the site to provide a summary of the evaluation and 
management plan once the consultation is complete. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption 
(eg, medical procedure or medications) will be contacted by telephone 3 (+ 0.5) months after the 
Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses.  If a patient is lost to follow-up, three documented attempts should be made to 
contact the patient by telephone.  If unable to contact the patient by telephone, a certified letter must be 
sent to the patient. 
If the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 
visit, then the Follow-up visit and the follow-up procedures performed under this protocol, including 
the follow-up bone densitometry scan at 6 (±1) months and status of menstruation recovery, may be 
waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1. 
Completed 24 weeks of study drug treatment and study participation in either MVT-601-3101 
or MVT-601-3102; 
2. 
Has voluntarily signed and dated the informed consent form prior to initiation of any study-
specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures 
for this study will be done under the informed consent for the parent study. 


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3. 
Is not expected to undergo gynecological surgery or other surgical procedures for treatment of 
endometriosis (including ablation, shaving, or excision) during the study, including during the 
Follow-Up Period, and the patient does not desire such treatment during this time frame; 
4. 
Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. 
Has agreed to continue to use only study-specified analgesic medications during the study and 
is not known to be intolerant to these; 
6. 
Agrees to continue to use acceptable non-hormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days after 
the last dose of study drug.  However, the patient is not required to use the specified non-
hormonal contraceptive methods if she: 
a. 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. 
Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), 
at least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
c. 
Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. 
Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as noted above; 
e. 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study. 
1. 
Has had a surgical procedure for treatment of endometriosis at any time during the parent study 
(MVT-601-3101 or MVT-601-3102); 
2. 
Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is 
treated with opioids or requires analgesics for ≥ 7 days per month; 
3. 
Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, bilateral 
hip replacement, spinal hardware in the lumbar spine); 
4. 
Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study 
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA 
assessment of bone mineral density; 
5. 
Anticipated to use any prohibited medications as detailed in Section 5.10.1; 
6. 
Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. 
Known, suspected, or history of breast cancer; 
b. 
Known or suspected estrogen-dependent neoplasia; 
c. 
Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to 
the Week 24/Baseline visit; 
d. 
History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. 
Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. 
Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 


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CONFIDENTIAL 
disorders, including Factor V Leiden; 
g. 
Migraine with aura; 
h. 
History of porphyria; 
7. 
Has current active liver disease from any cause; 
8. 
Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
syndromes, etc); psoriasis not requiring or anticipated to require systemic therapy is permitted; 
9. 
Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, 
if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. 
Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of 
normal (ULN); or 
b. 
Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome 
or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 1 month after the last dose of study drug, or plans to donate ova during the study period 
or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 
90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the parent 
study Baseline visit; or 
b. 
The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 
12. Is inappropriate for participation in this study because of conditions that may interfere with 
interpretation of study results or prevent the patient from complying with study requirements, 
as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 80 weeks (Open-Label 
Treatment Period). 
Concomitant Medicinal Products Systematically Prescribed for All Study 
Patients 
Two protocol-specified analgesics include a first-line non-steroidal anti-
inflammatory drug and a second-line opioid or opioid/acetaminophen or 
opioid/paracetamol combination for endometriosis-related pain relief as 
required.  The specific analgesic drugs offered may differ for different 
countries or regions.  The analgesics for each patient will be the same as those 
prescribed for her during the parent study. 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made 
between the parent study Baseline and Week 52, and between the parent study 


Clinical Study Protocol:  MVT-601-3103 
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CONFIDENTIAL 
Baseline and the end of the extension study (Week 104) for the following 
parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg 
norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate 
in the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this 
extension study for all change from baseline-related endpoints.  The pain 
scores during the Baseline Pain Assessment Period of the parent study will 
establish the patient’s baseline for both the parent study and the extension 
study. 
 
Primary Efficacy Endpoints 
Week 52 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their NMPP NRS scores. 
Week 104 
• 
Proportion of women who respond or maintain response at 
Week 104/Early Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at 
Week 104/Early Termination, based on their NMPP NRS scores. 
 
Secondary Efficacy Endpoints 
To be assessed at Week 52 and Week 104, unless otherwise specified 
• 
Change from the parent study Baseline in the EHP-30 Pain Domain 
scores; 
• 
Change from the parent study Baseline in the mean dysmenorrhea NRS 
score; 
• 
Proportion of patients who are better or much better on the PGIC for 
dysmenorrhea (at Week 52 only); 
• 
Change from the parent study Baseline in the mean NMPP NRS score; 
• 
Change from the parent Baseline in the mean NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using analgesics; 
• 
Proportion of patients who are better or much better on the PGIC for 
NMPP (at Week 52 only); 
• 
Change from the parent study Baseline in the mean dyspareunia NRS 
scores; 
• 
Proportion of patients who are better or much better on the PGIC for 
dyspareunia (at Week 52 only); 


Clinical Study Protocol:  MVT-601-3103 
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CONFIDENTIAL 
• 
Change from the parent study Baseline in the mean dyspareunia 
functional impairment on the sB&B scale; 
• 
Change from the parent study Baseline in severity scores on the PGA for 
pain; 
• 
Proportion of responders based on their EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline in function impairment on the 
PGA for function; 
• 
Change from the parent study Baseline in each of the non-pain EHP-30 
domains (Control and Powerlessness, Social Support, Emotional Well-
Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period in 
dysmenorrhea-related functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period in NMPP-
related functional effects (sB&B). 
 
Safety Endpoints 
To be assessed at Week 52 and Week 104 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline in bone mineral density at 
the lumbar spine (L1-L4), femoral neck, and total hip as assessed by 
DXA. 
 
Pharmacodynamic Endpoint 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose concentrations of serum 
estradiol. 
 
Exploratory Endpoints 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale total score; 
• 
Change from Baseline in the EHP Work Domain score; 
• 
Change from parent study Baseline in the EQ-5D-5L. 
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
There will be two analyses: one at Week 52 and one at Week 104.  A clinical study report will be 
generated from each analysis. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Parent Study Groups A, B, and C) for the modified Intent-to-Treat Population.  The analyses 
methods for efficacy endpoints are similar to those used for the parent studies, unless otherwise 
specified in the statistical analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic medications, 
proportion of responders based on NMPP scores and use of rescue analgesic medications) will be 
calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 


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Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, and bone mineral density with DXA.  Safety data 
analyses will use data from all patients from the parent studies who receive any amount of study drug 
(ie, from parent study Baseline to Week 52 or Week 104). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, high 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.  Laboratory values will be classified 
by toxicity grade based on the National Cancer Institute CTCAE.  Laboratory shift tables of the parent 
study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early Termination visits.  The 
absolute change and percent change from parent study Baseline and Z-scores will be summarized by 
visit and parent study treatment group. 
The mean percentage change from parent study Baseline to Week 52 in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3101 
or MVT-601-3102) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, 
bone mineral density loss for the relugolix add-back treatment will be considered insignificant.  The 
95% CI for mean percentage change at Week 104 from parent study Baseline in bone mineral density 
lumbar spine (L1-L4) will be provided along with descriptive statistics for bone mineral density loss at 
Week 104 as supportive analyses. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3101 or MVT-601-3102) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 


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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3103 
 
PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
and 
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
 
X 
 
 
X 
 
X 
 
X 
Xh 
 
Complete Physical 
Examination 
Xg 
 
 
 
 
Xi 
 
 
 
Xj 
Xh 
 
Visual Acuityk 
Xg 
 
 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-
Directed Physical 
Examinationl 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xh 
X 
12-Lead ECGm 
Xg 
 
 
 
 
X 
 
 
 
Xh 
Xh 
 
Clinical Laboratory 
Testsn 
Xg,o 
X 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
Xh 
Xee 


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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
and 
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Pharmacodynamics 
Samplep 
Xg,n 
 
 
 
 
Xn 
 
 
 
Xn 
Xh,n 
 
Urinalysis 
Xg 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Daily eDiaryq 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Site Review of eDiary 
Data 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Bone Densitometryr 
Xg 
 
X 
 
 
Xs,t 
 
 
 
Xr,s 
Xh 
Xee  
Endometrial Biopsy 
Xg,u 
 
 
 
 
X 
 
 
 
Xt 
Xh 
Xee 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Dispense or Prescribe 
Protocol-Specified 
Analgesic Drugsv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose 
in Clinic 
Xw 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Daily Self-
Administration of Study 
Treatmentx 
 
X -------------------------------------- X 
 
 
 
Take Protocol-Specified 
Rescue Analgesics as 
Neededy 
 
X --------------------------------------------------------------------------------------------
----- X 
 
 


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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week 
32 
Week 
36 
Week 
40 
and 
Week 
44 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
EHP-30 Questionnairez 
Xg 
 
X 
 
X 
X 
 
X 
 
X 
Xh 
 
Patient Global 
Assessment for Painy 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
[on paper] Patient Global 
Assessment for 
Functionaa 
Xg 
X 
X 
X 
X 
X 
X 
X 
X0 
X 
Xh 
 
Patient Global 
Impression of Changey 
Xg 
 
X 
 
 
X 
 
 
 
 
Xh 
 
[on paper] EHP Work 
Domainz 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
EQ-5D-5L 
Questionnairey 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
Adverse Event 
Collectionbb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
Xcc,ee 
Telephone Contactdd 
 
 
 
 
 
X 
(W57) 
X 
(W71) 
X 
(W85) 
X 
(W98) 
 
 
 
Mammogramdd 
 
 
 
 
 
Xdd 
 
 
 
Xdd 
Xdd 
 
BP = blood pressure; DXA = dual-energy x-ray absorptiometry; ECG = electrocardiogram; eDiary = electronic diary; EHP = Endometriosis Health Profile; EQ-5D-5L = European 
Quality of Life Five-Dimension Five-Level Scale; HR = heart rate; NRS = Numerical Rating Scale; PGA = Patient Global Assessment; sB&B = Subject Modified Biberoglu and 
Behrman; W = week. 
a The Week 52 visit should occur on or after the 1-year anniversary of Baseline Day 1 of the parent study (± 7 days), and the Week 104 visit should occur on or 
after the 2-year anniversary of Baseline Day 1 of the parent study. 
b Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents. 
c The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 visit. 


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d May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3103 is defined by 
administration of the first dose of MVT-601-3103 study drug. 
e Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up Period.  Concomitant 
medications with start date prior to the first dose of study drug for MVT-601-3103 should be reported as concomitant medications in the parent study (MVT-
601-3101 or MVT-601-3102).  If concomitant medication is ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report 
Form Completion Guidelines for instructions for recording the follow-up status. 
f Concomitant medications are recorded both for the parent study and for MVT-601-3103 at the Week 24/Baseline visit.  (See footnote e for further details). 
g This is a parent study (MVT-601-3101 or MVT-601-3102) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3103 and is 
covered under the informed consent for the parent study. 
h The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal 
laboratory test). 
i The Week 52 and Week 104 physical examinations will include a breast examination. 
j See parent study protocols (MVT-601-3101 or MVT-601-3102) for instructions on testing visual acuity. 
k The examination may include a gynecologic examination, if indicated based on signs and symptoms. 
l The 12-lead ECGs will be submitted for central reading. 
m Clinical chemistries will be collected at each visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, Week 52, Week 65, 
Week 78, Week 91, and Week 104.  At the Week 24/Baseline visit, Week 52 visit, and Week 104 visit, additional tests will include the following:  fasting (at 
least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
n Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period. 
o For Week 24/Baseline samples, see the parent protocol (MVT-601-3101 or MVT-601-3102).  At Week 104/Early Termination, collect a sample for analysis of 
estradiol concentrations only.  On days when pharmacodynamics samples are collected, administer the study treatment after the pharmacodynamics sample 
collections are collected. 
p All women enrolled in the study will continue to use the patient eDiary dispensed in the parent study.  Patients will complete daily eDiary entries, including 
NRS pain scores, menstruation information, analgesic drug use, date and time of study drug administration, and sB&B scale scores until Week 52.  After 
Week 52, eDiary scores will be entered over four eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 
visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
q Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
r See Section 6.5.2.6 for details on the timing and follow-up of bone densitometry. 
s Determination of bone mineral density by DXA at Early Termination and follow-up of findings will proceed based on the timing of the Early Termination visit.  
For Early Termination occurring after Week 24 and before Week 36, DXA is not required at Early Termination visit unless it will aid in the assessment of an 
adverse event, and follow-up DXA required at 6 months (± 1 month) if most recent DXA bone mineral density loss at lumbar spine (L1-L4) or total hip was 
> 2% relative to the parent study baseline.  For Early Termination occurring after Week 36 and before Week 52, DXA is required at Early Termination unless a 
DXA result is available from within six weeks prior to Early Termination, and follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan 
was at Week 24 and bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 2% or most recent DXA result was after Week 24 and bone 
mineral density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to the parent study baseline.  For Early Termination occurring between Week 
52 and Week 104, DXA is required at Early Termination unless a DXA result is available from within six weeks prior to Early Termination, and follow-up 
DXA is required at 6 months (± 1 month) if on the most recent DXA, bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 7%, relative to 
parent study baseline. 


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t Endometrial biopsies are to be done per instructions in the parent study.  Procedures for handling and shipping biopsy samples to the central laboratory for 
analysis are described in the Investigator Site File.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who 
participated in MVT-601-3101 only (see MVT-601-3101 protocol for details) and at Week 52 and Early Termination visit for all patients.  This procedure is 
not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, the procedure may be done if it will aid in the evaluation of an ongoing adverse event.  An endometrial biopsy 
at Week 104 is recommended for all patients who complete the open-label extension; however, patients will have the option to opt out. 
u Please see Appendix 1 for list of protocol-specified analgesics and see the Investigator Site File for information on where and how to obtain protocol-specified 
analgesic medications by country.  At the Week 104 visit, patients who will not be proceeding to another extension study will be re-dispensed or prescribed 
protocol-specified analgesic drugs, if needed, to ensure sufficient supply until the Follow-Up visit.  For patients proceeding to another extension study, refer to 
the protocol for that next study. 
v Pregnancy test must be negative before the study drug dose is administered.  For patients whose Baseline Day 1 visit is conducted on a different day than the 
parent study Week 24 visit, perform an unscheduled pregnancy test at Baseline Day 1 prior to administering the first dose of study drug. 
w Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  If necessary, for 
logistical reasons (eg, delayed availability of study drug supply on site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not given during this up 
to 10-day interval, the parent study follow-up procedures should be followed (ie, adverse event reporting, eDiary completion, etc.).  The first dose of study drug 
for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed.  Therefore, results of testing 
required for eligibility (eg, DXA) must be available on or prior to the Week 24/Baseline visit.  The last dose of study drug will be taken in the clinic during the 
Week 104/Early Termination visit. 
x Patients may only take their study-specified analgesics for pain.  Analgesics should not be taken prophylactically (ie, in anticipation of pain). 
y The patient will enter her response(s) into an electronic tablet device at the site.  On visits when both tablet and paper questionnaires are being performed at the 
site, the patient should complete the tablet questionnaires before the paper questionnaires. 
z The patient will enter her response onto a paper questionnaire at the site.  Paper questionnaires should be done in the following order:  PGA for function, EHP 
Work Domain. 
aa Collect adverse events from the time that the first dose of study drug for MVT-601-3103 is administered.  Adverse events with onset prior to the first dose of 
study drug for MVT-601-3103 should be reported as an adverse event in the parent study (MVT-601-3101 or MVT-601-3102).  If events originating in the 
parent study are ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report Form Completion Guidelines for instructions 
for recording the follow-up status. 
bb Patients whose menses have not resumed as of the Follow-up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and questioned about factors that 
may affect resumption of menses.  If a patient is lost to follow-up, three documented attempts should be made to contact the patient by telephone.  If unable to 
contact the patient by telephone, a certified letter must be sent to the patient. 
cc A telephone call will be performed at Weeks 57, 71, 85, and 98.  The following activities should be completed: a concomitant medication review, evaluation of 
adverse events, and a review of eDiary and study medication compliance. 
dd For patients ≥ 40 years old at the time of the Week 52 visit, Week 104 visit, or Early Termination visit only.  See Section 6.5.2.9. 
ee See Section 6.5.2.6, Section 6.5.2.7, and Section 6.5.2.8 to determine if additional follow-up is required. 


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2. 
INTRODUCTION 
2.1. 
Endometriosis-Associated Pain 
Endometriosis is a common chronic condition occurring primarily in women of reproductive age.  
It is one of the most common gynecologic disorders, evident in 70 to 90% of women with pelvic 
pain symptoms [Practice Committee of the American Society for Reproductive Medicine, 2014].  
The exact prevalence of endometriosis is unknown but estimates range from 2 to 10% of women 
of reproductive age [Dunselman, 2014].  Symptoms range from minimal to severely debilitating. 
The pathogenesis of endometriosis is the presence of endometrial glands and stroma outside the 
uterine cavity.  Although the ectopic endometriotic lesions are most commonly found in the 
pelvis, they may also be located in the bowel, in the pleural cavity, and elsewhere.  Women with 
endometriosis have an increased risk of abdominopelvic pain, dysmenorrhea, and dyspareunia 
compared with controls without endometriosis [Practice Committee of the American Society for 
Reproductive Medicine, 2014].  In a study of 940 women with endometriosis, the most common 
symptom leading to diagnosis was dysmenorrhea in approximately 90%, pelvic pain in 
approximately 80%, and dyspareunia in approximately 45%, with 34% of women diagnosed on 
the basis of all three symptoms [Sinaii, 2008].  Presenting symptoms of infertility (25%) and 
endometrioma (ovarian mass) (20%) were also common [Sinaii, 2008]. 
The mechanisms of pain in endometriosis are generally postulated to involve production of 
substances such as growth factors and cytokines, the direct and indirect effects of active bleeding 
from endometriotic implants, and irritation of pelvic floor nerves or direct invasion of those 
nerves by infiltrating endometriotic implants [Practice Committee of the American Society for 
Reproductive Medicine, 2014]. 
According to the American Society for Reproductive Medicine Practice Committee, 
“Endometriosis is a chronic disease that requires a lifelong management plan with the goal of 
maximizing the use of medical treatment and avoiding repeated surgical procedures” [Practice 
Committee of the American Society for Reproductive Medicine, 2014]. 
Although hysterectomy with bilateral salpingo-oopherectomy is a definitive treatment of 
endometriosis, the American Society of Reproductive Medicine recommends that this option be 
reserved as a last resort for women with debilitating endometriosis symptoms who have 
completed childbearing and have failed to respond to alternative treatments [Practice Committee 
of the American Society for Reproductive Medicine, 2014].  Other surgical options for treatment 
of endometriosis include uterosacral nerve ablation, presacral neurectomy, and laparoscopic 
resection.  Rates of recurrent dysmenorrhea 1 and 3 years after laparoscopic surgery with 
uterosacral nerve ablation were not better than with laparoscopic surgery without nerve ablation 
in a large randomized trial.  Presacral neurectomy, which involves interrupting the sympathetic 
innervation to the uterus, improves pain but is a technically challenging procedure associated 
with significant risk of bleeding from the adjacent venous plexus.  Patients may also experience 
constipation and/or urinary retention postoperatively.  Laparoscopic treatment of endometriosis 
was found to be more effective at reducing pain than diagnostic laparoscopy in a meta-analysis 
of 5 randomized controlled studies.  While laparoscopic treatment is effective, pain can recur, 
and the option of performing multiple surgeries is limited by risks that include the development 
of pelvic pain from adhesions and decreased ovarian reserve, resulting in reduced fertility.  In 


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one retrospective study, subsequent surgery was performed after laparoscopic treatment in 21%, 
47%, and 45% of women after 2, 5, and 7 years, respectively [Practice Committee of the 
American Society for Reproductive Medicine, 2014]. 
Medical management of endometriosis includes analgesics and treatments aimed at 
decidualization followed by atrophy of endometrial tissue with reduction or antagonism of 
estrogen production and induction of amenorrhea.  Compared to normal endometrium, 
endometriotic implants are characterized by overproduction of prostaglandins and local 
production of estrogens and cytokines, which synergize the activities of each other and promote 
implantation of ectopic endometrium.  In addition, the implants have upregulated estrogen 
synthesis pathways [Practice Committee of the American Society for Reproductive Medicine, 
2014].  Interventions that reduce ovarian estrogen production reduce this synergistic process, 
thereby reducing or eliminating endometriosis-associated pain. 
Medical hormonal options include hormonal contraceptives, progestins, gonadotropin-releasing 
hormone (GnRH) agonists, danazol, and aromatase inhibitors.  Because of lack of data 
supporting use of one treatment over another, the treatment choice is based upon symptom 
severity, patient preferences, side effects, efficacy, contraceptive needs, costs, and availability 
[Dunselman, 2014].  The main adverse effects of GnRH agonists relate to induction of a 
hypoestrogenic state (eg, bone mineral density loss and vasomotor symptoms) whereas danazol 
produces androgenic adverse effects such as hirsutism, weight gain, and deepening of the voice.  
Some patients treated with GnRH agonists also experience an initial “flare effect” (increased 
pain and bleeding), and this can result in premature discontinuation of treatment.  Side effects of 
progestin treatment can include irregular uterine bleeding, weight gain, mood changes such as 
depression, and bone mineral density loss with long-term use of certain agents. 
The goal of the relugolix phase 3 development plan is to demonstrate that relugolix can decrease 
dysmenorrhea and nonmenstrual pelvic pain (NMPP) in women with endometriosis safely 
through 12 months of therapy and to evaluate effects on pain-related quality of life and function.  
By enhancing the safety and tolerability of the active treatment arm with the co-administration of 
low-dose hormonal add-back therapy, the program ultimately aims to bring to women suffering 
endometriosis-associated pain a long-term oral medical therapy that significantly reduces pain 
and improves quality of life and provides an alternative to invasive procedures. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix Investigator Brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once-daily oral medication for the treatment of endometriosis-associated pain.  The proposed 
dose of relugolix is 40 mg administered orally once daily and the proposed doses of estradiol and 
norethindrone acetate are 1.0 mg and 0.5 mg once daily, respectively. 


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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 gonadotropin-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 
luteinizing hormone and follicle-stimulating hormone fall rapidly, followed by a decline over a 
few days in estradiol and progesterone levels.  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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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Descriptive assessments of long-term efficacy and safety will be made between the parent study 
Baseline and Week 52, and between the parent study Baseline the end of the extension study 
(Week 104) for the following parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily followed 
by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg estradiol and 
0.5 mg norethindrone acetate in the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this extension study for all 
change from baseline-related endpoints.  The pain scores during the Baseline Pain Assessment 
Period of the parent study will establish the patient’s baseline for both the parent study and the 
extension study. 
In women with endometriosis-associated pain, the study objectives and corresponding endpoints 
are as follows: 


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Objectives 
Endpoints 
Primary Efficacy 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 104 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
To be assessed at Week 52 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
Numerical Rating Scale (NRS) scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
 
To be assessed at Week 104 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their dysmenorrhea 
NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their NMPP NRS 
scores. 
 
Secondary Efficacy 
To be assessed at Week 52 and Week 104 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on the 
following: 
 
 
 
 
 
To be assessed at Week 52 and Week 104, unless 
otherwise specified 
 
• 
Function, as measured by the Endometriosis 
Health Profile (EHP)-30 Pain Domain; 
• 
Change from the parent study Baseline in the 
EHP-30 Pain Domain scores; 
• 
Dysmenorrhea, as measured by the NRS for 
dysmenorrhea; 
• 
Change from the parent study Baseline in the 
mean dysmenorrhea NRS score; 
• 
Patient Global Impression of Change (PGIC) 
for dysmenorrhea; 
• 
Proportion of patients who are better or much 
better on the PGIC for dysmenorrhea (at 
Week 52 only); 


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Objectives 
Endpoints 
• 
NMPP, as measured by the NRS for NMPP; 
 
• 
Overall pelvic pain, as measured by the NRS 
 
• 
Analgesic use 
• 
Change from the parent study Baseline in the 
mean NMPP NRS score; 
• 
Change from the parent Baseline in the mean 
NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using analgesics; 
• 
PGIC for NMPP 
• 
Proportion of patients who are better or much 
better on the PGIC for NMPP (at Week 52 
only); 
• 
Dyspareunia, as measured by the NRS; 
• 
Change from the parent study Baseline in the 
mean dyspareunia NRS scores; 
• 
PGIC for dyspareunia; 
• 
Proportion of patients who are better or much 
better on the PGIC for dyspareunia (at 
Week 52 only); 
• 
Dyspareunia-related functional effects 
(Subject Modified Biberoglu and Behrman 
[sB&B]); 
• 
Change from the parent study Baseline in the 
mean dyspareunia functional impairment on 
the sB&B scale; 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with 24 weeks of 
low-dose estradiol and norethindrone acetate 
compared with placebo on function measured 
by the EHP-30 Pain Domain; 
• 
Proportion of responders based on EHP-30 
Pain Domain scores; 
• 
Patient Global Assessment (PGA) for pain; 
• 
Change from the parent study Baseline in 
severity scores on the PGA for pain; 
• 
PGA for function; 
• 
Change from the parent study Baseline in 
function impairment on the PGA for function; 
• 
Endometriosis-associated quality of life, as 
measured by the EHP-30 Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image domains; 
• 
Change from the parent study in each of the 
non-pain EHP-30 domains (Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image); 
• 
Dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline pain 
assessment period in NMPP-related 
functional effects (sB&B). 
Safety 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including: 
 
 
 
 
 
To be assessed at Week 52 and Week 104 


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Objectives 
Endpoints 
• 
Adverse events; 
• 
Incidence of adverse events; 
• 
Changes in bone mineral density. 
• 
Percent change from the parent study Baseline 
in bone mineral density at the lumbar spine 
(L1-L4), femoral neck, and total hip as 
assessed by dual-energy x-ray absorptiometry 
(DXA). 
Pharmacodynamic 
 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 104 weeks, among patients 
who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
estradiol. 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose 
concentrations of serum estradiol. 
Exploratory 
 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life 
(EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life 
outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) for 
up to 104 weeks among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102). 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• 
Change from parent study Baseline in the 
EQ-5D-5L. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety study that will enroll eligible patients who have completed their participation 
in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3101 or MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg 
once daily co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for 
up to 80 weeks.  Approximately 800 women with endometriosis-associated pain will be enrolled.  
The objectives of the study are to evaluate long-term efficacy and safety through up to 
104 weeks of treatment (including treatment during the parent study) of relugolix 
co-administered with low-dose estradiol/norethindrone acetate.  Eligible patients will have 
completed participation in one of the parent studies and consented to participate in this extension 
study.  Baseline procedures will be done at the same visit for this extension study (referred to as 
the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit from the parent 
study and will be defined as the date of completion of the last Week 24 procedure in the parent 
study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent 
study have been completed, the investigator will assess patient eligibility for participation in the 
open-label extension study.  The eligibility assessment will be based on data available at the 
Week 24/Baseline visit.  No MVT-601-3103 study procedures will be performed until the 
consent form for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Therefore, results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline visit.  The administration of the first dose of study 
drug for MVT-601-3103 will define enrollment into this study.  Study participants will then take 
the open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 80 weeks.  If necessary for logistical reasons 
(eg, delayed availability of study drug supply on site, others), and with sponsor/designee 
approval, the first dose of open-label study drug for MVT-601-3103 may be administered up to 
10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not 
given during this up to 10-day interval, the parent study follow-up procedures should be 
followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  
Only study-specific rescue analgesic medications should be used starting with the 
Week 24/Baseline visit and through the Follow-Up visit and these medications will be taken for 
control of pain and not prophylactically.  Health-related quality of life questionnaires; PGIC for 
dysmenorrhea, NMPP, and dyspareunia; and PGA for pain and function will be completed 


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during the visits on an electronic tablet or on paper, according to the Schedule of Activities 
(Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, mammograms (for 
women ≥ 40 years of age), endometrial biopsies, and bone mineral density with DXA. 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via DXA.  Follow-up of bone densitometry findings will 
proceed according to the rules described in Section 6.5.2.6. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed (or is ongoing) as of the Follow-Up visit for whom there is no 
explanation for the lack of resumption (eg, medical procedure or medications) will be contacted 
by telephone 3 (+ 0.5) months after the Follow-Up visit to determine if menses has resumed and 
will be asked about factors that may affect resumption of menses.  If a patient is lost to follow-
up, three documented attempts should be made to contact the patient by telephone.  If unable to 
contact the patient by telephone, a certified letter must be sent to the patient. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 4-1. 


Clinical Study Protocol:  MVT-601-3103 
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Figure 4-1 
MVT-601-3103 Study Schematic 
 
4.2. 
Discussion of Study Design, Including Dosing 
The SPIRIT EXTENSION study (MVT-601-3103) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3101 and MVT-601-3102) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with endometriosis-associated pain.  This 
80-week extension study provides additional efficacy and safety data up to 104 weeks to 
demonstrate the benefit and safety of relugolix co-administered with low-dose estradiol (1 mg) 
and norethindrone acetate (0.5 mg).  The primary objectives of the study are to assess long-term 
efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks on dysmenorrhea and NMPP, common and 
burdensome symptoms of endometriosis.  The study will also evaluate safety of relugolix 40 mg 
once daily co-administered with low-dose estradiol and norethindrone acetate for up to 
104 weeks, among patients who previously completed a 24-week treatment period in one of the 
parent studies (MVT-601-3101 or MVT-601-3102), including adverse events and change in bone 
mineral density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily suppressed estradiol levels 
to below 20 pg/mL in the majority of women, and results were similar to those in the group of 
women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the relugolix 
40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary endpoint of 


Clinical Study Protocol:  MVT-601-3103 
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the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 
demonstrated the 40-mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from endometriosis-associated pain to move forward into phase 3 clinical 
development and, based on the DXA data from the phase 2 study, are not expected to prevent 
bone mineral density loss in a significant majority of women over 104 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 104 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in dysmenorrhea and NMPP.  It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2017; Lee, 2016; Franke, 2000] or endometriosis-associated 
pain [Wu, 2014].  The estradiol/norethindrone acetate combination proposed for evaluation in 
this phase 3 study is currently approved in the United States (US) as long-term hormone 
replacement therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal 
women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 


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Clinical Study Protocol:  MVT-601-3103 
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3. Is not expected to undergo gynecological surgery or other surgical procedures for 
treatment of endometriosis (including ablation, shaving, or excision) during the study, 
including during the Follow-Up Period, and the patient does not desire such treatment 
during this time frame; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Has agreed to continue to use only study-specified analgesic medications during the study 
and is not known to be intolerant to these; 
6. Agrees to continue to use acceptable non-hormonal contraceptive methods as described 
in Section 4.6 consistently during the Open-Label Treatment Period and for at least 
30 days after the last dose of study drug.  However, the patient is not required to use the 
specified non-hormonal contraceptive methods if she: 
a. 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 6 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
c. 
Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of non-hormonal contraception as noted above; 
e. 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria 
1. Has had a surgical procedure for treatment of endometriosis at any time during the parent 
study (MVT-601-3101 or MVT-601-3102); 
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, 
that is treated with opioids or requires analgesics for ≥ 7 days per month; 
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, 
bilateral hip replacement, spinal hardware in the lumbar spine); 
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent 
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study 
Week 24 DXA assessment of bone mineral density; 
5. Anticipated to use any prohibited medications as detailed in Section 5.10.1; 


Clinical Study Protocol:  MVT-601-3103 
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CONFIDENTIAL 
6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. 
Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. 
Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. 
Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. 
Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc); psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the 
upper limit of normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 
90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the 
parent study Baseline visit; or 
b. The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 


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12. Is inappropriate for participation in this study because of conditions that may interfere 
with interpretation of study results or prevent the patient from complying with study 
requirements, as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
4.4. 
Method of Assigning Patients to Treatment Group and Patient 
Identification Number 
Eligible patients who sign consent will be identified with the same Patient Identification (ID) 
Number assigned to the patient during the parent study.  This extension study is a single-arm, 
open-label study, and thus all eligible patients are assigned to the same treatment group of 
relugolix 40 mg co-administered with low-dose of estradiol and norethindrone acetate (see 
Section 5.1 for treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 104 visit defines completion of the study.  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 Early Termination visit (see the Week 104 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication).  When patients complete the study or early terminate from the study, they 
must be deactivated from the study in the interactive voice response system/interactive web 
response system (IVRS/IWRS), eDiary, and tablet device. 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• 
Any adverse event that is intolerable to the patient and 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; 
• 
If it is discovered after enrollment that a patient failed to meet protocol entry criteria and 
continued participation poses an unacceptable risk to the patient’s health; 
• 
If the following 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): 
− 
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 
international normalized ratio (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%); 


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• 
QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec read by 
a cardiologist; 
• 
Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial biopsy; 
• 
If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or femoral 
neck compared with the parent study Baseline; 
• 
If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  Gross noncompliance includes < 75% 
compliance with the study drug over > 2 consecutive months; missing multiple study visits; 
and persistent (> 2 consecutive months) noncompliance (< 50% of the required number of 
days) with eDiary completion up to Week 52 or persistent (≥ 2 eDiary collection cycles) 
noncompliance (< 50% of the required number of days) with eDiary completion from 
Week 52 to Week 104.  Investigators will follow up with the patient and encourage 
compliance with study drug or eDiary prior to discontinuing her from the study; 
• 
If the patient becomes pregnant at any time after providing a signed informed consent form, 
the patient must be withdrawn immediately (see Section 7.8 for information on pregnancy 
reporting); 
• 
Evidence of malignant breast lesion(s) or breast carcinoma on Week 52 or Week 104/Early 
Termination or most recent mammogram or additional breast imaging (see Section 6.5.2.9 
for more information on mammogram at Week 52 or Week 104/Early Termination); 
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 noncompliance.  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 three 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.” 
4.6. 
Contraception/Pregnancy Avoidance 
All patients should be counseled at every visit to adhere to the use of protocol allowed 
contraceptive methods.  In this study, medications and devices containing hormones for 
contraception are excluded, and patients must agree to use non-hormonal contraception 
throughout the study including through 30 days following the last dose of study drug, unless any 
of the following apply: 
• 
Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
• 
Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure) at 
least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 


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• 
Has a non-hormonal intrauterine device (eg, Paragard) placed in the uterus; 
• 
Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as described below; 
• 
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods do 
not apply are: 
• 
Condom (male or female condom) with or without spermicide (cream, spray, foam, gel, 
suppository, or polymer film); 
• 
Diaphragm with spermicide (condom may or may not be used); 
• 
Cervical cap with spermicide (condom may or may not be used); or 
• 
Vaginal sponge impregnated with spermicide used with a condom. 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed according to the Schedule of Activities (Table 1-1; 
including just prior to receiving the first dose of study drug), and patients will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures.  Patients 
who become pregnant during the study will be withdrawn from the study and followed for 
pregnancy outcome (see Section 7.8). 
4.7. 
Novel Coronavirus 2019 Guidance 
Guidance for conducting clinical trials during the novel coronavirus 2019 (COVID-19) pandemic 
is included in Appendix 9. 


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5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing 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. 
On Week 24/Baseline 1, Week 52, and Week 104 clinic visit days, study drug will be 
administered in the clinic rather than at home (see Schedule of Activities in Section 1.1). 
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 cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location at room 
temperature.  Follow storage conditions described on the drug labeling.  Study drug should be 
stored protected from light.  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.  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. 
Study drug will be labeled with the study protocol number, medication or lot/batch number, 
contents, directions for use, storage directions, clinical study statement, and any other labeling 
required by regulatory bodies in the study locations and will list Myovant Sciences GmbH as the 
sponsor.  Patients will be instructed to store study drug at room temperature out of the reach of 
children. 
All labels for relugolix and the estradiol/norethindrone acetate combination to be distributed will 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices:  Manufacture of investigational medicinal products (July 
2010) and/or other local regulations as applicable. 


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Please see Appendix 1 for a list of protocol-specified analgesics.  Further details on analgesic 
medication are provided in the Investigator Site File. 
5.7. 
Rescue Analgesic Medications 
Management of endometriosis-associated pain often requires treatment with analgesics and some 
patients require treatment with opioid drugs. Two tiers of pain medications are specified for this 
trial.  The study-specified pain medications for each patient will be the same as for the parent 
study.  Only study-specific Tier 1 and Tier 2 analgesic medications (see Appendix 1) should be 
taken starting with the Baseline/Week 24 visit and subsequently.  Analgesic medications will be 
taken for control of pain and not prophylactically. 
If a patient develops uncontrolled endometriosis-associated pain during the study despite use of 
the study-specified analgesics or an intolerance to a study-specified analgesic, please contact the 
medical monitor. 
Short-term use of non-study specified analgesics for the treatment of an intercurrent event (eg, 
injury or surgery) is allowed, if required.  Such events should be reported as adverse events when 
appropriate. 
Investigators must instruct the patient on the use of ibuprofen 200 mg tablets (ie, number of 
tablets per dose, dosing frequency, maximum number of tablets per day).  For patients who may 
need the Tier 2 analgesic medication, a prescription should also be written for this at the time of 
enrollment into this study.  This is to ensure that patients do not endure unnecessary pain during 
the conduct of the study. 
Quantities of opioids prescribed should be based on the patient’s expected usage until the next 
study visit.  Prescriptions for Tier 1 and Tier 2 rescue analgesic medications should be in 
accordance with their full prescribing information (ie, the local product labeling) and 
prescriptions for opioids should not provide for any refills.  Patients should be counseled on the 
safe use of opioids. 
Patients who are not prescribed the Tier 2 medication at the time of enrollment in this study, for 
example, because requirement for analgesics beyond the Tier 1 medication is not expected (eg, 
based on pain level and/or recent analgesic requirements) should be advised to contact the 
investigator if pain is inadequately controlled with the Tier 1 medication alone.  To avoid 
experiencing extended periods of uncontrolled pain, patients who require the Tier 2 medication 
should get a prescription from the investigator and initiate treatment with the Tier 2 medication 
as soon as feasible. 
Use of protocol-specified rescue analgesic medications and any other analgesics taken for any 
type of pain, must be recorded by the patient in the eDiary. 
5.8. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and should bring all unused and used 
(including partially used) study drug kits to each study visit.  At the Week 24/Baseline visit and 


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Week 104/Early Termination visit, all used, partially used, and unused study drug kits should be 
retained at the site.  At all other visits, only fully used study drug kits should be retained at the 
site.  New study drug should be dispensed as described in Section 1.1 (Schedule of Activities). 
Study drug accountability will be conducted and results will be recorded.  If a patient is 
persistently noncompliant with the study treatment, it may be appropriate to withdraw the patient 
from the study (see Section 4.5).  All patients should be reinstructed about the dosing 
requirement during study contacts.  The authorized study personnel conducting the re-education 
must document the process in the patient’s source records. 
Because of the importance to both safety and efficacy evaluation, patients who are grossly 
noncompliant with eDiary completion must undergo an Unscheduled visit to evaluate reasons for 
noncompliance and to develop a plan to improve compliance.  Failure to improve compliance 
may result in the sponsor withdrawing the patient from further study treatment (including study 
analgesics) and/or discontinuation from the study (see Section 4.5 for details). 
All patients should be reinstructed about the dosing requirement and eDiary 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 prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Drugs and drug classes in Table 5-2 are prohibited at any time 
during the study through the Follow-Up visit, except as noted in the table.  Consult the medical 
monitor if there is any uncertainty regarding patient use of a particular drug or drug class. 
Table 5-3 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zoledronic acid 
 
GnRH analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
 
Anti-androgens 
danazol 
 
Anticonvulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
Note: All other anticonvulsants are 
allowed 
Aromatase inhibitors 
anastrozole 
letrozole 
 


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Drug Class 
Examples 
Comments 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
Hormonal contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
NuvaRing 
 
Selective estrogen 
receptor modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
 
Selective progesterone 
receptor modulators  
mifepristone 
ulipristal acetate 
 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
 
Intrauterine devices 
levonorgestrel 
 
 
Bone agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use of systemic 
glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study.   
Note:  topical, inhaled, intranasal, 
otic, ophthalmic, intraarticular, or 
intralesional subcutaneous are 
permitted without restriction. 
Short duration (< 21 days) higher-
dose glucocorticoids required for 
acute events are permitted during 
the study. 


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Drug Class 
Examples 
Comments 
P-glycoprotein inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavirf 
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 and strong 
P-glycoprotein- inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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. 
Analgesic drugs other 
than those specified for 
use during the studyh 
Acetaminophen/paracetamol (other 
than any included in a 
study-specified analgesic) 
aspirin > 325 mg/day 
NSAIDs (other than study-specified 
NSAIDs) 
gabapentin 
pregabalin 
carbamazepine 
metamizole 
cannabinoids 
Note:  Aspirin ≤ 325 mg per day is 
allowed 


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Drug Class 
Examples 
Comments 
Antidepressants 
New treatment or 
changed doses of SSRI, 
SNRI, or TCA 
antidepressants 
SNRI examples: 
duloxetine 
venlafaxine 
desvenlafaxine 
SSRI examples: 
citalopram 
fluoxetine 
paroxetine 
fluvoxamine 
TCA examples: 
amitriptyline 
doxepin 
desipramine 
nortriptyline 
SSRI, SNRI, or TCA allowed if 
given at the same dose as used 
during the 3 months prior to the 
Run-In Period of MVT-601-3101 or 
MVT-601-3102. 
New start, dose change or 
discontinuation of these drugs is not 
allowed during the study.  Changes 
made for safety reasons are allowed 
with approval of the medical 
monitor. 
DHEA = dihydroepiandrosterone; GnRH = gonadotropin-releasing hormone; NSAID = nonsteroidal anti-
inflammatory drug; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake 
inhibitor; TCA = tricyclic antidepressant. 
 
a. 
Roxithromycin is allowed. 
b. 
All other angiotensin converting enzyme inhibitors are allowed. 
c. 
Tacrolimus is allowed. 
d. 
Amlodipine and nifedipine are allowed. 
e. 
Fluconazole is allowed. 
f. 
Integrase inhibitors are allowed. 
g. 
Clopidogrel is allowed. 
h. 
For situations where non-study analgesics may be allowed, see Section 5.7. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded in the electronic Case Report 
Forms (eCRFs), including the drug generic name, dose amount, route of administration, start 
date, and stop date. 
5.10.2.1. Analgesics 
All analgesics will be collected in the eDiary and recorded in the eCRFs. 
5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of endometriosis is prohibited from the Week 24/Baseline visit until the 
patient’s final study visit unless urgently needed for patient safety. 


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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 6.5.  Further details of the 
procedures are provided in the Investigator Site File.  Guidelines to address the COVID-19 
pandemic are included in Appendix 9. 
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 2 periods:  Open-Label Treatment 
Period and Safety Follow-Up Period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 104) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3101 or MVT-601-3102 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week 24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• 
Informed consent (unless signed previously); 
• 
Record concomitant medications; 
• 
Update the patient’s status in the IVRS/IWRS as being in the MVT-601-3103 and receive the 
lot numbers for study drug allocation; 
• 
Dispense study treatment; 
• 
Dispense or prescribe protocol-specified analgesic drugs; 
• 
Transition the patient within her eDiary from the parent study to MVT-601-3103 
• 
Take study drug dose in clinic; and 
• 
Record adverse events, if any. 
The Week 24 visit date in the parent study is defined as the date that the last procedures for the 
Week 24 visit were completed, acknowledging that the Week 24 visit procedures may be 
completed on different dates.  Patients will have received their last dose of study drug in the 
parent study on the day prior to the Week 24/Baseline visit and will receive their first dose of 
study drug for this extension study in the clinic after the patient is determined to be eligible for 
this extension study and has provided informed consent to participate.  Therefore, results of 
testing required for eligibility must be available on or prior to the Week 24/Baseline visit.  If 
necessary for logistical reasons (eg, delayed availability of study drug supply on site, others), and 


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with sponsor/designee approval, the first dose of open label study drug for MVT-601-3103 may 
be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first 
dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, eDiary completion, etc.). 
Patients will continue recording data in their eDiary daily and taking protocol-specified 
analgesics as needed until Week 52.  After Week 52, the eDiary will be collected on the 
following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 visit, Week 85 to 
the Week 91 visit, and Week 98 to the Week 104 visit.  Following the Week 24/Baseline visit, 
on-treatment study visits will occur at Weeks 28, 32, 36, 40, 44, 48, 52, 65, 78, 91, and 104.  
Sites will monitor diary completion using the Trial Manager web portal throughout the study. 
A telephone call will be performed at Weeks 57, 71, 85 and 98.  The following activities should 
be completed: a concomitant medication review, an evaluation of adverse events, a review of 
study medication compliance, and a reminder to the patient to start recording in the eDiary daily. 
Accountability for study drug will be performed at each visit.  Instructions for analgesic 
medication usage will be reinforced at each visit. 
Questionnaires are administered on the electronic tablet and on paper at each visit.  These 
procedures should occur before any other types of study procedures are performed.  When both 
electronic tablet and paper questionnaires are required at a visit, the electronic questionnaires 
should be done first.  The order in which the electronic tablet and paper questionnaires should be 
administered are as follows: 
• 
Electronic tablet questionnaires (in the order they appear in the tablet) 
• 
Paper questionnaires 
− 
PGA for function 
− 
EHP Work Domain [Week24/Baseline, Week 52, Week 78, and Week 104 only] 
Patients will bring their eDiary, analgesic medications, and study drug to each visit.  The site 
must document the start and stop dates of the patient’s menses. 
An endometrial biopsy will have been performed at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 (see MVT-601-3101 protocol for details).  An 
endometrial biopsy is required at Week 52 and the Early Termination visit for all patients.  This 
procedure is not required at the Early Termination visit in patients whose last dose of study drug 
was taken during Week 32 or earlier or within four weeks after completion of the Week 52 
endometrial biopsy.  However, the procedure may be done if it will aid in the evaluation of an 
ongoing adverse event.  An endometrial biopsy at Week 104 is recommended for all patients 
who complete the open-label extension ; however, patients will have the option to opt out.  
Safety monitoring for this study includes physical examination, clinical laboratory tests, 
pregnancy tests, and adverse event collection at each visit.  Clinical chemistries will be collected 
at each visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, 
Week 52, Week 65, Week 78, Week 91, and Week 104.  At the Week 24/Baseline visit, Week 52 
visit, and Week 104 visit, additional tests include fasting (at least 8 hours, other than water) 
glucose, lipid profile, and hemoglobin A1c. 
Electrocardiograms will be performed at the Week 24/Baseline and the Week 52 visits. 


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A mammogram will be performed at Week 52 or at Week 104/Early Termination for women 
who are or become ≥ 40 years old during the study (see Section 6.5.2.9). 
Bone densitometry will occur at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early 
Termination visits.  Follow-up of bone densitometry findings will proceed according to the rules 
described in Section 6.5.2.6. 
Bone densitometry and ECGs will be submitted for central reading. 
Study drug compliance will be reviewed at each visit.  Fasting (other than water) for at least 
8 hours is required prior to blood sampling on Week 24/Baseline and Week 52/Early 
Termination visits and for 1 hour after administration of the study drug in the clinic.  Laboratory 
requisitions must indicate whether or not the patient was not fasted for their chemistry and lipid 
testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment Period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 104.  An 
endometrial biopsy is required for all patients at the Early Termination visit except for patients 
whose last dose of study drug was taken during Week 32 or earlier or within four weeks after 
completion of the Week 52 endometrial biopsy.  However, the endometrial biopsy may be 
obtained if it will aid in the evaluation of an ongoing adverse event..  Bone densitometry may be 
performed at the investigator’s discretion, if it aids in follow-up of an ongoing adverse event(s).  
Follow-up bone densitometry findings for patients who terminate from the study early will 
proceed according to the rules provided in Section 6.5.2.6. 
Patients (including those who complete the Week 104 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
endometriosis, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 104 visit, the Follow-up visit may be 
waived. 
The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the 
Follow-up visit. 
Follow-up of bone densitometry findings for patients who terminate from the study early will 
proceed according to the rules provided in Section 6.5.2.6. 
6.4. 
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 source 


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documentation.  The following activities should be completed at Unscheduled visits:  recording 
of reason for the visit, concomitant medication review, and evaluation of adverse events.  In 
addition, procedures such as vital signs, weight, complete physical examination, sign- and 
symptom-directed physical examination, clinical laboratory assessment, urinalysis, urine 
pregnancy testing, pharmacodynamic sampling, mammogram (for women ≥ 40 years old), 
12-lead ECG, study drug compliance and dispensation, eDiary review, dispensation or 
prescription of protocol-specified analgesics, etc, may be conducted as needed.  See the Schedule 
of Activities (Section 1.1) for tests that may be performed, as indicated at an Unscheduled visit.  
The investigator should consult with the medical monitor, if needed, to discuss Unscheduled visit 
testing.  The investigator should obtain approval from the sponsor to perform an unscheduled 
endometrial biopsy or DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Pharmacodynamics Sample Collection 
A blood sample for the pharmacodynamic analysis of serum estradiol will be collected predose at 
the visits indicated in the study Schedule of Activities (see Section 1.1), other than at the 
Week 104 or the Early Termination visit, when no dose is administered.  These 
pharmacodynamic samples will be analyzed at a central laboratory.  These results will not be 
shared with the sites at any time. 
6.5.1.2. 
Patient eDiary 
All women enrolled in the study will continue to use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete daily eDiary entries, including NRS pain scores, 
menstruation information, analgesic drug use, date and time of study drug administration, and 
sB&B scale scores until Week 52.  After Week 52, eDiary scores will be entered over four 
eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to 
the Week 78 visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
The site should review the eDiary data at every visit. 
6.5.1.3. 
Endometriosis Health Profile-30 
The EHP-30 is used to evaluate the functional impact and the quality of life of patients with 
endometriosis (see Appendix 3).  Patients will complete the EHP-30 questionnaire at the site at 
visits indicated in Section 1.1 before other types of study procedures, such as blood draws and 
physical examinations, are performed.  The EHP-30 will be completed on a tablet device at the 
study site. 
6.5.1.4. 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes (see 
Appendix 4).  Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are 
each assessed on a 5-level categorical scale. 


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Patients will complete the EQ-5D-5L questionnaire at the site at visits indicated in Section 1.1 
before other types of study procedures, such as blood draws and physical examinations, are 
performed.  The EQ-5D-5L will be completed on a tablet device at the study site. 
6.5.1.5. 
Patient Global Assessment and Patient Global Impression of Change 
These simple questions are used by the patient to qualitatively describe severity of pain or effects 
on function (PGA) or impression of change in pain severity (PGIC) (see Appendix 5) on a 
schedule described in the Schedule of Activities (Section 1.1).  Patients should answer these 
questions before other types of study procedures, such as blood draws and physical 
examinations, are performed.  The PGA for pain severity and the PGIC will be completed on a 
tablet device at the study site.  The PGA for function will be completed on a paper questionnaire 
at the study site. 
6.5.1.6. 
Endometriosis Health Profile Work Domain 
This 5-question paper questionnaire will be completed by the patient to describe the effects of 
endometriosis on their work (Appendix 6).  Patients will complete the EHP Work Domain 
questionnaire at visits indicated in Section 1.1 before other types of study procedures, such as 
blood draws and physical examinations, are performed.  The EHP Work Domain will be 
completed on a paper questionnaire at the study site. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 
6.5.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest. 
6.5.2.3. 
Physical Examinations 
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.  The physical 
examinations at Week 52 and Week 104 will include a breast examination. 
6.5.2.4. 
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. 


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The samples collected for clinical laboratory tests are listed in Table 6-1. 
Table 6-4 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatine kinase 
Hemoglobin A1c 
Bilirubin total 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Alkaline phosphatase 
White blood cell count 
White blood cell differential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelet count 
Red blood cell morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and clarity 
pH 
Leucocyte esterase 
Ketones 
Nitrite 
Specific gravity 
Urine microscopy (reflex 
testing based on abnormal 
urine analysis) 
Hormones 
Lipids 
Pregnancy 
Estradiol 
Total cholesterol 
Low-density lipoprotein 
High-density lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
serum hormone levels.  Each study site will conduct urine pregnancy tests locally. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal values, determined to 
be clinically significant, should be reported as adverse events. 
For patients with incomplete recovery of bone mineral density loss at the 6- and 12-month 
post-treatment follow-up visit, clinical laboratory tests should be performed (see Section 6.5.2.6). 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 


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6.5.2.5. 
Electrocardiograms 
Electrocardiograms (12-lead) will be obtained at the time points described in the Schedule of 
Activities (Section 1.1).  Electrocardiograms will be measured using standardized equipment 
provided by the central core laboratory with the patient in a semi-supine or supine position after 
5 minutes of rest.  The ECGs will be assessed by central review and a report provided to the site.  
The investigator or sub-investigator (or a qualified individual at the investigational site) will 
interpret the ECG report provided by the central reviewer using one of the following categories:  
normal or abnormal.  The investigator or sub-investigator will judge if any of the findings are 
clinically significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3, and L4), total hip, and femoral neck (same leg within each patient) at the time 
points described in the Schedule of Activities (Section 1.1).  The scan will be read by the central 
imaging laboratory in accordance with the imaging charter.  Training, quality review, and 
readings will be done by a central radiology laboratory ad described in the central radiology 
charter for bone mineral density. 
Throughout the study, the same DXA apparatus will be used at each site and operated in the 
same scan mode for all scans for an individual patient and should be the same as used for the 
patient during the parent study (MVT-601-3101 and MVT-601-3102).  The central core imaging 
laboratory will collect and evaluate all DXA scan for acceptability.  Bone mineral density 
changes for individual patients will be monitored by the central imaging laboratory over the 
course of the study. 
Determination of bone mineral density by DXA at early termination and follow-up of findings 
will proceed according to the following rules: 
• 
For early termination occurring between Week 24 and Week 52: 
− 
For early termination occurring before Week 36, DXA is not required at the Early 
Termination visit unless it will aid in the assessment of an adverse event; 
Follow-up DXA required at 6 months (± 1 month) if most recent DXA bone 
mineral density loss at lumbar spine (L1-L4) or total hip was > 2% relative to the 
parent study baseline; 
− 
For early termination occurring after Week 36, DXA is required at early termination 
unless a DXA result is available from within six weeks prior to early termination; 
Follow-up DXA is required at 6 months (± 1 month) if the most recent DXA scan 
was at Week 24 and bone mineral density loss at the lumbar spine (L1-L4) or total 
hip was > 2%, relative to the parent study baseline; 
− 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA scan, 
bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 3%, relative to 
the parent study baseline; 
• 
For early termination occurring between Week 52 and Week 104: 


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− 
DXA is required at early termination unless a DXA result is available from within six 
weeks prior to early termination; 
Follow-up DXA is required at 6 months (± 1 month) if on the most recent DXA, 
bone mineral density loss at the lumbar spine (L1-L4) or total hip was > 7%, 
relative to the parent study baseline; 
• 
If patients have 6-month post-treatment follow-up scans that show bone loss of > 1.5% at the 
lumbar spine and/or > 2.5% at total hip compared with parent study baseline, patients are 
strongly encouraged to come back to the clinic for an additional post-treatment follow-up 
scan 12 months from the date of the last dose of the study drug.  Patients undergoing 6-month 
post-treatment follow-up should also have the following clinical laboratory evaluations 
(vitamin D, thyroid-stimulating hormone, parathyroid hormone, creatinine, calcium, and 
phosphorous). 
• 
If patients have 12-month post-treatment follow-up scans that show bone loss of ≥ 3% at the 
lumbar spine and/or total hip compared with parent study baseline, patients are referred to 
and strongly encouraged to see a bone specialist for further evaluation or the bone loss.  
Patients undergoing 12-month post-treatment follow-up should also have the following 
clinical laboratory evaluations (vitamin D, thyroid-stimulating hormone, parathyroid 
hormone, creatinine, calcium, and phosphorous). 
Note:  When a patient is referred to a bone specialist for evaluation and management, 
Myovant will provide a Bone Consultation Letter to the investigator for this 
additional bone consult and will request the site to provide a summary of the 
evaluation and management plan once the consultation is complete. 
6.5.2.7. 
Endometrial Biopsy 
For patients in parent study MVT-601-3101, an endometrial biopsy is performed at the Week 24 
visit.  If the required Week 24 biopsy is inadequate for diagnosis, it should be repeated, and a 
sample submitted to the central laboratory.  If the second sample is inadequate, ensure an 
endometrial thickness has been reported from the Week 24 transvaginal ultrasound and contact 
the medical monitor to review the findings.  Patients who have endometrial hyperplasia or 
endometrial carcinoma will be withdrawn from study drug treatment and followed per 
instructions in the parent study protocol. 
Additional assessment of the effects of relugolix co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will be performed at Week 52 and Early Termination 
visit for all patients.  An endometrial biopsy is required for all patients at the Early Termination 
visit except for patients whose last dose of study drug was taken during Week 32 or earlier or 
within four weeks after completion of the Week 52 endometrial biopsy.  However, the 
endometrial biopsy may be obtained if it will aid in the evaluation of an ongoing adverse event.  
An endometrial biopsy at Week 104 is recommended for all patients who complete the open-
label extension; however, patients will have the option to opt out.  Patient participation in the 
Week 104 endometrial biopsy is voluntary and refusal to participate will not preclude entry into 
the study or indicate withdrawal from the study. 
The Week 52, Week 104, and Early Termination visit endometrial biopsy samples will be 
submitted to the central laboratory.  If the Week 52,Week 104, or Early Termination visit biopsy 


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specimen is inadequate, a transvaginal ultrasound for endometrial thickness should be obtained 
and read locally.  The transvaginal ultrasound findings will be used to determine if further action 
is required: 
• 
Endometrial thickness ≤ 5 mm – no further action required. 
• 
Endometrial thickness > 5 mm at any location or any other endometrial abnormality – repeat 
endometrial sampling.  Contact medical monitor if second specimen is inadequate for 
diagnosis. 
Investigators should contact the medical monitor if a patient refuses to have an endometrial 
biopsy at Week 52 or the Early Termination visit.Unscheduled endometrial biopsies may also be 
performed when medically indicated and as deemed necessary by the investigator.  The 
investigator should obtain approval from the sponsor to perform an unscheduled endometrial 
biopsy, unless urgently indicated.  Additional consent is not required in this circumstance. 
6.5.2.8. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted by telephone 3 
(+0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses.  If a patient is lost to follow-up, three 
documented attempts should be made to contact the patient by telephone.  If unable to contact 
the patient by telephone, a certified letter must be sent to the patient. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
6.5.2.9. 
Mammogram 
A mammogram will be performed at Week 52 or Week 104/Early Termination visit (see the 
Schedule of Activities in Section 1.1) for patients ≥ 40 years of age at the time of the visit.  If a 
patient had a recent mammogram per standard of care within the six months before Week 52 that 
was Breast Imaging Reporting and Data System category 1 or 2 or equivalent or had benign 
findings, as determined by the investigator or medical monitor, a mammogram is not required at 
Week 52 but should be completed by Week 104/Early Termination.  If a patient turns 40 years 
old after the Week 52 visit has occurred, a mammogram should be performed no later than the 
Week 104/Early Termination visit. 
All mammogram results will be read locally using Breast Imaging Reporting and Data System 
categories or equivalent (see Appendix 8) and recorded in the eCRF.  The following actions will 
be taken depending on the reading: 
• 
Category 1 or 2 or equivalent:  normal mammogram; no further action is required unless 
determined by the investigator or medical monitor; 


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• 
Category 0 or 3 or equivalent:  adjunctive breast imaging or follow-up mammogram will be 
required, and the investigator should contact the medical monitor for approval of additional 
breast imaging; 
• 
Category 4 to 6 or equivalent:  the investigator should contact the medical monitor within 24 
hours. 


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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, ECGs, and bone mineral density assessments. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
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: 
− 
Induces clinical signs or symptoms; 
− 
Requires active intervention; 
− 
Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
• 
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event; 
• 
Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• 
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); 
• 
Endometriosis-associated pain is not considered an adverse event in this study because it is 
being quantitatively measured as the primary efficacy endpoint. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 


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(CTCAE).  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. 
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 participant 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 admitted to a hospital, 
independent of the duration of that hospitalization.  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) which 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 which 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 Institutional Review Board (IRB) or Independent Ethics Committee 
(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: 


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• 
“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 eDiary entries, including bleeding and answers to the other patient-reported 
outcome measures, 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 the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for endometriosis, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  Serious adverse events reported to the investigator after the 
safety reporting period should be reported to the sponsor regardless of causal relationship to 
study drug treatment. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
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 
following definitions are to be used for the relationship of the adverse event to study drug: 


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• 
Probably related:  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 
(rechallenge) or withdrawal (dechallenge). 
• 
Possibly related:  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.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 
Table 7-5 
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 
CTCAE = Common Terminology Criteria for Adverse Events. 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 


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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 × 
ULN. 
Any ALT or AST elevation of this degree or greater occurring during the Open-Label Treatment 
Period or the Follow-Up visit should be reported to the sponsor using the Safety Report 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 × ULN may be found in Appendix 7. 
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 × ULN; or 
• 
ALT or AST > 5 × ULN and persists for more than 2 weeks; or 
• 
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or the INR > 1.5; or 
• 
ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
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 × ULN; AND 
2. Total bilirubin increases to > 2 × ULN or INR > 1.5; AND 
3. Alkaline phosphatase value does not reach 2 × 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); 


Cli nical St u d y Pr ot oc ol:  M V T -6 0 1 -3 1 0 3  
A me n d me nt 3, 0 1 J ul  2 0 2 0  
M y o va nt Scie nces G m b H  
6 3  
C O N FI D E N TI A L  
− E x p os ure t o he pat ot o xic a ge nts/ dr u gs or he pat ot o xi ns, i ncl u di n g her bal a n d dietar y 
s u p ple me nts, plants, a n d m us hr o o ms ; 
− Alc o h olic he patitis ; 
− N o nalc o h olic steat o he patitis; 
− A ut oi m m u ne he patitis.  
If a n alter nati ve ca use f or he pat ot o xicit y is i de ntifie d, t he n it s h o ul d be deter mi ne d ( base d o n t he 
se verit y of t he he pat ot o xicit y or e ve nt) w het her st u d y dr u g treat me nt s h o ul d be wit h hel d or 
per ma ne ntl y disc o nti n ue d as a p pr o priate f or t he safet y of t he patie nt. 
7. 6.  
Seri o us A d verse E ve nt Re p orti n g  
Usi n g a Safet y Re p ort F or m, all seri o us a d verse e ve nts m ust be re p orte d wit hi n 2 4  h o urs of t he 
st u d y site pers o n nel’s k n o wle d ge of t he e ve nt, re gar dless of t he i n vesti gat or assess me nt of t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g. 
T he c o ntact i nf or mati o n f or s u b missi o n of seri o us a d verse e ve nts, a d verse e ve nts of cli nical 
i nterest ( defi ne d i n Secti o n  7. 5 ), a n d e ve nts of o ver d ose is a vaila ble o n t he Safet y Re p ort F or m 
a n d is as f oll o ws:  
Se n d c o m p lete d S afet y Re p ort F or ms t o I Q VI A R D S I nc. (f or merl y Q ui ntilesI M S): 
Site L oc ati o n  
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber  
( Sec o n d ar y re p orti n g met h o d)  
All st u d y sites  
 
 
F or q uesti o n s o n Seri o us A d verse E ve nt/ A d verse E ve nt of Cli nic al I nterest re p orti n g, 
ple ase c all:  
•  N ort h/ S o ut h A merica:  
 
•  E ur o pe, Asia- Pacific, a n d Africa:  see re gi o n- s pecific p h o ne n u m bers acc o m pa n yi n g t he 
Safet y Re p orti n g F or m 
T he i nitial re p ort s h o ul d i ncl u de: 
•  St u d y n u m ber ( M V T- 6 0 1 - 3 1 0 3); 
•  Site a d dress a n d n u m ber ; 
•  I n vesti gat or na me; 
•  Patie nt I D n u m ber, se x, a n d a ge; 
•  Details of st u d y dr u g a d mi nistrati o n ; 
•  T he date of t he re p ort; 
•  A descri pti o n  of t he seri o us a d verse e ve nt (e ve nt ter m, seri o us ness of t he e ve nt, date of o nset, 
i nte nsit y); 
•  Ca usal relati o ns hi p t o t he st u d y dr u g. 
P P D
P P D
P P D


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If the patient died, the report should include the cause of death as the event term (with death as 
outcome) and whether or not the event leading to death was related to study drug treatment, 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 > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 x the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose.  
In the event of an overdose, the investigator or treating physician should: 
• 
Contact the medical monitor within 24 hours; 
• 
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 
safety report  form according to Section 7.6, whether or not the overdose is associated with 
an adverse event; 
• 
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 any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  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 
form, as available.  Document the pregnancy in the eCRF as well. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 


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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.5.2 details the requirements for measurement of safety parameters including vital 
signs, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on endometriosis-associated pain.  Low-dose hormonal 
add-back therapy with estradiol and norethindrone acetate will be evaluated for maintenance of 
bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 
reproductive toxicity, and metabolic and cardiovascular changes (insulin resistance, 
dyslipidemia, increased weight) with an increased risk of diabetes mellitus and possible 
increased risk of cardiovascular disease.  Additionally, there are potential risks associated with 
the addition of estradiol/norethindrone acetate.  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 strategy for this protocol are outlined in Table 7-2. 
Table 7-6 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
Week 52, and 
Week 104/Early Termination 
visits with specified 
discontinuation and follow-
up criteria and all fractures 
will be reported as adverse 
events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 


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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52visits, and as 
clinically applicable; 
withdrawal for QTcF 
> 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
Period will be reported 
within 24 hours of study 
personnel awareness. 
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, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
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. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 


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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each study 
visit;  
A mammogram will be 
performed at Week 52 or at 
Week 104/Early Termination 
for women who are or 
become ≥ 40 years old 
during the study, with 
specified discontinuation 
criteria.  Adverse events will 
be recorded 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; QTc = corrected QT 
interval; QTcF = QT interval by the Fridericia correction; PLD = phospholipidosis; 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 (GCP) 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 GCP.  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 (WHO-DDE), 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. 


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9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  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. 
There will be two analyses: one at Week 52 and one at Week 104.  A clinical study report will be 
generated from each analysis. 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 80 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the Modified Intent-to-Treat (mITT) Population, 
defined as all patients who were randomized in a parent study (MVT-601-3101 or 
MVT-601-3102) and who have received any amount of randomized study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of randomized study drug. 
The analysis methods for safety and efficacy endpoints are the same as those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Justification 
Because this is an extension study, the sample size will be determined by the number of patients 
who have completed a parent study and who are eligible and willing to participate in the 
extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 
9.4. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the mITT Population.  
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
The point estimates and 2-sided 95% confidence intervals (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic 
medications, proportion of responders based on NMPP scores and use of rescue analgesic 
medications) will be calculated. 


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A responder at a given time point and for a specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that type of pain from Baseline in the parent study 
greater than or equal to a pre-determined threshold and who did not have an increase in the use 
of rescue analgesic medications for endometriosis-associated pain compared with the use at 
Baseline. Patients who had a pain reduction less than the pre-determined threshold or who had an 
increase in the use of analgesics for endometriosis-associated pain will be considered non-
responders.  The pain reduction thresholds will be determined for NMPP and dysmenorrhea 
separately (see the SAP for details) for the parent studies and these same thresholds will be 
applied to this study. 
Baseline values are calculated using the Baseline pain assessment period, which is defined as the 
period from the date of the first dose of placebo in the parent study Run-In Period through the 
day prior to the first dose of randomized study drug.  Patients’ average NRS pain scores and use 
of rescue analgesic medications for endometriosis-associated pain (dysmenorrhea or NMPP) will 
be compared between a given visit-specific pain assessment period (eg, Week 28, Week 32, etc.) 
and the Baseline pain assessment period.  The visit-specific pain assessment period is defined as 
the last 35 calendar days immediately prior to and including the last dose of study drug treatment 
received prior to the visit date. 
For any pain assessment period (Baseline or visit-specific), the average NRS scores will be 
calculated for dysmenorrhea and NMPP separately.  An average NRS score for dysmenorrhea is 
calculated as the average NRS score over the days with menses during a given pain assessment 
period.  An average NRS score for NMPP is calculated as the average NRS score over the days 
without menses during a given pain assessment period.  The analgesic use for a given pain 
assessment period is summarized by total dose count defined as the average daily dose count 
taken during the given pain assessment period multiplied by 35.  Additional details on 
calculating dose counts and on the precise definition of an increase in analgesic use will be 
provided in the SAP. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies at Week 52 and Week 104. 
• 
Change from the parent study Baseline in the EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline to in the mean dysmenorrhea NRS score; 
• 
Proportion of patients who are better or much better on the PGIC for dysmenorrhea; 
• 
Change from the parent study Baseline in the mean NMPP NRS score; 
• 
Change from the parent Baseline in the mean NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using analgesics; 
• 
Proportion of patients who are better or much better on the PGIC for NMPP; 
• 
Change from the parent study Baseline in the mean dyspareunia NRS scores; 
• 
Proportion of patients who are better or much better on the PGIC for dyspareunia; 


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• 
Change from the parent study Baseline in the mean dyspareunia functional impairment on the 
sB&B scale; 
• 
Change from the parent study Baseline in severity scores on the PGA for pain; 
• 
Proportion of responders based on EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline in function impairment on the PGA for function; 
• 
Change from the parent study Baseline in each of the non-pain EHP-30 domains (Control and 
Powerlessness, Social Support, Emotional Well-Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period in NMPP-related functional 
effects (sB&B). 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
For endpoint of proportion of responders based on EHP-30 Pain Domain scores, a responder is 
defined using the same within-patient score change threshold determined from the parent studies.  
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, 
mammograms (women ≥ 40 years of age), and endometrial biopsy.  Safety summaries by 
treatment group will be performed using treatment groups defined based on the actual 
randomized treatment received in the parent study. 
The treatment-emergent period will be defined as the period of time from the first dose date and 
time of randomized study drug in the parent study through 30 days after the last dose of study 
drug, or the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for endometriosis, whichever occurs 
first.  Safety will be assessed through summaries of adverse events, the frequency of treatment 
discontinuations due to adverse events, laboratory evaluations, and bone densitometry results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute CTCAE.  All adverse events will be coded to preferred term, high level term, 
and system organ class using MedDRA 20.0 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 to do the analyses.  The National Cancer Institute CTCAE will 
be used to categorize toxicity grade for the laboratory parameters.  Shift tables will be provided 


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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 
parent study Baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from parent study Baseline to each post-baseline study visit will be presented 
by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  Electrocardiograms will also 
be read centrally.  The distributions of QTc interval will be summarized at each visit.  All data 
will be listed and summarized by visit.  The change from parent study Baseline to each post-
baseline study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for percent change at 
Week 52 from parent study Baseline in bone mineral density will be provided based on mixed 
effects model (assumed missing at random) for each parent study treatment group.  The 95% CI 
for mean percentage change at Week 104 from parent study Baseline in bone mineral density 
lumbar spine (L1-L4) will be provided along with descriptive statistics for bone mineral density 
loss at Week 104 as supportive analyses. 
All data will be listed and summarized by visit.  The absolute change and percent change from 
parent study Baseline to Weeks 36, 52, and 104 and associated 95% CIs will be presented by the 
parent study treatment group for each bone mineral density parameter.  The number and 
percentage of patients meeting a bone mineral density decline of at least 4%, 5%, 6%, or 7% by 
body area (lumbar spine, total hip, or femoral neck) will be estimated with 95% CIs by the parent 
study treatment group. 
Additional analyses will be performed to examine the correlation between bone mineral density 
loss with demographic and baseline characteristics and with treatment exposure.  Details will be 
provided in the SAP. 


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9.6. 
Pharmacodynamics Analyses 
The change from the parent study Baseline to Week 52 and to Week 104 in predose 
concentrations of serum estradiol will be summarized.  Percentage of patients with 
concentrations of serum estradiol levels < 10 pg/mL and < 20 pg/mL will be provided. 
9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed at Week 52 and Week 104: 
• 
Change from Baseline in the EHP-30 scale total score; 
• 
Change from Baseline in the EHP Work Domain score; 
• 
Change from parent study Baseline in the EQ-5D-5L. 
9.8. 
Interim Analyses 
An interim analysis will be conducted at Week 52 in which all efficacy and safety endpoints will 
be assessed as described above.  A clinical study report will be generated based on these data to 
support submission of one-year data. 
9.9. 
Steering Committee 
The study will be overseen by a Steering Committee consisting of experts in the field of 
women’s health and staff members of Myovant Sciences GmbH.  The Steering Committee will 
participate in the design, conduct, analyses, and publication of the study. 


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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 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, 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, 1998, 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 1 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 
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 


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signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
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. 
10.1.5. 
Study Files and Retention of Records 
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 two 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 drug (drug dispensing, return, and 
accountability should be documented as well); 


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− 
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 indication; and 
− 
Date of study completion and reason for early termination, 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, decoding procedures for blinded studies, 
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. 
10.1.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed as specified in the Investigator Site File.  
The eCRF casebook for each study patient will be signed by the investigator or sub-investigator 
(as appropriate) listed on the 1572 and/or other appropriate local health authority documents.  
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. 
10.1.7. 
Investigational Product Accountability 
The investigator or investigator’s designee (eg, pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, accountability, and returned or destroyed study 


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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 once the study monitor has reviewed 
and returned used and unused study drug for accountability purposes.  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. 
10.1.8. 
Inspections 
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. 
10.1.9. 
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. 
Safety Reporting 
The sponsor will comply with safety reporting requirements consistent with US FDA, European 
Union (EU) National competent authority, and Health Canada Guidance 2.8.4, Health Canada 
Food and Drugs Act and Regulations, Division 5, Part C.05.014, and applicable ICH and 
regional regulatory safety reporting requirements. 
10.2.2. 
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 appropriate IRB or IEC 
for information and approval in accordance with local requirements and to the appropriate Health 
Authority (eg, FDA, Health Canada, EU National competent authority), if required.  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. 


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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. 
10.2.3. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies) at Week 52 
and a second clinical study report will be prepared at the end of the study (Week 104).  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).  An abbreviated report may be prepared in 
certain cases. 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
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 GCP 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.  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. 
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: 


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• 
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). 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
study must be submitted to Myovant for corporate review.  The Clinical Study Agreement 
among the institution, principal investigator, and Myovant will detail the procedures for, and 
timing of, Myovant’s review of publications. 


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11. 
REFERENCES 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 02 October 2017. 
Archer DF, Chwalisz K, Feldman R, et al.  Elagolix for the management of heavy menstrual 
bleeding (HMB) associated with uterine fibroids (UF): Results from a phase 2A proof-of-
concept study. Fertil Steril. 2017 Jul;108(1);152-60.e4. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J 
Obstet Gynec.1992 Feb;166(2):740-5. 
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for 
add-back therapy with gonadotropin-releasing hormone agonists in women with 
endometriosis. Reprod Sci. 2012 Mar;19(6):563-71. 
Dunselman GA, Vermeulen N, Becker Cet al. European Society of Human Reproduction and 
Embryology. ESHRE guideline: management of women with endometriosis. Hum 
Reprod. 2014 Mar;29(3):400-12. 
Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. US Dept. of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research, Center for Biologics 
Evaluation and Research. July 2009. 
Franke HR, van de Weijer PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist 
plus add-back’ hormone replacement therapy for treatment of endometriosis: a 
prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000 
Sep;74(3):534-9. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstet Gynecol. 1998 Jan;91(1):16-24. 
Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on hypoestrogenic 
problems by postoperative gonadotropin-releasing hormone agonist treatment in 
endometriosis. Obstet Gynecol Sci. 2016 Jan;59(1):32-8. 
Morris EP, Rymer J, Robinson J, Fogelman I. Efficacy of tibolone as add-back therapy’ in 
conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine 
fibroids. Fertil Steril. 2008 Feb;89(2):421-8. 
Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic 
pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reprod Health. 2015 Mar;21(1):16-23. 
Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P. Differences in 
characteristics among 1,000 women with endometriosis based on extent of disease. Fertil 
Steril. 2008 Mar;89(3):538-45. 
Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
therapy in treatment of endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014 
Sep;290(3):513-23. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
in the treatment of endometriosis-associated pain. Fertil Steril. 2004 Nov;82(5):1303-8. 
 


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12. 
APPENDICES 
 
Protocol-Specified Rescue Analgesics 
The medications below are listed based on their dose strength. The prescription (or instructions 
for use) for these medications may allow for use of more than one tablet at any given time. 
Analgesics should be prescribed in accordance with the respective country’s approved product 
labeling.  The subject’s historical use of opioid analgesics should be taken into consideration 
when prescribing these drugs.  
Only one Tier 2 medication should be selected for a given patient to be used throughout the 
study.  
Study-specified analgesics include: 
• 
Tier 1 
− 
ibuprofen (200 mg dose strength) 
• 
Tier 21 
− 
tramadol (37.5 mg) / paracetamol (325 mg) 
− 
tramadol (50 mg) 
− 
codeine (30 mg) 
− 
codeine (30 mg) / paracetamol (300 mg) 
− 
codeine (30 mg) / paracetamol (500 mg) 
− 
codeine 15 mg/ paracetamol (500 mg) 
− 
hydrocodone (5 mg) / acetaminophen 325 mg 
 
Please consult your site-specific instructions for study-specified analgesics for your country. 
 
 
 
 
 
1All second-tier drugs that contain acetaminophen or paracetamol are fixed-dose combination products (eg, single 
tablet containing both drugs). 
 


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Daily eDiary 
 


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Endometriosis Health Profile-30 
ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. 
Ben unable to go to social events 
because of the pain? 
 
 
 
 
 
 
 
2. 
Ben unable to do jobs around the 
house because of the pain? 
 
 
 
 
 
 
3. 
Found it dificult to stand because 
of the pain?
 
 
 
 
 
 
 
4. 
Found it dificult to sit because 
 
of the pain?
 
 
 
 
 
 
 
5. 
Found it dificult to walk because 
 
of the pain?
 
 
 
 
 
 
 
6. 
Found it dificult to exercise or do 
the leisure activities you would like 
to do because of the pain? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page.
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
7. 
Lost your apetite and/or ben 
unable to eat because of the pain?
 
 
 
 
 
 
 
8. 
Ben unable to slep properly 
because of the pain?
 
 
 
 
 
 
 
9. 
Had to go to bed/lie down because 
of the pain?
 
 
 
 
 
 
 
10. Ben unable to do the things you 
want because of the pain? 
 
 
 
 
 
 
11. Felt 
unable to cope with the pain?
 
 
 
 
 
 
 
12. Generaly felt unwel?
 
 
 
 
 
 
 
13. Felt frustrated because your 
symptoms are not geting beter? 
 
 
 
 
 
 
14. Felt frustrated becaus
e you are 
not 
able to control your symptoms? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page.
 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
15. Felt unable to forget your 
symptoms? 
 
 
 
 
 
 
16. Felt as though your symptoms 
are ruling your life?
 
 
 
 
 
 
 
17. Felt your symptoms are taking 
away your life? 
 
 
 
 
 
 
18. Felt depresed? 
 
 
 
 
 
 
19. Felt wepy/tearful? 
 
 
 
 
 
 
20. Felt miserable? 
 
 
 
 
 
 
21. Had mod swings? 
 
 
 
 
 
 
22. Felt bad-tempered or short-
tempered? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page.
 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
23. Felt violent or agresive? 
 
 
 
 
 
 
24. Felt unable to tel others how 
you fel?
 
 
 
 
 
 
 
25. Felt others do not understand 
what you are going through? 
 
 
 
 
 
 
26. Felt as though others think 
you are whining? 
 
 
 
 
 
 
27. Felt alone?
 
 
 
 
 
 
 
28. 
Felt frustrated that you canot 
always wear the clothes you 
would chose? 
 
 
 
 
 
 
29. Felt your apearance has ben 
afected?
 
 
 
 
 
 
 
30. Lacked confidence?
 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question. 
 


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CONFIDENTIAL 
 
European Quality of Life Five-Dimension Five-Level Scale 
 


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CONFIDENTIAL 
 
Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 


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Patient Global Impression of Change and Patient Global 
Assessments 
Patient Global Impression of Change (Dysmenorrhea) 
Compared to when you started the treatment in this study, painful periods are  
1. Much better  
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
Patient Global Impression of Change (Nonmenstrual Pelvic Pain) 
Compared to when you started the treatment in this study, your pelvic pain when you are not 
having a period (i.e. not on your period) overall is  
1. Much better 
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly 
button. 
Patient Global Impression of Change (Dyspareunia) 
Compared to when you started the treatment in this study, your pelvic pain when you have 
vaginal sexual intercourse is  
1. Much better 
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
ϒ Not applicable: I have not had vaginal sexual intercourse since starting the study treatment 
For this study, we define vaginal sexual intercourse as penetration of any duration. 


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Patient Global Assessment (for pain) 
How would you rate your pelvic pain right now? 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly button 
Absent 
Mild 
Moderate 
Severe 
Very Severe 
Patient Global Assessment (for function) 
How much were your daily activities limited by endometriosis over the last 4 weeks?  
Not at all 
Minimally 
Moderately 
Significantly  
Very significantly 
Note: PGA for function is administered via a paper questionnaire. 


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Endometriosis Health Profile - Work Domain 
 
Note: EHP Work Domain is administered via a paper questionnaire. 
 


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Assessment of Abnormal Liver Function Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) 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 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]), Alkaline Phosphatase, and INR Tests  
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities improve 
If ALT or AST ≥ 3 × 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 
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; 
• 
CBC 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; 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
CBC = complete blood count; 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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Breast Imaging Reporting and Data System 
Category 
Assessment 
Follow-Up 
0 
Need additional imaging evaluation:  means 
that more studies are necessary to gather more 
information. 
Additional imaging needed before a category can 
be assigned. 
1 
Negative:  means that there is no significant or 
noticeable abnormality to report. 
Continue annual screening mammography (for 
women over age 40). 
2 
Benign (noncancerous) finding: means that 
there has been a finding, such as benign 
calcifications or fibroadenoma, which is not 
cancerous. 
Continue annual screening mammography (for 
women over age 40). 
3 
Probably benign:  means that there is a finding 
that is most likely benign, but should be 
followed in a shorter period of time to see if the 
area of concern changes. 
Receive a 6-month follow-up mammogram. 
4 
Suspicious abnormality:  means that there are 
suspicious findings that could turn out to be 
cancer. 
May require biopsy. 
5 
Highly suggestive of malignancy (cancer):  
means that there are findings that look like and 
probably are cancer. 
Requires biopsy. 
6 
Known biopsy-proven malignancy (cancer):  
means that any findings on the mammogram 
have already proven to be cancer through a 
biopsy. 
Biopsy confirms presence of cancer before 
treatment begins. 
 
 


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Guidance for Study Conduct during the COVID-19 
Pandemic 
The novel coronavirus 2019 (COVID-19) pandemic has impacted the conduct of clinical trials 
globally.  Regional quarantine laws, travel restrictions, and site closures present challenges to 
normal study conduct and may lead to missed study visits or procedures or an interruption to a 
patient’s study drug supply. 
Myovant Sciences has thoroughly reviewed guidance documents from various country and 
regional regulatory agencies and has put mitigation plans in place to ensure the safety of patients 
is maintained, the study continues to be conducted in compliance with good clinical practice 
(GCP), and risks to the integrity of the study are minimized.  These plans will remain in place 
through the duration of the COVID-19 pandemic. 
Safety During the COVID-19 Pandemic 
Protecting study patients, investigational site staff and clinical service providers involved in 
Myovant Sciences clinical studies from activities that may unnecessarily increase the risk of 
contracting COVID-19 is of utmost importance.  Regulations and policies instituted for safety 
purposes during the COVID-19 pandemic at the institutional, local, country, and regional level 
should be adhered to. 
Protocol Adherence 
Wherever possible and safe, study visits and procedures must be performed as outlined in the 
protocol to ensure patient safety and to maintain the integrity and interpretability of the study 
data.  While modifications to normal study conduct may, in some cases, be necessary and 
unavoidable, they must be documented and reported where in conflict with the study protocol 
and this guidance.  Deviations from the protocol will be documented, but those resulting 
specifically from the COVID-19 pandemic will be marked as such.  All deviations resulting from 
the COVID-19 pandemic will be summarized in the clinical study report. 
Visit Schedules and Study Procedures 
Local policies, institutional restrictions, and/or patient ability/willingness to make site visits may 
curtail the ability to adhere to the in-person, on-site visit schedule required by the protocol.  
Investigators at clinical sites should evaluate the appropriateness of an on-site study visit during 
the COVID-19 pandemic. 
If a clinical study site remains open for on-site patient visits, patients should be encouraged to 
return for study visits, if willing and able, in the earliest allowable portion of the visit window, 
taking all measures to prevent contracting COVID-19. 
• 
All protocol required study procedures should be performed whenever possible. 
• 
Safety assessments should be prioritized if only limited assessments are performed. 
• 
If assessments are limited, Investigators should document whether the assessments 
performed are adequate to ensure it is safe for the patient to continue in the study. 


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• 
Investigators should use all available information to determine whether in-person 
visits are necessary to fully assure the safety of study patients (for example to carry 
out procedures necessary to assess safety or the safe use of the study drug 
appropriately) or whether alternative means of assessment are adequate to assure the 
safety of continuing patients in the study.  Such decisions should be documented.  
Investigators can contact the Myovant medical monitor for consultation as necessary. 
If the clinical study site is closed or the patient is unable/unwilling to attend on-site study 
visits due to the COVID-19 pandemic, alternative methods for completing assessments (eg, 
phone contact or virtual visit) should be implemented. 
• 
Investigators must assess and evaluate the patient’s continued participation and dosing with 
limited safety assessment. 
• 
At a minimum, investigational site staff should make every attempt to contact the patient via 
telephone when an expected visit is due or missed to assess for adverse events, document 
concomitant medications, and study drug dosing since the last study visit. 
• 
If the safety blood draws cannot be performed through the central laboratory per protocol, the 
investigator may advise the patient to have blood drawn at a local laboratory if there is a 
safety concern.  If two consecutive study visits are missed and the patient is unable to return 
to the site, the investigator should advise the patient to have protocol specified safety labs 
completed at a local laboratory to assess for any safety concerns. In both cases, the local 
laboratory results should be documented in the eCRF. 
• 
Investigational sites should report all serious adverse events, adverse events of clinical 
interest, overdose, and pregnancy that the patient reports during these calls within 24 hours of 
awareness. 
• 
Patients should be reminded of the importance of taking study treatment daily, adhering to 
protocol-specified analgesics, and taking non-hormonal contraception. 
• 
Study patients should continue to complete their daily eDiary, even if they run out of study 
drug, and site staff should motivate them to do so. 
Patients should have the contact details of the investigational site medical staff to report any 
medical issues, including adverse events  they may experience in real time. 
As soon as the study patients are able to return to the investigational site for an on-site visit, they 
should return either for their next scheduled visit (if still within protocol window) or for an 
unscheduled visit (if outside of expected protocol visit window). 
Study Participant Study Drug Supply 
If a regional lockdown, travel restrictions, or site closure is imminent due to the COVID-19 
pandemic, sites are encouraged to dispense additional study drug at an expected study visit or 
request patients to return for an unscheduled visit for additional study drug dispensation so 
patients have sufficient supply until their next upcoming visit.  Patients should be instructed to 
contact the site to report any medical issues they may experience and site staff should 
communicate with the patients to determine if it is appropriate for the patient to continue dosing 
with study drug if/when in-person study visits are not possible. 


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For cases where study patients are unable to visit the investigational site to pick up study drug, a 
direct-to-patient (DTP) delivery of study drug by site staff or shipment via contracted courier 
may be possible.  Consent authorizing DTP supply will be obtained.  Sites should defer to 
national guidance on how this will occur.  Where permitted by national guidance, verbal consent 
will be taken via telephone or video call and noted in the patient’s source file. Where required, 
by national guidance, this will be followed up with written consent during the next clinic visit.  
Every effort will be made to obtain the patient’s written consent for DTP prior to delivery or 
shipment, where this is required by national guidance. 
In the event that none of the above are possible for participants to continue taking study 
medication, a patient may need to be discontinued per the study protocol.  Such decisions will be 
made on a case-by-case basis in discussion with the Investigator and medical monitor. 
Onsite Study Monitoring Restrictions 
In the event study monitors/clinical research associates are not allowed to travel and/or return to 
a clinical site to monitor and source document verify study data, Myovant has developed plans to 
ensure monitors: 
• 
Remotely verify source documentation as much data as reasonably possible without 
burdening sites, if allowed by the study site and country regulations, focusing on pages key 
to the interpretability of the study and the safety of participants. 
• 
Remotely monitor study data through cross checking of various systems housing patient data 
against what is captured in the eCRFs. 
Additional guidance on conducting clinical trials during the COVID-19 pandemic may be found 
in the following documents released by Regional Health Authorities, which may be updated 
(updates supersede the versions listed here): 
• 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic Guidance for Industry, Investigators, and Institutional Review Boards (March 
2020 – updated June 03, 2020); 
• 
European Medicines Agency Guidance on the Management of Clinical Trials during the 
COVID-19 (Coronavirus) pandemic (28 April 2020). 
 


 
Clinical Study Protocol 
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CONFIDENTIAL 
AMENDMENT 3:  SUMMARY OF CHANGES 
The MVT-601-3103 clinical study protocol has been amended as described in the table below.  
The primary purpose of the amendment is to include a mammogram at Week 52 or Week 
104/Early Termination for women ≥ 40 years old. 
A detailed list of changes is described below, where deleted text is indicated by strikethrough 
and new text is indicated with bold formatting.  Note that the correction of typos, minor 
clarifications, and minor wording changes to improve readability, understanding, and 
consistency may not be included in this table. 
 


 
Clinical Study Protocol 
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Section 
Item 
Original 
Amendment 3 
Rationale 
Title Page 
Amendment 2: 11 Dec 2018 
Amendment 2: 11 Dec 2018 
Amendment 3: 01 JUL 2020 
Added current version and date. 
Sponsor Signature 
Page 
Protocol Number:  MVT-601-3103 Amendment 
2 
Protocol Number:  MVT-601-3103 Amendment 
3 
Updated amendment number. 
List of 
Abbreviations 
 
COVID-19 
novel coronavirus 2019 
 
Added new abbreviation. 
List of 
Abbreviations 
 
DTP 
direct-to-patient 
 
Added new abbreviation. 
List of 
Abbreviations 
 
SDV 
source data verification 
 
Added new abbreviation. 
1.  Synopsis 
Secondary Efficacy 
Objectives 
• 
Nonmenstrual pelvic pain (NMPP), as 
measured by the NRS for NMPP; 
• 
PGIC for NMPP; 
• 
Nonmenstrual pelvic pain (NMPP), as 
measured by the NRS for NMPP; 
• 
Overall pelvic pain, as measured by the 
NRS; 
• 
Analgesic use; 
• PGIC for NMPP; 
Included additional objectives 
to evaluate pelvic pain and 
analgesic use. 
1.  Synopsis 
Secondary Efficacy 
Endpoints 
 
• 
Change from the parent Baseline in the 
mean NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using 
analgesics; 
Included additional endpoints 
to evaluate pelvic pain and 
analgesic use. 
1.  Synopsis 
Study Design 
Safety will be assessed throughout the study by 
the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical 
laboratory tests, 12-lead ECGs, and bone mineral 
density with DXA. 
Safety will be assessed throughout the study 
by the monitoring of adverse events, vital 
signs and weight, physical examinations, 
clinical laboratory tests, 12-lead ECGs, 
mammograms (for women ≥ 40 years of 
age), endometrial biopsies, and bone 
mineral density with DXA. 
Added mammogram for 
patients over 40 years age. 
1.  Synopsis 
Study Design 
 
• If patients have 6-month post-treatment 
follow-up scans that show bone loss of 
> 1.5% at the lumbar spine and/or > 2.5% 
at total hip compared with parent study 
baseline, patients are strongly encouraged 
to come back to the clinic for an additional 
post-treatment follow-up scan 12 months 
Clarified follow-up procedures 
for bone mineral density loss. 


 
Clinical Study Protocol 
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CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3 
Rationale 
from the date of the last dose of the study 
drug. 
• If patients have 12-month post-treatment 
follow-up scans that show bone loss of 
≥ 3% at the lumbar spine and/or total hip 
compared with parent study baseline, 
patients are referred to and strongly 
encouraged to see a bone specialist for 
further evaluation of the bone loss. 
Note:  When a patient is referred to a bone 
specialist for evaluation and management, 
Myovant will provide a Bone Consultation 
Letter to the investigator for this 
additional bone consult and will request 
the site to provide a summary of the 
evaluation and management plan once 
achieved. 
1.  Synopsis 
Study Design 
Status of menstruation recovery will be 
documented at the Follow-up visit.  Patients 
whose menses has not resumed as of the 
Follow-Up visit for whom there is no 
explanation for the lack of resumption 
(eg, medical procedure or medications) will be 
contacted again by telephone 3 (+ 0.5) months 
after the Follow-Up visit to determine if menses 
has resumed and will be asked about factors that 
may affect resumption of menses. 
Status of menstruation recovery will be 
documented at the Follow-up visit.  Patients 
whose menses has not resumed as of the 
Follow-Up visit for whom there is no 
explanation for the lack of resumption 
(eg, medical procedure or medications) will be 
contacted by telephone 3 (+ 0.5) months after the 
Follow-Up visit to determine if menses has 
resumed and will be asked about factors that may 
affect resumption of menses.  If a patient is lost 
to follow-up, three documented attempts 
should be made to contact the patient by 
telephone.  If unable to contact the patient by 
telephone, a certified letter must be sent to the 
patient. 
Clarified procedures for when a 
patient is lost to follow-up. 
1.1. 
 Schedule 
of Activities 
12-Lead ECG 
Week 104/Early 
Termination 
 
Xh 
Added ECG at Week 104/Early 
Termination visit. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3 
 
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CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3 
Rationale 
1.1.  Schedule of 
Activities 
Clinical Laboratory 
Tests during Safety 
Follow-up 
 
Xee 
Added clinical laboratory tests 
during follow-up period since 
they may be included as part of 
bone densitometry follow-up. 
1.1.  Schedule of 
Activities 
Bone Densitometry 
during Safety 
Follow-up 
 
Xee 
Added bone densitometry 
follow-up. 
1.1.  Schedule of 
Activities 
Endometrial 
Biopsy during 
Safety Follow-up 
 
Xee 
Added endometrial biopsy 
follow-up. 
1.1.  Schedule of 
Activities 
Status of 
Menstruation 
Recovery during 
Safety Follow-up 
Xbb 
Xbb,ee 
Added clarifying footnote for 
status of menstruation recovery 
during safety follow-up. 
1.1.  Schedule of 
Activities 
 
Mammogram at Week 52, Week 104/Early 
Termination, and Unscheduled 
 
Xdd 
Added mammogram for 
patients over 40 years age. 
1.1.  Schedule of 
Activities 
Footnote r 
This procedure is not required at the Early 
Termination visit in patients whose last dose of 
study drug was taken during Week 32 or earlier 
or within 4 weeks after completion of the Week 
36 or Week 52 scan. However, the procedure 
may be done if it will aid in the evaluation of an 
ongoing adverse event. 
See Section 6.5.2.6 for details on the timing 
and follow-up of bone densitometry. 
Clarified bone densitometry 
follow-up. 
1.1.  Schedule of 
Activities 
Footnote t 
Endometrial biopsies are to be done per 
instructions in the parent study.  Procedures for 
handling and shipping biopsy samples to the 
central laboratory for analysis are described in 
the Investigator Site File.  An endometrial biopsy 
will have been performed at the parent study 
Endometrial biopsies are to be done per 
instructions in the parent study.  Procedures for 
handling and shipping biopsy samples to the 
central laboratory for analysis are described in 
the Investigator Site File.  An endometrial biopsy 
will have been performed at the parent study 
Clarified endometrial biopsy 
procedures. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3 
 
Myovant Sciences GmbH 
5 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3 
Rationale 
Week 24 visit for all patients who participated in 
MVT-601-3101 only (see MVT-601-3101 
protocol for details), at Week 52 for all patients.  
All patients are eligible for a biopsy at Week 
104; however, patients will have the option to 
opt out. 
Week 24 visit for all patients who participated in 
MVT-601-3101 only (see MVT-601-3101 
protocol for details) and at Week 52 and Early 
Termination visit for all patients.  This 
procedure is not required at the Early 
Termination visit in patients whose last dose 
of study drug was taken during Week 32 or 
earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, 
the procedure may be done if it will aid in the 
evaluation of an ongoing adverse event.  An 
endometrial biopsy at Week 104 is 
recommended for all patients who complete 
the open-label extension; however, patients will 
have the option to opt out. 
1.1.  Schedule of 
Activities 
Footnote bb 
Patients whose menses have not resumed as of 
the Follow-up visit for whom there is no 
explanation for the lack of resumption (eg, 
medical procedure or medications) will be 
contacted again by telephone 3 (+0.5) months 
after the Follow-Up visit to determine if menses 
has resumed and questioned about factors that 
may affect resumption of menses. 
Patients whose menses have not resumed as of 
the Follow-up visit for whom there is no 
explanation for the lack of resumption (eg, 
medical procedure or medications) will be 
contacted by telephone 3 (+0.5) months after the 
Follow-Up visit to determine if menses has 
resumed and questioned about factors that may 
affect resumption of menses.  If a patient is lost 
to follow-up, three documented attempts 
should be made to contact the patient by 
telephone.  If unable to contact the patient by 
telephone, a certified letter must be sent to the 
patient. 
Clarified procedures for when a 
patient is lost-follow-up. 
1.1.  Schedule of 
Activities 
Footnote dd 
 
For patients ≥ 40 years old at the time of the 
Week 52 visit, Week 104 visit, or Early 
Termination visit only.  See Section 6.5.2.9. 
Added clarification on timing 
of mammograms. 
1.1.  Schedule of 
Activities 
Footnote ee 
 
See Section 6.5.2.6, Section 6.5.2.7, and 
Section 6.5.2.8 to determine if additional 
follow-up is required. 
Add cross-references for 
additional information on safety 
follow-up. 
3.  Study 
Objectives and 
Endpoints 
 
Objectives 
• Overall pelvic pain, as measured by the 
NRS; 
• Analgesic use; 
Included additional objectives 
and corresponding endpoints to 
evaluate pelvic pain and 
analgesic use. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3 
 
Myovant Sciences GmbH 
6 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3 
Rationale 
Endpoints 
• Change from the parent Baseline in the 
mean NRS score; 
• Proportion of patients not using opioids; 
• Proportion of patients not using 
analgesics; 
4.1.  Overall Study 
Design 
Safety will be assessed throughout the study by 
the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical 
laboratory tests, 12-lead ECGs, and bone mineral 
density with DXA. 
 
Safety will be assessed throughout the study by 
the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical 
laboratory tests, 12-lead ECGs, mammograms 
(for women ≥ 40 years of age), endometrial 
biopsies, and bone mineral density with DXA. 
 
Added mammogram for 
patients over 40 years age. 
4.1.  Overall Study 
Design 
Status of menstruation recovery will be 
documented at the Follow-up visit.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted again by 
telephone 3 (+ 0.5) months after the Follow-Up 
visit to determine if menses has resumed and will 
be asked about factors that may affect 
resumption of menses. 
Status of menstruation recovery will be 
documented at the Follow-up visit.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted by telephone 3 
(+ 0.5) months after the Follow-Up visit to 
determine if menses has resumed and will be 
asked about factors that may affect resumption of 
menses.  If a patient is lost to follow-up, three 
documented attempts should be made to 
contact the patient by telephone.  If unable to 
contact the patient by telephone, a certified 
letter must be sent to the patient. 
Clarified procedures for when a 
patient is lost to follow-up. 
4.5.  Removal of 
Patients from 
Therapy 
 
Evidence of malignant breast lesion(s) or 
breast carcinoma on Week 52 or 
Week 104/Early Termination or most recent 
mammogram or additional breast imaging 
(see Section 6.5.2.9 for more information on 
mammogram at Week 52 or Week 104/Early 
Termination); 
Included removal criteria for 
findings resulting from 
mammogram. 
4.6.  Contraception 
/Pregnancy 
Avoidance 
In this study, medications and devices containing 
hormones for contraception are excluded, and 
patients must agree to use non-hormonal 
All patients should be counseled at every visit 
to adhere to the use of protocol allowed 
contraceptive methods.  In this study, 
Added language for increased 
counselling on contraception. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3 
 
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contraception throughout the study including 
through 30 days following the last dose of study 
drug, unless any of the following apply: 
medications and devices containing hormones 
for contraception are excluded, and patients must 
agree to use non-hormonal contraception 
throughout the study including through 30 days 
following the last dose of study drug, unless any 
of the following apply: 
4.7.  Novel 
Coronavirus 2019 
Guidance 
 
Guidance for conducting clinical trials during 
the novel coronavirus 2019 (COVID-19) 
pandemic is included in Appendix 9. 
Included COVID-19 guidance. 
5.1.  Treatments 
Administered 
Table 5-1 
Description of MVT-601-3003 Study Drugs 
Description of MVT-601-3103 Study Drugs 
Corrected study number. 
5.10.1.  Prohibited 
Medications 
Table 5-2 
Intrauterine devices:  levonorgestrel 
 
copper 
Intrauterine devices:  levonorgestrel 
Removed copper to reduce 
confusion with inclusion 
criterion 6c. 
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 6.5.  Further 
details of the procedures are provided in the 
Investigator Site File. 
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 6.5.  Further 
details of the procedures are provided in the 
Investigator Site File.  Guidelines to address 
the COVID-19 pandemic are included in 
Appendix 9. 
Included COVID-19 guidance. 
6.2.  Open-Label 
Treatment Period 
(Week 24/Baseline 
to Week 104) 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see MVT-
601-3101 protocol for details), at Week 52 for all 
subjects.  All patients will be eligible for the 
Week 104 biopsy; however, patients will have 
the option to opt out.  Safety monitoring for this 
study includes physical examination, clinical 
laboratory tests, pregnancy tests, and adverse 
event collection at each visit.  Clinical 
chemistries will be collected at each visit.  A 
complete blood count will be collected at Week 
24/Baseline, Week 28, Week 36, Week 52, Week 
65, Week 78, and Week 104.  At the Week 
24/Baseline visit, Week 52 visit, and Week 104 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see MVT-
601-3101 protocol for details).  An endometrial 
biopsy is required at Week 52 and the Early 
Termination visit for all patients.  This 
procedure is not required at the Early 
Termination visit in patients whose last dose 
of study drug was taken during Week 32 or 
earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, 
the procedure may be done if it will aid in the 
evaluation of an ongoing adverse event.  An 
endometrial biopsy at Week 104 is 
recommended for all patients who complete 
Clarified endometrial biopsy 
timing. 


 
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visit, additional tests include fasting (at least 8 
hours, other than water) glucose, lipid profile, 
and hemoglobin A1c. 
the open-label extension; however, patients will 
have the option to opt out.  Safety monitoring for 
this study includes physical examination, clinical 
laboratory tests, pregnancy tests, and adverse 
event collection at each visit.  Clinical 
chemistries will be collected at each visit.  A 
complete blood count will be collected at Week 
24/Baseline, Week 28, Week 36, Week 52, Week 
65, Week 78, Week 91, and Week 104.  At the 
Week 24/Baseline visit, Week 52 visit, and 
Week 104 visit, additional tests include fasting 
(at least 8 hours, other than water) glucose, lipid 
profile, and hemoglobin A1c. 
6.2.  Open-Label 
Treatment Period 
(Week 24/Baseline 
to Week 104) 
 
A mammogram will be performed at Week 52 
or at Week 104/Early Termination for women 
who are or become ≥ 40 years old during the 
study (see Section 6.5.2.9). 
Added mammogram for 
patients over 40 years age. 
6.3.  Early 
Termination Visit 
and Follow-up 
Visit 
All patients withdrawing from the study prior to 
Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 104.  Bone 
densitometry may be performed at the 
investigator’s discretion, if it aids in follow-up of 
an ongoing adverse event(s).  Follow-up bone 
densitometry findings for patients who terminate 
from the study early will proceed according to 
the rules provided in Section 6.5.2.6. 
All patients withdrawing from the study prior to 
Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 104.  An endometrial 
biopsy is required for all patients at the Early 
Termination visit except for patients whose 
last dose of study drug was taken during 
Week 32 or earlier or within four weeks after 
completion of the Week 52 endometrial 
biopsy.  However, the endometrial biopsy may 
be obtained if it will aid in the evaluation of an 
ongoing adverse event.  Bone densitometry may 
be performed at the investigator’s discretion, if it 
aids in follow-up of an ongoing adverse event(s).  
Follow-up bone densitometry findings for 
patients who terminate from the study early will 
proceed according to the rules provided in 
Section 6.5.2.6. 
Clarified endometrial biopsy 
timing. 
6.4.  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 
Unscheduled visits may be performed at any 
time during the study whenever necessary to 
assess for or follow-up on adverse events, at the 
Added mammogram for 
patients over 40 years age. 


 
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patient’s request, or as deemed necessary by the 
investigator.  The date and reason for the 
Unscheduled visit should be recorded in the 
source documentation.  The following activities 
should be completed at Unscheduled visits:  
recording of reason for the visit, concomitant 
medication review, and evaluation of adverse 
events.  In addition, procedures such as vital 
signs, weight, complete physical examination, 
sign- and symptom-directed physical 
examination, clinical laboratory assessment, 
urinalysis, urine pregnancy testing, 
pharmacodynamic sampling, 12-lead ECG, study 
drug compliance and dispensation, eDiary 
review, dispensation or prescription of protocol-
specified analgesics, etc, may be conducted as 
needed.  See the Schedule of Activities (Section 
1.1) for tests that may be performed, as indicated 
at an Unscheduled visit.  The investigator should 
consult with the medical monitor, if needed, to 
discuss Unscheduled visit testing.  The 
investigator should obtain approval from the 
sponsor to perform an unscheduled endometrial 
biopsy or DXA, unless urgently indicated. 
patient’s request, or as deemed necessary by the 
investigator.  The date and reason for the 
Unscheduled visit should be recorded in the 
source documentation.  The following activities 
should be completed at Unscheduled visits:  
recording of reason for the visit, concomitant 
medication review, and evaluation of adverse 
events.  In addition, procedures such as vital 
signs, weight, complete physical examination, 
sign- and symptom-directed physical 
examination, clinical laboratory assessment, 
urinalysis, urine pregnancy testing, 
pharmacodynamic sampling, mammogram (for 
women ≥ 40 years old), 12-lead ECG, study 
drug compliance and dispensation, eDiary 
review, dispensation or prescription of protocol-
specified analgesics, etc, may be conducted as 
needed.  See the Schedule of Activities (Section 
1.1) for tests that may be performed, as indicated 
at an Unscheduled visit.  The investigator should 
consult with the medical monitor, if needed, to 
discuss Unscheduled visit testing.  The 
investigator should obtain approval from the 
sponsor to perform an unscheduled endometrial 
biopsy or DXA, unless urgently indicated. 
6.5.2.4.  Clinical 
Laboratory Tests 
 
For patients with incomplete recovery of bone 
mineral density loss at the 6- and 12-month 
post-treatment follow-up visit, clinical 
laboratory tests should be performed (see 
Section 6.5.2.6). 
Included clinical laboratory 
evaluations associated with 
bone densitometry follow-up. 
6.5.2.6.  Bone 
Mineral Density 
 
• If patients have 6-month post-treatment 
follow-up scans that show bone loss of 
> 1.5% at the lumbar spine and/or > 2.5% 
at total hip compared with parent study 
baseline, patients are strongly encouraged 
to come back to the clinic for an additional 
post-treatment follow-up scan 12 months 
from the date of the last dose of the study 
Clarified follow-up procedures 
for bone mineral density loss. 


 
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drug.  Patients undergoing 6-month post-
treatment follow-up should also have the 
following clinical laboratory evaluations 
(vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, 
and phosphorous). 
• If patients have 12-month post-treatment 
follow-up scans that show bone loss of 
≥ 3% at the lumbar spine and/or total hip 
compared with parent study baseline, 
patients are referred to and strongly 
encouraged to see a bone specialist for 
further evaluation of the bone loss.  
Patients undergoing 12-month post-
treatment follow-up should also have the 
following clinical laboratory evaluations 
(vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, 
and phosphorous). 
Note:  When a patient is referred to a bone 
specialist for evaluation and management, 
Myovant will provide a Bone Consultation 
Letter to the investigator for this 
additional bone consult and will request 
the site to provide a summary of the 
evaluation and management plan once 
achieved. 
6.5.2.7.  
Endometrial 
Biopsy 
Additional assessment of the effects of relugolix 
co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will 
be performed at Week 52 for all patients.  At 
Week 104, all patients will be eligible for an 
additional endometrial biopsy; however, patients 
will have the option to opt out.  Patient 
participation in the Week 104 endometrial biopsy 
is voluntary and refusal to participate will not 
preclude entry into the study or indicate 
withdrawal from the study. 
Additional assessment of the effects of relugolix 
co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will 
be performed at Week 52 and Early 
Termination visit for all patients.  An 
endometrial biopsy is required for all patients 
at the Early Termination visit except for 
patients whose last dose of study drug was 
taken during Week 32 or earlier or within 
four weeks after completion of the Week 52 
endometrial biopsy.  However, the 
Clarified endometrial biopsy 
timing. 


 
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The Week 52 and Week 104 endometrial biopsy 
samples will be submitted to the central 
laboratory.  If the Week 52 or Week 104 biopsy 
specimen is inadequate, a transvaginal ultrasound 
for endometrial thickness should be obtained and 
read locally.  The transvaginal ultrasound 
findings will be used to determine if further 
action is required: 
endometrial biopsy may be obtained if it will 
aid in the evaluation of an ongoing adverse 
event.  An endometrial biopsy at Week 104 is 
recommended for all patients who complete 
the open-label extension; however, patients will 
have the option to opt out.  Patient participation 
in the Week 104 endometrial biopsy is voluntary 
and refusal to participate will not preclude entry 
into the study or indicate withdrawal from the 
study. 
The Week 52, Week 104, and Early 
Termination visit endometrial biopsy samples 
will be submitted to the central laboratory.  If the 
Week 52, Week 104, or Early Termination 
visit biopsy specimen is inadequate, a 
transvaginal ultrasound for endometrial thickness 
should be obtained and read locally.  The 
transvaginal ultrasound findings will be used to 
determine if further action is required: 
6.5.2.7.  
Endometrial 
Biopsy 
 
Investigators should contact the medical 
monitor if a patient refuses to have an 
endometrial biopsy at Week 52 or the Early 
Termination visit. 
Clarified investigator role in 
communicating to sponsor 
when a patient refuses the 
endometrial biopsy. 
6.5.2.8.  Status of 
Menstruation 
Recovery 
If the first menstruation after the end of study 
treatment administration is observed before the 
Follow-up visit, the date of onset of the first 
menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted again by 
telephone 3 (+0.5) months after the Follow-Up 
visit to determine if menses has resumed and will 
be asked about factors that may affect 
resumption of menses. 
If the first menstruation after the end of study 
treatment administration is observed before the 
Follow-up visit, the date of onset of the first 
menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted by telephone 3 
(+0.5) months after the Follow-Up visit to 
determine if menses has resumed and will be 
asked about factors that may affect resumption of 
menses.  If a patient is lost to follow-up, three 
documented attempts should be made to 
contact the patient by telephone.  If unable to 
Clarified procedures for when a 
patient is lost to follow-up. 


 
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contact the patient by telephone, a certified 
letter must be sent to the patient. 
6.5.2.9.  
Mammogram 
 
A mammogram will be performed at Week 52 
or Week 104/Early Termination visit (see the 
Schedule of Activities in Section 1.1) for 
patients ≥ 40 years of age at the time of the 
visit.  If a patient had a recent mammogram 
per standard of care within the six months 
before Week 52 that was Breast Imaging 
Reporting and Data System category 1 or 2 or 
equivalent or had benign findings, as 
determined by the investigator or medical 
monitor, a mammogram is not required at 
Week 52 but should be completed by Week 
104/Early Termination.  If a patient turns 40 
years old after the Week 52 visit has occurred, 
a mammogram should be performed no later 
than the Week 104/Early Termination visit. 
All mammogram results will be read locally 
using Breast Imaging Reporting and Data 
System categories or equivalent (see Appendix 
8) and recorded in the eCRF.  The following 
actions will be taken depending on the 
reading: 
• Category 1 or 2 or equivalent:  normal 
mammogram; no further action is 
required unless determined by the 
investigator or medical monitor; 
• Category 0 or 3 or equivalent:  adjunctive 
breast imaging or follow-up mammogram 
will be required, and the investigator 
should contact the medical monitor for 
approval of additional breast imaging; 
• Category 4 to 6 or equivalent:  the 
investigator should contact the medical 
monitor within 24 hours. 
Added mammogram for 
patients over 40 years age. 


 
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7.2.1.  Adverse 
Event Reporting 
Period 
Adverse events and serious adverse events will 
be collected under this extension study protocol 
from the administration of the first dose of 
extension study drug until the Follow-up visit 
approximately 30 days after the last dose of 
study drug or the date of initiation of another 
investigational agent or hormonal therapy 
affecting the hypothalamic-pituitary-gonadal axis 
or surgical intervention for endometriosis, 
whichever occurs first, as also specified in the 
study Schedule of Activities (Section 1.1).  
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. 
Adverse events and serious adverse events will 
be collected under this extension study protocol 
from the administration of the first dose of 
extension study drug until the Follow-up visit 
approximately 30 days after the last dose of 
study drug or the date of initiation of another 
investigational agent or hormonal therapy 
affecting the hypothalamic-pituitary-gonadal axis 
or surgical intervention for endometriosis, 
whichever occurs first, as also specified in the 
study Schedule of Activities (Section 1.1).  
Serious adverse events reported to the 
investigator after the safety reporting period 
should be reported to the sponsor regardless of 
causal relationship to study drug treatment. 
Clarified reporting instructions. 
7.7.  Study Drug 
Overdose 
Management 
Contact the medical monitor immediately; 
Contact the medical monitor within 24 hours; 
Clarified timing of overdose 
reporting requirements. 
7.8.  Pregnancy 
Reporting 
A pregnancy is to be reported to the sponsor 
within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms 
and contact information in Section 7.6.  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 
form, as available. 
A pregnancy is to be reported to the sponsor 
within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms 
and contact information in Section 7.6.  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 
form, as available.  Document the pregnancy in 
the eCRF as well. 
Added clarification about the 
documentation of pregnancy. 
Section 7.10 
Table 7-2 
Monitoring and Withdrawal Criteria 
Clinical chemistries assessing liver tests, fasting 
glucose and lipids, and urine pregnancy tests will 
be performed throughout the study.  Adverse 
events will be recorded at each visit. 
Monitoring and Withdrawal Criteria 
Clinical chemistries assessing liver tests, fasting 
glucose and lipids, and urine pregnancy tests will 
be performed throughout the study.  Adverse 
events will be recorded at each study visit;  
A mammogram will be performed at Week 52 
or at Week 104/Early Termination for women 
who are or become ≥ 40 years old during the 
Added details to correspond 
with the addition of 
mammaograms. 


 
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study, with specified discontinuation criteria.  
Adverse events will be recorded 
9.4.  Efficacy 
Analyses 
 
• 
Change from the parent Baseline in the 
mean NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using 
analgesics; 
Included additional endpoints 
to evaluate pelvic pain and 
analgesic use. 
9.5 Safety 
Analyses 
Safety assessments will include treatment-
emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 
12-lead ECG, and bone mineral density with 
DXA.  Safety summaries by treatment group will 
be performed using treatment groups defined 
based on the actual randomized treatment 
received in the parent study. 
Safety assessments will include treatment-
emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 
12-lead ECG, bone mineral density with DXA, 
mammograms (women ≥ 40 years of age), and 
endometrial biopsy.  Safety summaries by 
treatment group will be performed using 
treatment groups defined based on the actual 
randomized treatment received in the parent 
study. 
Included added assessments. 
Appendix 8 
 
Added appendix. 
Corresponding information for 
the addition of mammograms. 
Appendix 9 
 
Added appendix. 
Details regarding the conduct 
of clinical trials during the 
COVID-19 pandemic. 
 


 
 
1 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, 
Single-Arm, Safety and Efficacy Extension Study to Evaluate 
Relugolix Co-Administered with Low-Dose Estradiol and 
Norethindrone Acetate in Women with Endometriosis-
Associated Pain 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3103 
Indication: 
Treatment of Endometriosis-Associated Pain  
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Regulatory Identifiers: 
IND No.  076642 
EudraCT No.  2017-004066-10 
Version and 
Effective Date: 
Original:  06 NOV 2017 
Amendment 1:  20 MAR 2018 
Amendment 2:  11 Dec 2018 
Amendment 3.1:  25 Aug 2020 
 
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. 
DocuSign Envelope ID: B602C976-C6CA-4AA2-8F62-33169BA9B06F


Cli nical St u d y Pr ot o c ol:  M V T -6 0 1 -3 1 0 3  
A me n d me nt 3. 1, 2 5 A u g 2 0 2 0  
M y o v a nt S cie n ces G m b H  
2 
C O N FI D E N TI A L  
S P O N S O R SI G N A T U R E P A G E  
S PI RI T E X T E N SI O N:  A n I nter nati o n al P hase 3 O pe n -La bel, Si n gle -Ar m, Safet y a n d Efficac y 
E xte nsi o n  St u d y t o E val uate Rel u g oli x C o -A d mi nistere d wit h L o w -D ose Estra di ol a n d 
N oret hi n dr o ne Acetate i n W o me n wit h E n d o metri osis -Ass ociate d Pai n  
Pr ot oc ol N u m ber:  M V T- 6 0 1- 3 1 0 3 A me n d me nt 3. 1 
 
T his pr ot oc ol has bee n a p pr o ve d b y M y o va nt Scie nces G m b H.  T he f oll o wi n g si g nat ures 
d oc u me nt t his a p pr o val.  
 
 
 
Date  
 
 
 
 
 
Date  
 
 
 
Date  
 
 
 
D o c u Si g n E n v el o p e I D: B 6 0 2 C 9 7 6- C 6 C A- 4 A A 2- 8 F 6 2- 3 3 1 6 9 B A 9 B 0 6 F
2 5 - A u g - 2 0 2 0  |  1 2 : 2 3  P M  P D T
2 5 - A u g - 2 0 2 0  |  3 : 1 5  P M  P D T
2 5 - A u g - 2 0 2 0  |  1 1 : 4 2  A M  P D T
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Clinical Study Protocol:  MVT-601-3103 
Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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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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Clinical Study Protocol:  MVT-601-3103 
Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR STATEMENT ...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SYNOPSIS ...........................................................................................10 
1.1. 
Schedule of Activities .................................................................................................19 
2. 
INTRODUCTION ......................................................................................................24 
2.1. 
Endometriosis-Associated Pain ..................................................................................24 
2.2. 
Relugolix.....................................................................................................................25 
2.2.1. 
Indication ....................................................................................................................25 
2.2.2. 
Pharmacology .............................................................................................................26 
3. 
STUDY OBJECTIVES AND ENDPOINTS..............................................................27 
4. 
INVESTIGATIONAL PLAN .....................................................................................31 
4.1. 
Overall Study Design ..................................................................................................31 
4.2. 
Discussion of Study Design, Including Dosing ..........................................................33 
4.3. 
Selection of Study Population ....................................................................................35 
4.3.1. 
Inclusion/Exclusion Criteria .......................................................................................35 
4.4. 
Method of Assigning Patients to Treatment Group and Patient Identification 
Number .......................................................................................................................38 
4.5. 
Removal of Patients from Therapy .............................................................................38 
4.6. 
Contraception/Pregnancy Avoidance .........................................................................39 
4.7. 
Novel Coronavirus 2019 Guidance ............................................................................40 
5. 
TREATMENTS ..........................................................................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Identity of Investigational Product .............................................................................41 
5.2.1. 
Product Characteristics ...............................................................................................41 
5.3. 
Randomization and Stratification ...............................................................................42 
5.4. 
Directions for Administration .....................................................................................42 
5.5. 
Dose Reduction/Dose Administration ........................................................................42 
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Clinical Study Protocol:  MVT-601-3103 
Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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5.6. 
Storage, Packaging, and Labeling ..............................................................................42 
5.7. 
Rescue Analgesic Medications ...................................................................................43 
5.8. 
Blinding ......................................................................................................................43 
5.9. 
Study Drug Accountability and Treatment Compliance ............................................43 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ..................................44 
5.10.1. 
Prohibited Medications ...............................................................................................44 
5.10.2. 
Permitted Medications ................................................................................................47 
5.10.3. 
Prohibited Non-Drug Therapies .................................................................................47 
6. 
STUDY ASSESSMENTS AND PROCEDURES......................................................48 
6.1. 
Schedule of Observations and Procedures ..................................................................48 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 104) ..............................48 
6.3. 
Early Termination Visit and Follow-Up Visit ............................................................50 
6.4. 
Unscheduled Visits .....................................................................................................51 
6.5. 
Study Procedures ........................................................................................................51 
6.5.1. 
Efficacy-Related Procedures ......................................................................................51 
6.5.2. 
Safety-Related Procedures ..........................................................................................52 
7. 
SAFETY CONSIDERATIONS..................................................................................58 
7.1. 
Adverse Event Definitions ..........................................................................................58 
7.1.1. 
Adverse Event .............................................................................................................58 
7.1.2. 
Serious Adverse Event ................................................................................................59 
7.2. 
Adverse Event Reporting ............................................................................................59 
7.2.1. 
Adverse Event Reporting Period ................................................................................60 
7.3. 
Assigning Causal Relationship to Study Drug ...........................................................60 
7.4. 
Assigning Severity Rating for Adverse Events ..........................................................61 
7.5. 
Adverse Events of Clinical Interest Reporting ...........................................................62 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities......................................................................................................62 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities ............................................................................................62 
7.6. 
Serious Adverse Event Reporting ...............................................................................63 
7.7. 
Study Drug Overdose Management ............................................................................64 
7.8. 
Pregnancy Reporting ..................................................................................................64 
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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures ........................................65 
7.10. 
Benefit/Risk Assessment ............................................................................................65 
8. 
DATA QUALITY ASSURANCE ..............................................................................68 
8.1. 
Clinical Procedures .....................................................................................................68 
8.2. 
Monitoring ..................................................................................................................68 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................69 
9.1. 
Randomization Methods .............................................................................................69 
9.2. 
Analysis Populations ..................................................................................................69 
9.3. 
Sample Size Justification ............................................................................................69 
9.4. 
Efficacy Analyses .......................................................................................................69 
9.5. 
Safety Analyses ..........................................................................................................71 
9.6. 
Pharmacodynamics Analyses .....................................................................................73 
9.7. 
Exploratory Analyses..................................................................................................73 
9.8. 
Interim Analyses .........................................................................................................73 
9.9. 
Steering Committee ....................................................................................................73 
10. 
RESPONSIBILITIES .................................................................................................74 
10.1. 
Investigator Responsibilities .......................................................................................74 
10.1.1. 
Good Clinical Practice ................................................................................................74 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................74 
10.1.3. 
Informed Consent .......................................................................................................74 
10.1.4. 
Confidentiality ............................................................................................................75 
10.1.5. 
Study Files and Retention of Records ........................................................................75 
10.1.6. 
Electronic Case Report Forms ....................................................................................76 
10.1.7. 
Investigational Product Accountability ......................................................................76 
10.1.8. 
Inspections ..................................................................................................................77 
10.1.9. 
Protocol Compliance ..................................................................................................77 
10.2. 
Sponsor Responsibilities .............................................................................................77 
10.2.1. 
Safety Reporting .........................................................................................................77 
10.2.2. 
Protocol Modifications ...............................................................................................77 
10.2.3. 
Study Report ...............................................................................................................78 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers ......................78 
10.3. 
Joint Investigator/Sponsor Responsibilities ................................................................78 
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10.3.1. 
Access to Information Monitoring..............................................................................78 
10.3.2. 
Access to Information for Auditing or Inspections ....................................................78 
10.3.3. 
Study Discontinuation ................................................................................................78 
10.3.4. 
Publications.................................................................................................................78 
11. 
REFERENCES ...........................................................................................................80 
12. 
APPENDICES ............................................................................................................81 
 Protocol-Specified Rescue Analgesics ...................................................................81 
 Daily eDiary ...........................................................................................................82 
 Endometriosis Health Profile-30 ..........................................................................106 
 European Quality of Life Five-Dimension Five-Level Scale...............................110 
 Patient Global Impression of Change and Patient Global Assessments...............112 
 Endometriosis Health Profile - Work Domain .....................................................114 
 Assessment of Abnormal Liver Function Tests ...................................................115 
 Breast Imaging Reporting and Data System ........................................................117 
 Guidance for Study Conduct during the COVID-19 Pandemic ...........................118 
 
LIST OF TABLES 
Table 1-1 Schedule of Activities for Study MVT-601-3103 ......................................................19 
Table 5-1 Description of MVT-601-3103 Study Drugs ..............................................................41 
Table 5-2 Prohibited Medications ...............................................................................................44 
Table 6-1 Clinical Laboratory Tests ...........................................................................................53 
Table 7-1 Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................61 
Table 7-2 Protocol Risk Assessment and Mitigation Strategies .................................................65 
Appendix Table 1 Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .........115 
Appendix Table 2 Investigations of Alternative Causes for Abnormal Liver Tests .................116 
 
LIST OF FIGURES 
Figure 4-1 MVT-601-3103 Study Schematic ...............................................................................33 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
novel coronavirus 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dehydroepiandrosterone 
DTP 
direct-to-patient 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EHP 
Endometriosis Health Profile 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
EU 
European Union 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HR 
heart rate 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NMPP 
nonmenstrual pelvic pain 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 
PLD 
phospholipidosis 
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Term 
Explanation 
QTc 
corrected QT (interval) 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
SDV 
source data verification 
SNRI 
serotonin and norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TCA  
tricyclic antidepressant 
ULN 
upper limit of normal 
US 
United States 
W 
Week 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced  
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1. 
PROTOCOL SYNOPSIS 
Study Title 
SPIRIT EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Safety and Efficacy Extension Study to Evaluate Relugolix Co-Administered 
with Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain 
Protocol Number 
MVT-601-3103 
Location 
Multinational, including North and South America, Europe, Africa, 
New Zealand, and Australia 
Study Centers 
Approximately 320 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with endometriosis-associated pain 
Number of Patients 
Planned 
Approximately 800 
Study Objectives 
In women with endometriosis-associated pain, the study objectives are as 
follows: 
Primary Efficacy Objectives 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously completed a 24-week treatment 
period in one of the parent studies (MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up to 
104 weeks, among patients who previously completed a 24-week treatment 
period in one of the parent studies (MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
 
Secondary Efficacy Objectives 
To be assessed at Week 52 and Week 104 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate, among 
patients who previously completed a 24-week treatment period in one of the 
parent studies (MVT-601-3101 or MVT-601-3102), on the following: 
o Function, as measured by the Endometriosis Health Profile (EHP)-30 
Pain Domain; 
o Dysmenorrhea, as measured by the Numerical Rating Scale (NRS) for 
dysmenorrhea; 
o Patient Global Impression of Change (PGIC) for dysmenorrhea; 
o Nonmenstrual pelvic pain (NMPP), as measured by the NRS for 
NMPP; 
o Overall pelvic pain, as measured by the NRS; 
o Analgesic use; 
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o PGIC for NMPP; 
o Dyspareunia, as measured by the NRS; 
o PGIC for dyspareunia; 
o Dyspareunia-related functional effects (Subject Modified Biberoglu and 
Behrman [sB&B]); 
o To determine the benefit of relugolix 40 mg once daily co-administered 
with 24 weeks of low-dose estradiol and norethindrone acetate 
compared with placebo on function measured by the EHP-30 Pain 
Domain; 
o Patient Global Assessment (PGA) for pain; 
o PGA for function; 
o Endometriosis-associated quality of life, as measured by the EHP-30 
Control and Powerlessness, Social Support, Emotional Well-Being, and 
Self-Image domains; 
o Dysmenorrhea-related functional effects (sB&B); 
o NMPP-related functional effects (sB&B). 
 
Safety Objectives 
• 
To evaluate the safety of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for up to 104 weeks, among 
patients who previously completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or MVT-601-3102), including: 
o Adverse events; 
o Changes in bone mineral density. 
 
Pharmacodynamic Objective 
• 
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 104 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3101 or 
MVT-601-3102), on estradiol. 
 
Exploratory Objective 
• 
To evaluate the benefit of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate on endometriosis-associated 
quality of life (EHP-30 total score), work (EHP Work Domain), and 
patient-reported quality of life outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) for up to 104 weeks among 
patients who previously completed a 24-week treatment period in one of 
the parent studies (MVT-601-3101 or MVT-601-3102). 
Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term efficacy 
and safety study that will enroll eligible patients who have completed their participation in one of the 
phase 3 randomized, double-blind, placebo-controlled parent studies (MVT-601-3101 or 
MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg once daily co-administered 
with low-dose- estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 80 weeks.  Approximately 
800 women with endometriosis-associated pain will be enrolled.  The objectives of the study are to 
evaluate long-term efficacy and safety through up to 104 weeks of treatment (including treatment 
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during the parent study) of relugolix co-administered with low-dose estradiol/norethindrone acetate.  
Eligible patients will have completed participation in one of the parent studies and consented to 
participate in this extension study.  Baseline procedures will be done at the same visit for this extension 
study (referred to as the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit 
from the parent study and will be defined as the date of completion of the last Week 24 procedure in 
the parent study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent study have 
been completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 24/Baseline 
visit.  No MVT-601-3103 study procedures will be performed until the consent form for this extension 
study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  Therefore, results of testing required for eligibility must be available on or prior 
to the Week 24/Baseline visit.  The administration of the first dose of study drug for MVT-601-3103 
will define enrollment into this study.  Study participants will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once 
daily for 80 weeks.  If necessary for logistical reasons (eg, delayed availability of study drug supply on 
site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  
If the first dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients will 
continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, analgesic 
use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  Only study-
specific rescue analgesic medications should be used starting with the Week 24/Baseline visit and 
through the Follow-Up visit and these medications will be taken for control of pain and not 
prophylactically.  Health-related quality of life questionnaires; PGIC for dysmenorrhea, NMPP, and 
dyspareunia; and PGA for pain and function will be completed during the visits on an electronic tablet 
or on paper, according to the Schedule of Activities (Section 1.1). 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via dual-energy x-ray absorptiometry (DXA).   
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, mammograms (for patients 
required to have this procedure; see Section 6.5.2.9), endometrial biopsies, and bone mineral density 
with DXA. 
Determination of bone mineral density by DXA at the Early Termination or Week 104 visit and follow-
up of findings will proceed according to the following rules: 
 
Early Termination and 6-Month Post-Treatment DXA 
• 
For patients who Early Terminate: 
− 
For Early Termination occurring before Week 36, DXA is not required at the Early 
Termination visit unless it will aid in the assessment of an adverse event or if the most 
recent DXA bone mineral density loss at lumbar spine (L1-L4) or total hip was > 2% 
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relative to the parent study baseline.  In this case, follow-up DXA is required at 
6 months (± 1 month). 
− 
For Early Termination occurring at or after the Week 36 visit, DXA is required at 
Early Termination unless a DXA result is available from within six weeks prior to 
Early Termination. 
− 
Most recent DXA was at the Week 24 visit:  Follow-up DXA is required at 
6 months (± 1 month) if the most recent DXA scan was at Week 24 and bone 
mineral density loss at the lumbar spine (L1-L4) or total hip was > 2%, relative to 
the parent study baseline. 
− 
Most recent DXA was after the Week 24 visit:  Follow-up DXA is required at 
6 months (± 1 month) if on the most recent DXA scan, bone mineral density loss at 
the lumbar spine (L1-L4) or total hip was > 3%, relative to the parent study 
baseline. 
Study Completion and 6-Month Post-Treatment DXA 
• 
For patients who complete the open-label extension study:  
− 
Follow-up DXA is required at 6 months (± 1 month) if, at the Week 104 visit or on the 
most recent DXA scan, bone mineral density loss at the lumbar spine (L1-L4) or total 
hip was > 3%, relative to the parent study baseline. 
Note:  Patients undergoing 6-month post-treatment follow-up should also have the 
following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous.  
12-Month Post-Treatment DXA 
• 
If patients have 6-month post-treatment follow-up scans that show bone loss of > 1.5% at 
the lumbar spine and/or > 2.5% at total hip compared with the parent study baseline, 
patients are strongly encouraged to come back to the clinic for an additional post-treatment 
follow-up scan 12 months from the date of the last dose of the study drug.  If patients have 
12-month post-treatment follow-up scans that show bone loss of ≥ 3% at the lumbar spine 
and/or total hip compared with the parent study baseline, patients are recommended to be 
referred to and strongly encouraged to see a bone specialist for further evaluation of the 
bone loss. 
Note:  When a patient is referred to a bone specialist for evaluation and management, 
Myovant will provide a Bone Consultation Letter to the investigator for this additional 
bone consult and will request the site to provide a summary of the evaluation and 
management plan once the consultation is complete. 
Status of menstruation recovery will be documented at the Follow-Up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption 
(eg, medical procedure or medications) will be contacted by telephone 3 months (+ 0.5 months) after 
the Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses.  If a patient is lost to follow-up, three documented attempts should be made to 
contact the patient by telephone.  If unable to contact the patient by telephone, a certified letter must be 
sent to the patient.  A mammogram will be performed at Week 52 or at Week 104/Early Termination 
for women who are or become ≥ 40 years old during the study (see Section 6.5.2.9). 
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If the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 
visit, then the Follow-Up visit and the follow-up procedures performed under this protocol, including 
the follow-up bone densitometry scan at 6 months (± 1 month) and status of menstruation recovery, 
may be waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1. Completed 24 weeks of study drug treatment and study participation in either MVT-601-3101 
or MVT-601-3102; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any study-
specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures 
for this study will be done under the informed consent for the parent study. 
3. Is not expected to undergo gynecological surgery or other surgical procedures for treatment of 
endometriosis (including ablation, shaving, or excision) during the study, including during the 
Follow-Up Period, and the patient does not desire such treatment during this time frame; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Has agreed to continue to use only study-specified analgesic medications during the study and 
is not known to be intolerant to these; 
6. Agrees to continue to use acceptable non-hormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment Period and for at least 30 days after 
the last dose of study drug.  However, the patient is not required to use the specified non-
hormonal contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), 
at least 6 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
c. Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study. 
1. Has had a surgical procedure for treatment of endometriosis at any time during the parent study 
(MVT-601-3101 or MVT-601-3102); 
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, that is 
treated with opioids or requires analgesics for ≥ 7 days per month; 
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, bilateral 
hip replacement, spinal hardware in the lumbar spine); 
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study 
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA 
assessment of bone mineral density; 
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5. Anticipated to use any prohibited medications as detailed in Section 5.10.1; 
6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to 
the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
syndromes, etc.); psoriasis not requiring or anticipated to require systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or, 
if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of 
normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert syndrome 
or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 1 month after the last dose of study drug, or plans to donate ova during the study period 
or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the parent 
study Baseline visit; or 
b. The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 
12. Is inappropriate for participation in this study because of conditions that may interfere with 
interpretation of study results or prevent the patient from complying with study requirements, 
as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
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Duration of 
Treatment 
Study treatment will be self-administered for 80 weeks (Open-Label Treatment 
Period). 
Concomitant Medicinal Products Systematically Prescribed for All Study 
Patients 
Two protocol-specified analgesics include a first-line non-steroidal anti-
inflammatory drug and a second-line opioid or opioid/acetaminophen or 
opioid/paracetamol combination for endometriosis-related pain relief as 
required.  The specific analgesic drugs offered may differ for different countries 
or regions.  The analgesics for each patient will be the same as those prescribed 
for her during the parent study. 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made between 
the parent study Baseline and Week 52, and between the parent study Baseline 
and the end of the extension study (Week 104) for the following parent study 
treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg norethindrone 
acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in 
the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this extension 
study for all change from baseline-related endpoints.  The pain scores during 
the Baseline Pain Assessment Period of the parent study will establish the 
patient’s baseline for both the parent study and the extension study. 
 
Primary Efficacy Endpoints 
Week 52 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at Week 52/Early 
Termination, based on their NMPP NRS scores. 
Week 104 
• 
Proportion of women who respond or maintain response at Week 104/Early 
Termination, based on their dysmenorrhea NRS scores; 
• 
Proportion of women who respond or maintain response at Week 104/Early 
Termination, based on their NMPP NRS scores. 
 
Secondary Efficacy Endpoints 
To be assessed at Week 52 and Week 104, unless otherwise specified 
• 
Change from the parent study Baseline in the EHP-30 Pain Domain scores; 
• 
Change from the parent study Baseline in the mean dysmenorrhea NRS 
score; 
• 
Proportion of patients who are better or much better on the PGIC for 
dysmenorrhea (at Week 52 only); 
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• 
Change from the parent study Baseline in the mean NMPP NRS score; 
• 
Change from the parent Baseline in the mean NRS score; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using analgesics; 
• 
Proportion of patients who are better or much better on the PGIC for NMPP 
(at Week 52 only); 
• 
Change from the parent study Baseline in the mean dyspareunia NRS 
scores; 
• 
Proportion of patients who are better or much better on the PGIC for 
dyspareunia (at Week 52 only); 
• 
Change from the parent study Baseline in the mean dyspareunia functional 
impairment on the sB&B scale; 
• 
Change from the parent study Baseline in severity scores on the PGA for 
pain; 
• 
Proportion of responders based on their EHP-30 Pain Domain score; 
• 
Change from the parent study Baseline in function impairment on the PGA 
for function; 
• 
Change from the parent study Baseline in each of the non-pain EHP-30 
domains (Control and Powerlessness, Social Support, Emotional Well-
Being, and Self-Image); 
• 
Change from the parent study Baseline pain assessment period in 
dysmenorrhea-related functional effects (sB&B); 
• 
Change from the parent study Baseline pain assessment period in NMPP-
related functional effects (sB&B). 
 
Safety Endpoints 
To be assessed at Week 52 and Week 104 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline in bone mineral density at 
the lumbar spine (L1-L4), femoral neck, and total hip as assessed by DXA. 
 
Pharmacodynamic Endpoint 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose concentrations of serum 
estradiol. 
 
Exploratory Endpoints 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale total score; 
• 
Change from Baseline in the EHP Work Domain score; 
• 
Change from parent study Baseline in the EQ-5D-5L. 
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
There will be two analyses:  one at Week 52 and one at Week 104.  A clinical study report will be 
generated from each analysis. 
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Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Parent Study Groups A, B, and C) for the Extension Study Population.  The analyses 
methods for efficacy endpoints are similar to those used for the parent studies, unless otherwise 
specified in the statistical analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic medications, 
proportion of responders based on NMPP scores and use of rescue analgesic medications) will be 
calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA scan, 
mammograms (for patients required to have this procedure, see Section 6.5.2.9), and endometrial 
biopsy.  Safety data analyses will use data from all patients from the parent studies who receive any 
amount of study drug (ie, from parent study Baseline to Week 52 or Week 104). 
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 Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, high 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.  Laboratory values will be classified 
by toxicity grade based on the National Cancer Institute CTCAE.  Laboratory shift tables of the parent 
study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early Termination visits.  The 
absolute change and percent change from parent study Baseline and Z-scores will be summarized by 
visit and parent study treatment group. 
The mean percentage change from parent study Baseline to Week 52 in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3101 
or MVT-601-3102) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, 
bone mineral density loss for the relugolix add-back treatment will be considered insignificant.  The 
95% CI for mean percentage change at Week 104/Early Termination from parent study Baseline in 
bone mineral density lumbar spine (L1-L4) will be provided along with descriptive statistics for bone 
mineral density loss at Week 104/Early Termination as supportive analyses. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3101 or MVT-601-3102) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3103 
 
PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week
32 
Week 
36 
Week 
40 
and 
Week4
4 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Informed Consent 
Xc 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medicationsd 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
Weight 
Xg 
 
X 
 
 
X 
 
X 
 
X 
Xh 
 
Complete Physical 
Examination 
Xg 
 
 
 
 
Xh 
 
 
 
Xi 
Xh 
 
Visual Acuityj 
Xg 
 
 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-
Directed Physical 
Examinationk 
 
X 
X 
X 
X 
 
X 
X 
X 
 
Xh 
X 
12-Lead ECGl 
Xg 
 
 
 
 
X 
 
 
 
Xh 
Xh 
 
Clinical Laboratory 
Testsm 
Xg,n 
X 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
Xh 
Xee 
Pharmacodynamics 
Sampleo 
Xg,n 
 
 
 
 
Xn 
 
 
 
Xn 
Xh,n 
 
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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week
32 
Week 
36 
Week 
40 
and 
Week4
4 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Urinalysis 
Xg 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Daily eDiaryp 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Site Review of eDiary 
Data 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Bone Densitometryq 
Xg 
 
X 
 
 
Xr,s 
 
 
 
Xr,s 
Xh 
Xee  
Endometrial Biopsy 
Xg,t 
 
 
 
 
X 
 
 
 
Xt 
Xh 
Xee 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Dispense or Prescribe 
Protocol-Specified 
Analgesic Drugsu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose in 
Clinic 
Xv 
 
 
 
 
X 
 
 
 
X 
Xh 
 
Daily Self- 
Administration of Study 
Treatmentw 
 
X -------------------------------------- X 
 
 
 
Take Protocol-Specified 
Rescue Analgesics as 
Neededx 
 
X ------------------------------------------------------------------------------------ X 
 
 
EHP-30 Questionnairey 
Xg 
 
X 
 
X 
X 
 
X 
 
X 
Xh 
 
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PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3101/-3102) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
and 
Week
32 
Week 
36 
Week 
40 
and 
Week4
4 
Week 
48 
Week 
52a 
Week 
65 
Week 
78 
Week 
91 
Week 104a/ 
Early 
Termination 
Un-
scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
-10/+20 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
- 
-3 to +18 
Patient Global 
Assessment for Painy 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
[on paper] Patient Global 
Assessment for Functionz 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Patient Global Impression 
of Changey 
Xg 
 
X 
 
 
X 
 
 
 
 
Xh 
 
[on paper] EHP Work 
Domainz 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
EQ-5D-5L Questionnairey 
Xg 
 
 
 
 
X 
 
X 
 
X 
Xh 
 
Adverse Event 
Collectionaa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
Xbb,ee 
Telephone Contactcc 
 
 
 
 
 
X 
(W57) 
X 
(W71) 
X 
(W85) 
X 
(W98) 
 
 
 
Mammogramdd 
 
 
 
 
 
Xdd 
 
 
 
Xdd 
Xdd 
 
BP = blood pressure; DXA = dual-energy x-ray absorptiometry; ECG = electrocardiogram; eDiary = electronic diary; EHP = Endometriosis Health Profile; EQ-5D-5L = European 
Quality of Life Five-Dimension Five-Level Scale; HR = heart rate; NRS = Numerical Rating Scale; PGA = Patient Global Assessment; sB&B = Subject Modified Biberoglu and 
Behrman; W = week. 
a The Week 52 visit should occur on or after the 1-year anniversary of Baseline Day 1 of the parent study (± 7 days), and the Week 104 visit should occur on or 
after the 2-year anniversary of Baseline Day 1 of the parent study. 
b Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents. 
c The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 104 visit. 
d May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3103 is defined by 
administration of the first dose of MVT-601-3103 study drug. 
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e Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up Period.  Concomitant 
medications with start date prior to the first dose of study drug for MVT-601-3103 should be reported as concomitant medications in the parent study 
(MVT-601-3101 or MVT-601-3102).  If concomitant medication is ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case 
Report Form Completion Guidelines for instructions for recording the follow-up status. 
f Concomitant medications are recorded both for the parent study and for MVT-601-3103 at the Week 24/Baseline visit.  (See footnote e for further details). 
g This is a parent study (MVT-601-3101 or MVT-601-3102) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3103 and is 
covered under the informed consent for the parent study. 
h The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal 
laboratory test). 
i The Week 52 and Week 104 physical examinations will include a breast examination. 
j See parent study protocols (MVT-601-3101 or MVT-601-3102) for instructions on testing visual acuity. 
k The examination may include a gynecologic examination, if indicated based on signs and symptoms. 
l The 12-lead ECGs will be submitted for central reading. 
m Clinical chemistries will be collected at each visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, Week 52, Week 65, 
Week 78, Week 91, and Week 104/Early Termination.  At the Week 24/Baseline visit, Week 52 visit, and Week 104/Early Termination visit, additional tests 
will include the following:  fasting (at least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
n Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period. 
o For Week 24/Baseline samples, see the parent protocol (MVT-601-3101 or MVT-601-3102).  At Week 104/Early Termination, collect a sample for analysis of 
estradiol concentrations only.  On days when pharmacodynamics samples are collected, administer the study treatment after the pharmacodynamics sample 
collections are collected. 
p All women enrolled in the study will continue to use the patient eDiary dispensed in the parent study.  Patients will complete daily eDiary entries, including 
NRS pain scores, menstruation information, analgesic drug use, date and time of study drug administration, and sB&B scale scores until Week 52.  After 
Week 52, eDiary scores will be entered over four eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 
visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
q Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
r See Section 6.5.2.6 for details on the timing and follow-up of bone densitometry. 
s Determination of bone mineral density by DXA at Early Termination and follow-up of findings will proceed based on the timing of the Early Termination visit. 
See Section 6.5.2.6.   
t Endometrial biopsies are to be done per instructions in the parent study.  Procedures for handling and shipping biopsy samples to the central laboratory for 
analysis are described in the Investigator Site File.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who 
participated in MVT-601-3101 only (see MVT-601-3101 protocol for details) and at Week 52 and Early Termination visit for all patients.  This procedure is 
not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, the procedure may be done if it will aid in the evaluation of an ongoing adverse event.  An endometrial biopsy 
at Week 104 is recommended for all patients who complete the open-label extension; however, patients will have the option to opt out. 
u Please see Appendix 1 for list of protocol-specified analgesics and see the Investigator Site File for information on where and how to obtain protocol-specified 
analgesic medications by country.  At the Week 104 visit, patients who will not be proceeding to another extension study will be re-dispensed or prescribed 
protocol-specified analgesic drugs, if needed, to ensure sufficient supply until the Follow-Up visit.  For patients proceeding to another extension study, refer to 
the protocol for that next study. 
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v Pregnancy test must be negative before the study drug dose is administered.  For patients whose Baseline Day 1 visit is conducted on a different day than the 
parent study Week 24 visit, perform an unscheduled pregnancy test at Baseline Day 1 prior to administering the first dose of study drug. 
w Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  If necessary, for 
logistical reasons (eg, delayed availability of study drug supply on site, others), and with sponsor/designee approval, the first dose of open label study drug for 
MVT-601-3103 may be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not given during this up 
to 10-day interval, the parent study follow-up procedures should be followed (ie, adverse event reporting, eDiary completion, etc.).  The first dose of study drug 
for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed.  Therefore, results of testing 
required for eligibility (eg, DXA) must be available on or prior to the Week 24/Baseline visit.  The last dose of study drug will be taken in the clinic during the 
Week 104/Early Termination visit. 
x Patients may only take their study-specified analgesics for pain.  Analgesics should not be taken prophylactically (ie, in anticipation of pain). 
y The patient will enter her response(s) into an electronic tablet device at the site.  On visits when both tablet and paper questionnaires are being performed at the 
site, the patient should complete the tablet questionnaires before the paper questionnaires. 
z The patient will enter her response onto a paper questionnaire at the site.  Paper questionnaires should be done in the following order:  PGA for function, EHP 
Work Domain. 
aa Collect adverse events from the time that the first dose of study drug for MVT-601-3103 is administered.  Adverse events with onset prior to the first dose of 
study drug for MVT-601-3103 should be reported as an adverse event in the parent study (MVT-601-3101 or MVT-601-3102).  If events originating in the 
parent study are ongoing at the time of the first dose of study drug for MVT-601-3103, please see the Case Report Form Completion Guidelines for instructions 
for recording the follow-up status. 
bb Patients whose menses have not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted by telephone 3 months (+ 0.5 months) after the Follow-Up visit to determine if menses has resumed and questioned about 
factors that may affect resumption of menses.  If a patient is lost to follow-up, three documented attempts should be made to contact the patient by telephone.  
If unable to contact the patient by telephone, a certified letter must be sent to the patient. 
cc A telephone call will be performed at Weeks 57, 71, 85, and 98.  The following activities should be completed: a concomitant medication review, evaluation of 
adverse events, a reminder of compliance with non-hormonal contraception requirements and the need to call the investigator if pregnancy is suspected, and a 
review of eDiary and study medication compliance. 
dd For patients ≥ 40 years old at the time of the Week 52 visit, Week 104 visit, or Early Termination visit only.  See Section 6.5.2.9. 
ee See Section 6.5.2.6, Section 6.5.2.7, and Section 6.5.2.8 to determine if additional follow-up is required. 
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2. 
INTRODUCTION 
2.1. 
Endometriosis-Associated Pain 
Endometriosis is a common chronic condition occurring primarily in women of reproductive age.  
It is one of the most common gynecologic disorders, evident in 70 to 90% of women with pelvic 
pain symptoms [Practice Committee of the American Society for Reproductive Medicine, 2014].  
The exact prevalence of endometriosis is unknown but estimates range from 2 to 10% of women 
of reproductive age [Dunselman, 2014].  Symptoms range from minimal to severely debilitating. 
The pathogenesis of endometriosis is the presence of endometrial glands and stroma outside the 
uterine cavity.  Although the ectopic endometriotic lesions are most commonly found in the 
pelvis, they may also be located in the bowel, in the pleural cavity, and elsewhere.  Women with 
endometriosis have an increased risk of abdominopelvic pain, dysmenorrhea, and dyspareunia 
compared with controls without endometriosis [Practice Committee of the American Society for 
Reproductive Medicine, 2014].  In a study of 940 women with endometriosis, the most common 
symptom leading to diagnosis was dysmenorrhea in approximately 90%, pelvic pain in 
approximately 80%, and dyspareunia in approximately 45%, with 34% of women diagnosed on 
the basis of all three symptoms [Sinaii, 2008].  Presenting symptoms of infertility (25%) and 
endometrioma (ovarian mass) (20%) were also common [Sinaii, 2008]. 
The mechanisms of pain in endometriosis are generally postulated to involve production of 
substances such as growth factors and cytokines, the direct and indirect effects of active bleeding 
from endometriotic implants, and irritation of pelvic floor nerves or direct invasion of those 
nerves by infiltrating endometriotic implants [Practice Committee of the American Society for 
Reproductive Medicine, 2014]. 
According to the American Society for Reproductive Medicine Practice Committee, 
“Endometriosis is a chronic disease that requires a lifelong management plan with the goal of 
maximizing the use of medical treatment and avoiding repeated surgical procedures” [Practice 
Committee of the American Society for Reproductive Medicine, 2014]. 
Although hysterectomy with bilateral salpingo-oophorectomy is a definitive treatment of 
endometriosis, the American Society of Reproductive Medicine recommends that this option be 
reserved as a last resort for women with debilitating endometriosis symptoms who have 
completed childbearing and have failed to respond to alternative treatments [Practice Committee 
of the American Society for Reproductive Medicine, 2014].  Other surgical options for treatment 
of endometriosis include uterosacral nerve ablation, presacral neurectomy, and laparoscopic 
resection.  Rates of recurrent dysmenorrhea 1 and 3 years after laparoscopic surgery with 
uterosacral nerve ablation were not better than with laparoscopic surgery without nerve ablation 
in a large randomized trial.  Presacral neurectomy, which involves interrupting the sympathetic 
innervation to the uterus, improves pain but is a technically challenging procedure associated 
with significant risk of bleeding from the adjacent venous plexus.  Patients may also experience 
constipation and/or urinary retention postoperatively.  Laparoscopic treatment of endometriosis 
was found to be more effective at reducing pain than diagnostic laparoscopy in a meta-analysis 
of 5 randomized controlled studies.  While laparoscopic treatment is effective, pain can recur, 
and the option of performing multiple surgeries is limited by risks that include the development 
of pelvic pain from adhesions and decreased ovarian reserve, resulting in reduced fertility.  In 
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one retrospective study, subsequent surgery was performed after laparoscopic treatment in 21%, 
47%, and 45% of women after 2, 5, and 7 years, respectively [Practice Committee of the 
American Society for Reproductive Medicine, 2014]. 
Medical management of endometriosis includes analgesics and treatments aimed at 
decidualization followed by atrophy of endometrial tissue with reduction or antagonism of 
estrogen production and induction of amenorrhea.  Compared to normal endometrium, 
endometriotic implants are characterized by overproduction of prostaglandins and local 
production of estrogens and cytokines, which synergize the activities of each other and promote 
implantation of ectopic endometrium.  In addition, the implants have upregulated estrogen 
synthesis pathways [Practice Committee of the American Society for Reproductive Medicine, 
2014].  Interventions that reduce ovarian estrogen production reduce this synergistic process, 
thereby reducing or eliminating endometriosis-associated pain. 
Medical hormonal options include hormonal contraceptives, progestins, gonadotropin-releasing 
hormone (GnRH) agonists, danazol, and aromatase inhibitors.  Because of lack of data 
supporting use of one treatment over another, the treatment choice is based upon symptom 
severity, patient preferences, side effects, efficacy, contraceptive needs, costs, and availability 
[Dunselman, 2014].  The main adverse effects of GnRH agonists relate to induction of a 
hypoestrogenic state (eg, bone mineral density loss and vasomotor symptoms) whereas danazol 
produces androgenic adverse effects such as hirsutism, weight gain, and deepening of the voice.  
Some patients treated with GnRH agonists also experience an initial “flare effect” (increased 
pain and bleeding), and this can result in premature discontinuation of treatment.  Side effects of 
progestin treatment can include irregular uterine bleeding, weight gain, mood changes such as 
depression, and bone mineral density loss with long-term use of certain agents. 
The goal of the relugolix phase 3 development plan is to demonstrate that relugolix can decrease 
dysmenorrhea and nonmenstrual pelvic pain (NMPP) in women with endometriosis safely 
through 12 months of therapy and to evaluate effects on pain-related quality of life and function.  
By enhancing the safety and tolerability of the active treatment arm with the co-administration of 
low-dose hormonal add-back therapy, the program ultimately aims to bring to women suffering 
endometriosis-associated pain a long-term oral medical therapy that significantly reduces pain 
and improves quality of life and provides an alternative to invasive procedures. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix Investigator Brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once-daily oral medication for the treatment of endometriosis-associated pain.  The proposed 
dose of relugolix is 40 mg administered orally once daily and the proposed doses of estradiol and 
norethindrone acetate are 1.0 mg and 0.5 mg once daily, respectively. 
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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 gonadotropin-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 
luteinizing hormone and follicle-stimulating hormone fall rapidly, followed by a decline over a 
few days in estradiol and progesterone levels.  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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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Descriptive assessments of long-term efficacy and safety will be made between the parent study 
Baseline and Week 52, and between the parent study Baseline the end of the extension study 
(Week 104) for the following parent study treatment groups: 
• Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent 
study; 
• Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg 
estradiol and 0.5 mg norethindrone acetate in the parent study; 
• Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for this extension study for all 
change from baseline-related endpoints.  The pain scores during the Baseline Pain Assessment 
Period of the parent study will establish the patient’s baseline for both the parent study and the 
extension study. 
In women with endometriosis-associated pain, the study objectives and corresponding endpoints 
are as follows: 
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Objectives 
Endpoints 
Primary Efficacy 
To be assessed at Week 52 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
 
To be assessed at Week 104 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate 
for up to 104 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
endometriosis-associated pain. 
To be assessed at Week 52 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their dysmenorrhea 
Numerical Rating Scale (NRS) scores; 
• 
Proportion of women who respond or 
maintain response at Week 52/Early 
Termination, based on their NMPP NRS 
scores. 
 
To be assessed at Week 104 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their dysmenorrhea 
NRS scores; 
• 
Proportion of women who respond or 
maintain response at Week 104/Early 
Termination, based on their NMPP NRS 
scores. 
 
Secondary Efficacy 
To be assessed at Week 52 and Week 104 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on the 
following: 
 
 
 
 
 
 
To be assessed at Week 52 and Week 104, unless 
otherwise specified 
• 
Function, as measured by the Endometriosis 
Health Profile (EHP)-30 Pain Domain; 
• 
Change from the parent study Baseline in the 
EHP-30 Pain Domain scores; 
• 
Dysmenorrhea, as measured by the NRS for 
dysmenorrhea; 
• 
Change from the parent study Baseline in the 
mean dysmenorrhea NRS score; 
• 
Patient Global Impression of Change (PGIC) 
for dysmenorrhea; 
• 
Proportion of patients who are better or much 
better on the PGIC for dysmenorrhea (at 
Week 52 only); 
• 
NMPP, as measured by the NRS for NMPP; 
• 
Change from the parent study Baseline in the 
mean NMPP NRS score; 
• 
Overall pelvic pain, as measured by the NRS; 
• 
Change from the parent Baseline in the mean 
NRS score; 
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Objectives 
Endpoints 
• 
Analgesic use; 
• 
Proportion of patients not using opioids; 
• 
Proportion of patients not using analgesics; 
• 
PGIC for NMPP; 
• 
Proportion of patients who are better or much 
better on the PGIC for NMPP (at Week 52 
only); 
• 
Dyspareunia, as measured by the NRS; 
• 
Change from the parent study Baseline in the 
mean dyspareunia NRS scores; 
• 
PGIC for dyspareunia; 
• 
Proportion of patients who are better or much 
better on the PGIC for dyspareunia (at 
Week 52 only); 
• 
Dyspareunia-related functional effects 
(Subject Modified Biberoglu and Behrman 
[sB&B]); 
• 
Change from the parent study Baseline in the 
mean dyspareunia functional impairment on 
the sB&B scale; 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with 24 weeks of 
low-dose estradiol and norethindrone acetate 
compared with placebo on function measured 
by the EHP-30 Pain Domain; 
• 
Proportion of responders based on EHP-30 
Pain Domain scores; 
• 
Patient Global Assessment (PGA) for pain; 
• 
Change from the parent study Baseline in 
severity scores on the PGA for pain; 
• 
PGA for function; 
• 
Change from the parent study Baseline in 
function impairment on the PGA for function; 
• 
Endometriosis-associated quality of life, as 
measured by the EHP-30 Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image domains; 
• 
Change from the parent study in each of the 
non-pain EHP-30 domains (Control and 
Powerlessness, Social Support, Emotional 
Well-Being, and Self-Image); 
• 
Dysmenorrhea-related functional effects 
(sB&B); 
• 
Change from the parent study Baseline pain 
assessment period in dysmenorrhea-related 
functional effects (sB&B); 
• 
NMPP-related functional effects (sB&B). 
• 
Change from the parent study Baseline pain 
assessment period in NMPP-related 
functional effects (sB&B). 
Safety 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), including: 
 
 
 
 
 
To be assessed at Week 52 and Week 104 
• 
Adverse events; 
• 
Incidence of adverse events; 
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Objectives 
Endpoints 
• 
Changes in bone mineral density. 
• 
Percent change from the parent study Baseline 
in bone mineral density at the lumbar spine 
(L1-L4), femoral neck, and total hip as 
assessed by dual-energy x-ray absorptiometry 
(DXA). 
Pharmacodynamic 
 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 104 weeks, among patients 
who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102), on 
estradiol. 
To be assessed at Week 52 and Week 104 
• 
Change from parent study Baseline in predose 
concentrations of serum estradiol. 
Exploratory 
 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on 
endometriosis-associated quality of life 
(EHP-30 total score), work (EHP Work 
Domain), and patient-reported quality of life 
outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) for 
up to 104 weeks among patients who 
previously completed a 24-week treatment 
period in one of the parent studies 
(MVT-601-3101 or MVT-601-3102). 
To be assessed at Week 52 and Week 104 
• 
Change from Baseline in the EHP-30 scale 
total score; 
• 
Change from Baseline in the EHP Work 
Domain score; 
• 
Change from parent study Baseline in the 
EQ-5D-5L. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The SPIRIT EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety study that will enroll eligible patients who have completed their participation 
in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3101 or MVT-601-3102).  All patients will receive open-label oral relugolix 40 mg 
once daily co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for 
up to 80 weeks.  Approximately 800 women with endometriosis-associated pain will be enrolled.  
The objectives of the study are to evaluate long-term efficacy and safety through up to 
104 weeks of treatment (including treatment during the parent study) of relugolix 
co-administered with low-dose estradiol/norethindrone acetate.  Eligible patients will have 
completed participation in one of the parent studies and consented to participate in this extension 
study.  Baseline procedures will be done at the same visit for this extension study (referred to as 
the “Week 24/Baseline visit” in this study) that coincides with the Week 24 visit from the parent 
study and will be defined as the date of completion of the last Week 24 procedure in the parent 
study.  The Week 24/Baseline visit will include vital signs, physical examination, laboratory 
assessments, a 12-lead electrocardiogram (ECG), bone densitometry, patient-reported outcome 
assessments, and endometrial biopsy (if required).  When Week 24 procedures in the parent 
study have been completed, the investigator will assess patient eligibility for participation in the 
open-label extension study.  The eligibility assessment will be based on data available at the 
Week 24/Baseline visit.  No MVT-601-3103 study procedures will be performed until the 
consent form for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Therefore, results of testing required for eligibility must be 
available on or prior to the Week 24/Baseline visit.  The administration of the first dose of study 
drug for MVT-601-3103 will define enrollment into this study.  Study participants will then take 
the open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 80 weeks.  If necessary for logistical reasons 
(eg, delayed availability of study drug supply on site, others), and with sponsor/designee 
approval, the first dose of open-label study drug for MVT-601-3103 may be administered up to 
10 days following the parent study Week 24/Baseline visit.  If the first dose of study drug is not 
given during this up to 10-day interval, the parent study follow-up procedures should be 
followed (ie, adverse event reporting, electronic diary [eDiary] completion, etc.). 
During the 80-week Open-Label Treatment Period and the ~30-day Follow-Up Period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary.  
Only study-specific rescue analgesic medications should be used starting with the 
Week 24/Baseline visit and through the Follow-Up visit and these medications will be taken for 
control of pain and not prophylactically.  Health-related quality of life questionnaires; PGIC for 
dysmenorrhea, NMPP, and dyspareunia; and PGA for pain and function will be completed 
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during the visits on an electronic tablet or on paper, according to the Schedule of Activities 
(Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, mammograms (for 
patients required to have this procedure; see Section 6.5.2.9), endometrial biopsies, and bone 
mineral density with DXA. 
At the Week 36, Week 52, and Week 104/Early Termination visits, each patient will have an 
assessment of bone mineral density via DXA.  Follow-up of bone densitometry findings will 
proceed according to the rules described in Section 6.5.2.6. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted by telephone 3 months 
(+ 0.5 months) after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses.  If a patient is lost to follow-up, three 
documented attempts should be made to contact the patient by telephone.  If unable to contact 
the patient by telephone, a certified letter must be sent to the patient.  A mammogram will be 
performed at Week 52 or at Week 104/Early Termination for women who are or become ≥ 40 
years old during the study (see Section 6.5.2.9). 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, then the Follow-Up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 months (± 1 month) and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 4-1. 
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Figure 4-1 
MVT-601-3103 Study Schematic 
 
4.2. 
Discussion of Study Design, Including Dosing 
The SPIRIT EXTENSION study (MVT-601-3103) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3101 and MVT-601-3102) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with endometriosis-associated pain.  This 
80-week extension study provides additional efficacy and safety data up to 104 weeks to 
demonstrate the benefit and safety of relugolix co-administered with low-dose estradiol (1 mg) 
and norethindrone acetate (0.5 mg).  The primary objectives of the study are to assess long-term 
efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 104 weeks on dysmenorrhea and NMPP, common and 
burdensome symptoms of endometriosis.  The study will also evaluate safety of relugolix 40 mg 
once daily co-administered with low-dose estradiol and norethindrone acetate for up to 
104 weeks, among patients who previously completed a 24-week treatment period in one of the 
parent studies (MVT-601-3101 or MVT-601-3102), including adverse events and change in bone 
mineral density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily suppressed estradiol levels 
to below 20 pg/mL in the majority of women, and results were similar to those in the group of 
women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the relugolix 
40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary endpoint of 
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the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 
demonstrated the 40-mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from endometriosis-associated pain to move forward into phase 3 clinical 
development and, based on the DXA data from the phase 2 study, are not expected to prevent 
bone mineral density loss in a significant majority of women over 104 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 104 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in dysmenorrhea and NMPP.  It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2017; Lee, 2016; Franke, 2000] or endometriosis-associated 
pain [Wu, 2014].  The estradiol/norethindrone acetate combination proposed for evaluation in 
this phase 3 study is currently approved in the United States (US) as long-term hormone 
replacement therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal 
women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 
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lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Activella US Prescribing Information, 2013]) would not provide sufficient serum estradiol 
concentrations to protect against the loss of bone mineral density resulting from the 
hypoestrogenic state induced by once daily administration of relugolix 40 mg. 
The doses of estradiol and norethindrone acetate used in this study (1.0 mg and 0.5 mg, 
respectively) were used in the parent studies (MVT-601-3101 and MVT-601-3102) and represent 
less than one fifth the estrogenic effects of an oral contraceptive pill containing 30 µg of ethinyl 
estradiol.  Therefore, this low-dose hormonal add-back therapy is added solely to improve the 
safety of relugolix therapy, and it is expected to have either a neutral or a marginal detrimental 
effect on efficacy, while mitigating the side effects of relugolix on bone mineral density loss and 
vasomotor symptoms. 
In summary, relugolix at a dose of 40 mg once daily resulted in a significant decrease in 
endometriosis-associated pain in a well-designed large phase 2 study.  However, its 
administration was associated with a degree of bone mineral density loss unacceptable for 
long-term treatment.  This phase 3 study extension study will assess long-term efficacy and 
safety of relugolix 40 mg co-administered with low-dose estradiol and norethindrone acetate to 
decrease dysmenorrhea and NMPP and to prevent the bone mineral density loss and ameliorate 
some of the other side effects of a hypoestrogenic state such as hot flushes. 
This open-label extension study will allow for a description of long-term efficacy data and safety 
for an additional 80 weeks of treatment, providing approximately 1 year of efficacy and safety 
data from the women originally randomized to relugolix in studies (MVT-601-3101 and 
MVT-601-3102).  This study design will allow eligible patients with endometriosis-associated 
pain, including those randomized to placebo in the parent study, to receive relugolix 
co-administered with low-dose hormonal add-back therapy during the extension. 
4.3. 
Selection of Study Population 
The study population will include approximately 800 premenopausal women aged 18 to 51 years 
with endometriosis-associated pain. 
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. 
4.3.1. 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization): 
1. Completed 24 weeks of study drug treatment and study participation in either 
MVT-601-3101 or MVT-601-3102; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
study-specific procedures for MVT-601-3103; 
Note:  Procedures conducted as part of the parent study that also serve as baseline 
procedures for this study will be done under the informed consent for the parent study. 
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3. Is not expected to undergo gynecological surgery or other surgical procedures for 
treatment of endometriosis (including ablation, shaving, or excision) during the study, 
including during the Follow-Up Period, and the patient does not desire such treatment 
during this time frame; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Has agreed to continue to use only study-specified analgesic medications during the study 
and is not known to be intolerant to these; 
6. Agrees to continue to use acceptable non-hormonal contraceptive methods as described 
in Section 4.6 consistently during the Open-Label Treatment Period and for at least 
30 days after the last dose of study drug.  However, the patient is not required to use the 
specified non-hormonal contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 6 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
c. Has a non-hormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of non-hormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
Exclusion Criteria 
1. Has had a surgical procedure for treatment of endometriosis at any time during the parent 
study (MVT-601-3101 or MVT-601-3102); 
2. Has any chronic pain or frequently recurring pain condition, other than endometriosis, 
that is treated with opioids or requires analgesics for ≥ 7 days per month; 
3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that 
precludes an adequate DXA measurement at the lumbar spine and proximal femur (eg, 
bilateral hip replacement, spinal hardware in the lumbar spine); 
4. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent 
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study 
Week 24 DXA assessment of bone mineral density; 
5. Anticipated to use any prohibited medications as detailed in Section 5.10.1; 
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6. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
7. Has current active liver disease from any cause; 
8. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc.); psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
9. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or, if available, any subsequent visit in one of the parent studies (MVT-601-3101 or 
MVT-601-3102): 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 times the 
upper limit of normal (ULN); or 
b. Bilirubin (total bilirubin) > 1.5 x ULN (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome); 
10. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
11. Has a decline in presenting visual acuity score, as defined below (unless explained by 
refractive error or approved by the sponsor): 
a. 90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the 
parent study Baseline visit; or 
b. The presenting visual acuity score has decreased by ten or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  Visual acuity score must have been obtained with corrective lenses, if applicable. 
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12. Is inappropriate for participation in this study because of conditions that may interfere 
with interpretation of study results or prevent the patient from complying with study 
requirements, as determined by the investigator, sub-investigator, or medical monitor; 
13. Met a withdrawal criterion in the parent study (MVT-601-3101 or MVT-601-3102). 
4.4. 
Method of Assigning Patients to Treatment Group and Patient 
Identification Number 
Eligible patients who sign consent will be identified with the same Patient Identification (ID) 
Number assigned to the patient during the parent study.  This extension study is a single-arm, 
open-label study, and thus all eligible patients are assigned to the same treatment group of 
relugolix 40 mg co-administered with low-dose of estradiol and norethindrone acetate (see 
Section 5.1 for treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 104 visit defines completion of the study.  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 Early Termination visit (see the Week 104 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication).  When patients complete the study or early terminate from the study, they 
must be deactivated from the study in the interactive voice response system/interactive web 
response system (IVRS/IWRS), eDiary, and tablet device. 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• Any adverse event that is intolerable to the patient and 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; 
• If it is discovered after enrollment that a patient failed to meet protocol entry criteria 
and continued participation poses an unacceptable risk to the patient’s health; 
• If the following 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): 
− 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 
international normalized ratio (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%); 
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• QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec 
read by a cardiologist; 
• Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial 
biopsy; 
• If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or 
femoral neck compared with the parent study Baseline; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  Gross noncompliance includes 
< 75% compliance with the study drug over > 2 consecutive months; missing multiple 
study visits; and persistent (> 2 consecutive months) noncompliance (< 50% of the 
required number of days) with eDiary completion up to Week 52 or persistent 
(≥ 2 eDiary collection cycles) noncompliance (< 50% of the required number of days) 
with eDiary completion from Week 52 to Week 104.  Investigators will follow up 
with the patient and encourage compliance with study drug or eDiary prior to 
discontinuing her from the study; 
• If the patient becomes pregnant at any time after providing a signed informed consent 
form, the patient must be withdrawn immediately (see Section 7.8 for information on 
pregnancy reporting); 
• Evidence of malignant breast lesion(s) or breast carcinoma on Week 52 or 
Week 104/Early Termination or most recent mammogram or additional breast 
imaging (see Section 6.5.2.9 for more information on mammogram at Week 52 or 
Week 104/Early Termination). 
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 noncompliance.  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 three 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.” 
4.6. 
Contraception/Pregnancy Avoidance 
All patients should be counseled at every visit to adhere to the use of protocol allowed 
contraceptive methods.  In this study, medications and devices containing hormones for 
contraception are excluded, and patients must agree to use non-hormonal contraception 
throughout the study including through 30 days following the last dose of study drug, unless any 
of the following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure) at least 6 months prior to the Week 24/Baseline visit (patients with Essure 
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must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
• Has a non-hormonal intrauterine device (eg, Paragard) placed in the uterus; 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of non-hormonal contraception as described below; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods do 
not apply are: 
• Condom (male or female condom) with or without spermicide (cream, spray, foam, 
gel, suppository, or polymer film); 
• Diaphragm with spermicide (condom may or may not be used); 
• Cervical cap with spermicide (condom may or may not be used); or 
• Vaginal sponge impregnated with spermicide used with a condom. 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed according to the Schedule of Activities (Table 1-1; 
including just prior to receiving the first dose of study drug), and patients will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures.  Patients 
should call the investigator immediately if they suspect they may be pregnant.  Patients who 
become pregnant during the study will be withdrawn from the study and followed for pregnancy 
outcome (see Section 7.8). 
4.7. 
Novel Coronavirus 2019 Guidance 
Guidance for conducting clinical trials during the novel coronavirus 2019 (COVID-19) pandemic 
is included in Appendix 9. 
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5. 
TREATMENTS 
5.1. 
Treatments Administered 
In this extension study, all patients will receive the following open-label oral study treatment: 
• 80 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg 
estradiol, and 0.5 mg norethindrone acetate. 
Each patient will be instructed to take one tablet and one capsule per day. 
Table 5-1 
Description of MVT-601-3103 Study Drugs 
Name of Investigational 
Product 
Relugolix 
Estradiol / Norethindrone 
Acetate 
Formulation Description 
Round film-coated pink tablet 
A Swedish orange, over-
encapsulated round film-coated 
white tablet with back-fill 
material 
Dosage Form 
Tablet 
Capsule 
Unit Dose Strength 
40 mg 
Estradiol 1.0 mg / norethindrone 
acetate 0.5 mg 
Route of Administration/ 
Duration 
Oral once daily/ 
80 weeks 
Oral once daily/ 
80 weeks 
Two protocol-specified analgesics include a first-line non-steroidal anti-inflammatory drug 
(NSAID) and a second-line opioid or opioid/acetaminophen (or paracetamol) combination for 
endometriosis-related pain relief as required.  The specific analgesic drugs offered may differ for 
different countries or regions.  A list of study-specified analgesics is provided in Appendix 1.  
For directions on prescribing rescue analgesic medications, see Section 5.7. 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name 1-(4-{1-[(2,6-difluorophenyl)methyl]-5-
[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl}phenyl)-3-methoxyurea. 
Estradiol (1.0 mg) and norethindrone acetate (0.5 mg) is a fixed-dose combination product. 
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 common 
excipients. 
The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
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5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing 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. 
On Week 24/Baseline 1, Week 52, and Week 104 clinic visit days, study drug will be 
administered in the clinic rather than at home (see Schedule of Activities in Section 1.1). 
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 cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location at room 
temperature.  Follow storage conditions described on the drug labeling.  Study drug should be 
stored protected from light.  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.  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. 
Study drug will be labeled with the study protocol number, medication or lot/batch number, 
contents, directions for use, storage directions, clinical study statement, and any other labeling 
required by regulatory bodies in the study locations and will list Myovant Sciences GmbH as the 
sponsor.  Patients will be instructed to store study drug at room temperature out of the reach of 
children. 
All labels for relugolix and the estradiol/norethindrone acetate combination to be distributed will 
meet all applicable requirements of the US Food and Drug Administration (FDA) and Annex 13 
of Good Manufacturing Practices:  Manufacture of investigational medicinal products (July 
2010) and/or other local regulations as applicable. 
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Please see Appendix 1 for a list of protocol-specified analgesics.  Further details on analgesic 
medication are provided in the Investigator Site File. 
5.7. 
Rescue Analgesic Medications 
Management of endometriosis-associated pain often requires treatment with analgesics and some 
patients require treatment with opioid drugs. Two tiers of pain medications are specified for this 
trial.  The study-specified pain medications for each patient will be the same as for the parent 
study.  Only study-specific Tier 1 and Tier 2 analgesic medications (see Appendix 1) should be 
taken starting with the Baseline/Week 24 visit and subsequently.  Analgesic medications will be 
taken for control of pain and not prophylactically. 
If a patient develops uncontrolled endometriosis-associated pain during the study despite use of 
the study-specified analgesics or an intolerance to a study-specified analgesic, please contact the 
medical monitor. 
Short-term use of non-study specified analgesics for the treatment of an intercurrent event (eg, 
injury or surgery) is allowed, if required.  Such events should be reported as adverse events when 
appropriate. 
Investigators must instruct the patient on the use of ibuprofen 200 mg tablets (ie, number of 
tablets per dose, dosing frequency, maximum number of tablets per day).  For patients who may 
need the Tier 2 analgesic medication, a prescription should also be written for this at the time of 
enrollment into this study.  This is to ensure that patients do not endure unnecessary pain during 
the conduct of the study. 
Quantities of opioids prescribed should be based on the patient’s expected usage until the next 
study visit.  Prescriptions for Tier 1 and Tier 2 rescue analgesic medications should be in 
accordance with their full prescribing information (ie, the local product labeling) and 
prescriptions for opioids should not provide for any refills.  Patients should be counseled on the 
safe use of opioids. 
Patients who are not prescribed the Tier 2 medication at the time of enrollment in this study, for 
example, because requirement for analgesics beyond the Tier 1 medication is not expected (eg, 
based on pain level and/or recent analgesic requirements) should be advised to contact the 
investigator if pain is inadequately controlled with the Tier 1 medication alone.  To avoid 
experiencing extended periods of uncontrolled pain, patients who require the Tier 2 medication 
should get a prescription from the investigator and initiate treatment with the Tier 2 medication 
as soon as feasible. 
Use of protocol-specified rescue analgesic medications and any other analgesics taken for any 
type of pain, must be recorded by the patient in the eDiary. 
5.8. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.9. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and should bring all unused and used 
(including partially used) study drug kits to each study visit.  At the Week 24/Baseline visit and 
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Week 104/Early Termination visit, all used, partially used, and unused study drug kits should be 
retained at the site.  At all other visits, only fully used study drug kits should be retained at the 
site.  New study drug should be dispensed as described in Section 1.1 (Schedule of Activities). 
Study drug accountability will be conducted and results will be recorded.  If a patient is 
persistently noncompliant with the study treatment, it may be appropriate to withdraw the patient 
from the study (see Section 4.5).  All patients should be reinstructed about the dosing 
requirement during study contacts.  The authorized study personnel conducting the re-education 
must document the process in the patient’s source records. 
Because of the importance to both safety and efficacy evaluation, patients who are grossly 
noncompliant with eDiary completion must undergo an Unscheduled visit to evaluate reasons for 
noncompliance and to develop a plan to improve compliance.  Failure to improve compliance 
may result in the sponsor withdrawing the patient from further study treatment (including study 
analgesics) and/or discontinuation from the study (see Section 4.5 for details). 
All patients should be reinstructed about the dosing requirement and eDiary 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 prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Drugs and drug classes in Table 5-2 are prohibited at any time 
during the study through the Follow-Up visit, except as noted in the table.  Consult the medical 
monitor if there is any uncertainty regarding patient use of a particular drug or drug class. 
Table 5-2 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zoledronic acid 
 
GnRH analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
 
Anti-androgens 
danazol 
 
Anticonvulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
Note: All other anticonvulsants are 
allowed. 
Aromatase inhibitors 
anastrozole 
letrozole 
 
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Drug Class 
Examples 
Comments 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
Hormonal contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
NuvaRing 
 
Selective estrogen 
receptor modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
 
Selective progesterone 
receptor modulators  
mifepristone 
ulipristal acetate 
 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
 
Intrauterine devices 
levonorgestrel 
 
Bone agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use of systemic 
glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study.   
Note:  topical, inhaled, intranasal, 
otic, ophthalmic, intraarticular, or 
intralesional subcutaneous are 
permitted without restriction. 
Short duration (< 21 days) higher-
dose glucocorticoids required for 
acute events are permitted during 
the study. 
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Drug Class 
Examples 
Comments 
P-glycoprotein inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavirf 
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 and strong 
P-glycoprotein- inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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. 
Analgesic drugs other 
than those specified for 
use during the studyh 
Acetaminophen/paracetamol (other 
than any included in a 
study-specified analgesic) 
aspirin > 325 mg/day 
NSAIDs (other than study-specified 
NSAIDs) 
gabapentin 
pregabalin 
carbamazepine 
metamizole 
cannabinoids 
Note:  Aspirin ≤ 325 mg per day is 
allowed. 
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Drug Class 
Examples 
Comments 
Antidepressants 
New treatment or 
changed doses of SSRI, 
SNRI, or TCA 
antidepressants 
SNRI examples: 
duloxetine 
venlafaxine 
desvenlafaxine 
SSRI examples: 
citalopram 
fluoxetine 
paroxetine 
fluvoxamine 
TCA examples: 
amitriptyline 
doxepin 
desipramine 
nortriptyline 
SSRI, SNRI, or TCA allowed if 
given at the same dose as used 
during the 3 months prior to the 
Run-In Period of MVT-601-3101 or 
MVT-601-3102. 
New start, dose change or 
discontinuation of these drugs is not 
allowed during the study.  Changes 
made for safety reasons are allowed 
with approval of the medical 
monitor. 
DHEA = dihydroepiandrosterone; GnRH = gonadotropin-releasing hormone; NSAID = nonsteroidal anti-
inflammatory drug; SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake 
inhibitor; TCA = tricyclic antidepressant. 
 
a. 
Roxithromycin is allowed. 
b. All other angiotensin converting enzyme inhibitors are allowed. 
c. 
Tacrolimus is allowed. 
d. Amlodipine and nifedipine are allowed. 
e. 
Fluconazole is allowed. 
f. 
Integrase inhibitors are allowed. 
g. Clopidogrel is allowed. 
h. For situations where non-study analgesics may be allowed, see Section 5.7. 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded in the electronic Case Report 
Forms (eCRFs), including the drug generic name, dose amount, route of administration, start 
date, and stop date. 
5.10.2.1. Analgesics 
All analgesics will be collected in the eDiary and recorded in the eCRFs. 
5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of endometriosis is prohibited from the Week 24/Baseline visit until the 
patient’s final study visit unless urgently needed for patient safety. 
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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 6.5.  Further details of the 
procedures are provided in the Investigator Site File.  Guidelines to address the COVID-19 
pandemic are included in Appendix 9. 
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 2 periods:  Open-Label Treatment 
Period and Safety Follow-Up Period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 104) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3101 or MVT-601-3102 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week 24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• Informed consent (unless signed previously); 
• Record concomitant medications; 
• Update the patient’s status in the IVRS/IWRS as being in the MVT-601-3103 and 
receive the lot numbers for study drug allocation; 
• Dispense study treatment; 
• Dispense or prescribe protocol-specified analgesic drugs; 
• Transition the patient within her eDiary from the parent study to MVT-601-3103; 
• Take study drug dose in clinic; and 
• Record adverse events, if any. 
The Week 24 visit date in the parent study is defined as the date that the last procedures for the 
Week 24 visit were completed, acknowledging that the Week 24 visit procedures may be 
completed on different dates.  Patients will have received their last dose of study drug in the 
parent study on the day prior to the Week 24/Baseline visit and will receive their first dose of 
study drug for this extension study in the clinic after the patient is determined to be eligible for 
this extension study and has provided informed consent to participate.  Therefore, results of 
testing required for eligibility must be available on or prior to the Week 24/Baseline visit.  If 
necessary for logistical reasons (eg, delayed availability of study drug supply on site, others), and 
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with sponsor/designee approval, the first dose of open label study drug for MVT-601-3103 may 
be administered up to 10 days following the parent study Week 24/Baseline visit.  If the first 
dose of study drug is not given during this up to 10-day interval, the parent study follow-up 
procedures should be followed (ie, adverse event reporting, eDiary completion, etc.). 
Patients will continue recording data in their eDiary daily and taking protocol-specified 
analgesics as needed until Week 52.  After Week 52, the eDiary will be collected on the 
following schedule:  Week 57 to the Week 65 visit, Week 71 to the Week 78 visit, Week 85 to 
the Week 91 visit, and Week 98 to the Week 104 visit.  Following the Week 24/Baseline visit, 
on-treatment study visits will occur at Weeks 28, 32, 36, 40, 44, 48, 52, 65, 78, 91, and 104.  
Sites will monitor diary completion using the Trial Manager web portal throughout the study. 
A telephone call will be performed at Weeks 57, 71, 85 and 98.  The following activities should 
be completed: a concomitant medication review, an evaluation of adverse events, a review of 
study medication compliance, a reminder of compliance with non-hormonal contraception 
requirements and the need to call the investigator if pregnancy is suspected, and a reminder to 
the patient to start recording in the eDiary daily. 
Accountability for study drug will be performed at each visit.  Instructions for analgesic 
medication usage will be reinforced at each visit. 
Questionnaires are administered on the electronic tablet and on paper at each visit.  These 
procedures should occur before any other types of study procedures are performed.  When both 
electronic tablet and paper questionnaires are required at a visit, the electronic questionnaires 
should be done first.  The order in which the electronic tablet and paper questionnaires should be 
administered are as follows: 
• Electronic tablet questionnaires (in the order they appear in the tablet) 
• Paper questionnaires 
− PGA for function 
− EHP Work Domain [Week24/Baseline, Week 52, Week 78, and Week 104 only] 
Patients will bring their eDiary, analgesic medications, and study drug to each visit.  The site 
must document the start and stop dates of the patient’s menses. 
An endometrial biopsy will have been performed at the parent study Week 24 visit for all 
patients who participated in MVT-601-3101 (see MVT-601-3101 protocol for details).  An 
endometrial biopsy is required at Week 52 and the Early Termination visit for all patients.  This 
procedure is not required at the Early Termination visit in patients whose last dose of study drug 
was taken during Week 32 or earlier or within four weeks after completion of the Week 52 
endometrial biopsy.  However, the procedure may be done if it will aid in the evaluation of an 
ongoing adverse event.  An endometrial biopsy at Week 104 is recommended for all patients 
who complete the open-label extension; however, patients will have the option to opt out.  Safety 
monitoring for this study includes physical examination, clinical laboratory tests, pregnancy 
tests, and adverse event collection at each visit.  Clinical chemistries will be collected at each 
visit.  A complete blood count will be collected at Week 24/Baseline, Week 28, Week 36, Week 
52, Week 65, Week 78, Week 91, and Week 104/Early Termination.  At the Week 24/Baseline 
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visit, Week 52 visit, and Week 104/Early Termination visit, additional tests include fasting (at 
least 8 hours, other than water) glucose, lipid profile, and hemoglobin A1c. 
Electrocardiograms will be performed at the Week 24/Baseline, Week 52, and Week 104/Early 
Termination visits. 
A mammogram will be performed at Week 52 or at Week 104/Early Termination for women 
who are or become ≥ 40 years old during the study (see Section 6.5.2.9). 
Bone densitometry will occur at the Week 24/Baseline, Week 36, Week 52, and Week 104/Early 
Termination visits.  Follow-up of bone densitometry findings will proceed according to the rules 
described in Section 6.5.2.6. 
Bone densitometry and ECGs will be submitted for central reading. 
Study drug compliance will be reviewed at each visit.  Fasting (other than water) for at least 
8 hours is required prior to blood sampling on Week 24/Baseline and Week 52/Early 
Termination visits and for 1 hour after administration of the study drug in the clinic.  Laboratory 
requisitions must indicate whether or not the patient was not fasted for their chemistry and lipid 
testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment Period. 
6.3. 
Early Termination Visit and Follow-Up Visit 
All patients withdrawing from the study prior to Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 104.  An 
endometrial biopsy is required for all patients at the Early Termination visit except for patients 
whose last dose of study drug was taken during Week 32 or earlier or within four weeks after 
completion of the Week 52 endometrial biopsy.  However, the endometrial biopsy may be 
obtained if it will aid in the evaluation of an ongoing adverse event.  Follow-up bone 
densitometry findings for patients who terminate from the study early will proceed according to 
the rules provided in Section 6.5.2.6. 
Patients (including those who complete the Week 104 visit and those who withdraw early from 
this study) will have a Follow-Up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
endometriosis, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 104 visit, the Follow-Up visit may be 
waived. 
The Follow-Up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the 
Follow-Up visit. 
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6.4. 
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 source 
documentation.  The following activities should be completed at Unscheduled visits:  recording 
of reason for the visit, concomitant medication review, and evaluation of adverse events.  In 
addition, procedures such as vital signs, weight, complete physical examination, sign- and 
symptom-directed physical examination, clinical laboratory assessment, urinalysis, urine 
pregnancy testing, pharmacodynamic sampling, mammogram (for patients required to have this 
procedure; see Section 6.5.2.9), 12-lead ECG, study drug compliance and dispensation, eDiary 
review, dispensation or prescription of protocol-specified analgesics, etc., may be conducted as 
needed.  See the Schedule of Activities (Section 1.1) for tests that may be performed, as 
indicated at an Unscheduled visit.  The investigator should consult with the medical monitor, if 
needed, to discuss Unscheduled visit testing.  The investigator should obtain approval from the 
sponsor to perform an unscheduled endometrial biopsy or DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Pharmacodynamics Sample Collection 
A blood sample for the pharmacodynamic analysis of serum estradiol will be collected predose at 
the visits indicated in the study Schedule of Activities (see Section 1.1), other than at the 
Week 104 or the Early Termination visit, when no dose is administered.  These 
pharmacodynamic samples will be analyzed at a central laboratory.  These results will not be 
shared with the sites at any time. 
6.5.1.2. 
Patient eDiary 
All women enrolled in the study will continue to use the patient eDiary dispensed in the parent 
study (see Appendix 2).  Patients will complete daily eDiary entries, including NRS pain scores, 
menstruation information, analgesic drug use, date and time of study drug administration, and 
sB&B scale scores until Week 52.  After Week 52, eDiary scores will be entered over four 
eDiary collection cycles on the following schedule:  Week 57 to the Week 65 visit, Week 71 to 
the Week 78 visit, Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. 
The site should review the eDiary data at every visit. 
6.5.1.3. 
Endometriosis Health Profile-30 
The EHP-30 is used to evaluate the functional impact and the quality of life of patients with 
endometriosis (see Appendix 3).  Patients will complete the EHP-30 questionnaire at the site at 
visits indicated in Section 1.1 before other types of study procedures, such as blood draws and 
physical examinations, are performed.  The EHP-30 will be completed on a tablet device at the 
study site. 
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6.5.1.4. 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes (see 
Appendix 4).  Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are 
each assessed on a 5-level categorical scale. 
Patients will complete the EQ-5D-5L questionnaire at the site at visits indicated in Section 1.1 
before other types of study procedures, such as blood draws and physical examinations, are 
performed.  The EQ-5D-5L will be completed on a tablet device at the study site. 
6.5.1.5. 
Patient Global Assessment and Patient Global Impression of Change 
These simple questions are used by the patient to qualitatively describe severity of pain or effects 
on function (PGA) or impression of change in pain severity (PGIC) (see Appendix 5) on a 
schedule described in the Schedule of Activities (Section 1.1).  Patients should answer these 
questions before other types of study procedures, such as blood draws and physical 
examinations, are performed.  The PGA for pain severity and the PGIC will be completed on a 
tablet device at the study site.  The PGA for function will be completed on a paper questionnaire 
at the study site. 
6.5.1.6. 
Endometriosis Health Profile Work Domain 
This 5-question paper questionnaire will be completed by the patient to describe the effects of 
endometriosis on their work (Appendix 6).  Patients will complete the EHP Work Domain 
questionnaire at visits indicated in Section 1.1 before other types of study procedures, such as 
blood draws and physical examinations, are performed.  The EHP Work Domain will be 
completed on a paper questionnaire at the study site. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 
6.5.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest. 
6.5.2.3. 
Physical Examinations 
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.  The physical 
examinations at Week 52 and Week 104 will include a breast examination. 
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6.5.2.4. 
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. 
Table 6-1 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatine kinase 
Hemoglobin A1c 
Bilirubin total 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transferase 
Alkaline phosphatase 
White blood cell count 
White blood cell differential 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
Platelet count 
Red blood cell morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and clarity 
pH 
Leucocyte esterase 
Ketones 
Nitrite 
Specific gravity 
Urine microscopy (reflex 
testing based on abnormal 
urine analysis) 
Hormones 
Lipids 
Pregnancy 
Estradiol 
Total cholesterol 
Low-density lipoprotein 
High-density lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
serum hormone levels.  Each study site will conduct urine pregnancy tests locally. 
All laboratory tests with values that are considered abnormal and clinically significant during 
participation in the study or within 30 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized.  Abnormal values, determined to 
be clinically significant, should be reported as adverse events. 
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For patients with incomplete recovery of bone mineral density loss at the 6- and 12-month 
post-treatment follow-up visit, clinical laboratory tests should be performed (see Section 6.5.2.6).  
These laboratory assessments will be submitted to the central laboratory.  If these laboratory 
assessments are scheduled to occur after the study database is locked, they will be performed at a 
local laboratory.  The investigator will maintain a copy of the reference ranges (with the record 
of the reference ranges) for the laboratory or laboratories used. 
6.5.2.5. 
Electrocardiograms 
Electrocardiograms (12-lead) will be obtained at the time points described in the Schedule of 
Activities (Section 1.1).  Electrocardiograms will be measured using standardized equipment 
provided by the central core laboratory with the patient in a semi-supine or supine position after 
5 minutes of rest.  The ECGs will be assessed by central review and a report provided to the site.  
The investigator or sub-investigator (or a qualified individual at the investigational site) will 
interpret the ECG report provided by the central reviewer using one of the following categories:  
normal or abnormal.  The investigator or sub-investigator will judge if any of the findings are 
clinically significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3, and L4), total hip, and femoral neck (same leg within each patient) at the time 
points described in the Schedule of Activities (Section 1.1).  The scans will be read by the central 
imaging laboratory in accordance with the imaging charter.  Training, quality review, and 
readings will be done by a central radiology laboratory as described in the central radiology 
charter for bone mineral density. 
Throughout the study, the same DXA apparatus will be used at each site and operated in the 
same scan mode for all scans for an individual patient and should be the same as used for the 
patient during the parent study (MVT-601-3101 and MVT-601-3102).  The central core imaging 
laboratory will collect and evaluate all DXA scans for acceptability.  Bone mineral density 
changes for individual patients will be monitored by the central imaging laboratory over the 
course of the study. 
Determination of bone mineral density by DXA at the Early Termination visit or at the Week 
104 visit and follow-up of findings will proceed according to the following rules: 
Early Termination and 6-Month Post-Treatment DXA 
• For patients who early terminate: 
− For Early Termination occurring before Week 36, DXA is not required at the 
Early Termination visit unless it will aid in the assessment of an adverse event or 
if the most recent DXA bone mineral density loss at lumbar spine (L1-L4) or total 
hip was > 2% relative to the parent study baseline.  In this case, follow-up DXA is 
required at 6 months (± 1 month). 
- 
For Early Termination occurring at or after the Week 36 visit, DXA is required 
at Early Termination unless a DXA result is available from within six weeks prior 
to Early Termination. 
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Most recent DXA was at the Week 24 visit:  Follow-up DXA is required 
at 6 months (± 1 month) if the most recent DXA scan was at Week 24 and 
bone mineral density loss at the lumbar spine (L1-L4) or total hip was 
> 2%, relative to the parent study baseline; 
Most recent DXA was after the Week 24 visit:  Follow-up DXA is required 
at 6 months (± 1 month) if, on the most recent DXA scan in the open-label 
extension study, bone mineral density loss at the lumbar spine (L1-L4) or 
total hip was > 3%, relative to the parent study baseline. 
Study Completion and 6-Month Post-Treatment DXA 
• For patients who complete the open-label extension study: 
Follow-up DXA is required at 6 months (± 1 month) if, at the Week 104 visit or 
on the most recent DXA scan, bone mineral density loss at the lumbar spine 
(L1-L4) or total hip was > 3%, relative to the parent study baseline. 
Note:  Patients undergoing 6-month post-treatment follow-up should also have the 
following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous. 
Patients Who Have Previously Completed or Early Terminated from the Study 
Patients who have previously completed or early terminated from the study prior to 
Protocol Amendment 3.1 may not have undergone post-treatment DXA according to the 
current protocol requirements.  To allow for further follow-up of these patients, it is 
strongly recommend that attempts be made to contact the patients who met the protocol 
specified threshold of > 3% bone loss at or after the Week 36 DXA scan to obtain a 
post-study follow-up DXA scan at 6 months (± 1 month) from last dose of study drug, if 
such a scan has not been scheduled or performed.  For patients who are already out of this 
6-month window, an unscheduled post-treatment follow-up DXA scan is recommended. 
12-Month Post-Treatment DXA 
• If patients have 6-month post-treatment follow-up scans that show bone loss of 
> 1.5% at the lumbar spine and/or > 2.5% at total hip compared with the parent study 
baseline, patients are strongly encouraged to come back to the clinic for an additional 
post-treatment follow-up scan 12 months from the date of the last dose of the study 
drug.  Patients undergoing 12-month post-treatment follow-up should also have the 
following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous. 
• If patients have 12-month post-treatment follow-up scans that show bone loss of 
≥ 3% at the lumbar spine and/or total hip compared with the parent study baseline, 
patients are recommended to be referred to and strongly encouraged to see a bone 
specialist for further evaluation or the bone loss.   
Note 1:  Patients undergoing 6-month post-treatment follow-up should also have the 
following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous. 
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Note 2:  When a patient is referred to a bone specialist for evaluation and 
management, Myovant will provide a Bone Consultation Letter to the investigator for 
this additional bone consult and will request the site to provide a summary of the 
evaluation and management plan once the consultation is complete. 
6.5.2.7. 
Endometrial Biopsy 
For patients in parent study MVT-601-3101, an endometrial biopsy is performed at the Week 24 
visit.  If the required Week 24 biopsy is inadequate for diagnosis, it should be repeated, and a 
sample submitted to the central laboratory.  If the second sample is inadequate, ensure an 
endometrial thickness has been reported from the Week 24 transvaginal ultrasound and contact 
the medical monitor to review the findings.   
Patients who have endometrial hyperplasia or endometrial carcinoma will be withdrawn from 
study drug treatment and followed per instructions in the parent and/or extension study protocol. 
Additional assessment of the effects of relugolix co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will be performed at the Week 52 and Early 
Termination visit for all patients.  An endometrial biopsy is required for all patients at the Early 
Termination visit except for patients whose last dose of study drug was taken during Week 32 or 
earlier or within four weeks after completion of the Week 52 endometrial biopsy.  However, the 
endometrial biopsy may be obtained if it will aid in the evaluation of an ongoing adverse event.  
An endometrial biopsy at Week 104 is recommended for all patients who complete the 
open-label extension; however, patients will have the option to opt out.  Patient participation in 
the Week 104 endometrial biopsy is voluntary and refusal to participate will not indicate 
withdrawal from the study. 
The Week 52, Week 104, and Early Termination endometrial biopsy samples will be submitted 
to the central laboratory.  If the Week 52, Week 104, or Early Termination biopsy specimen is 
inadequate, a transvaginal ultrasound for endometrial thickness should be obtained and read 
locally.  The transvaginal ultrasound findings will be used to determine if further action is 
required: 
• Endometrial thickness ≤ 5 mm:  no further action required; 
• Endometrial thickness > 5 mm at any location or any other endometrial abnormality:  
repeat endometrial sampling.  Contact medical monitor if second specimen is 
inadequate for diagnosis. 
Investigators should contact the medical monitor if a patient refuses to have an endometrial 
biopsy at Week 52 or the Early Termination visit.  Unscheduled endometrial biopsies may also 
be performed when medically indicated and as deemed necessary by the investigator.  The 
investigator should obtain approval from the sponsor to perform an unscheduled endometrial 
biopsy, unless urgently indicated.  Additional consent is not required in this circumstance. 
6.5.2.8. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-Up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted by telephone 
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3 months (+ 0.5 months) after the Follow-Up visit to determine if menses has resumed and will 
be asked about factors that may affect resumption of menses.  If a patient is lost to follow-up, 
three documented attempts should be made to contact the patient by telephone.  If unable to 
contact the patient by telephone, a certified letter must be sent to the patient. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
6.5.2.9. 
Mammogram 
A mammogram will be performed at the Week 52 or Week 104/Early Termination visit (see the 
Schedule of Activities in Section 1.1) for patients ≥ 40 years of age at the time of the visit.  If a 
patient had a recent mammogram per standard of care within the 6 months before Week 52 that 
was Breast Imaging Reporting and Data System category 1 or 2 or equivalent or had benign 
findings, as determined by the investigator or medical monitor, a mammogram is not required at 
Week 52 but should be completed by Week 104/Early Termination.  If a patient turns 40 years 
old after the Week 52 visit has occurred, a mammogram should be performed no later than the 
Week 104/Early Termination visit. 
All mammogram results will be read locally using Breast Imaging Reporting and Data System 
categories or equivalent (see Appendix 8) and recorded in the eCRF.  The following actions will 
be taken depending on the reading: 
• Category 1 or 2 or equivalent:  normal mammogram; no further action is required 
unless determined by the investigator or medical monitor; 
• Category 0 or 3 or equivalent:  adjunctive breast imaging or follow-up mammogram 
will be required, and the investigator should contact the medical monitor for approval 
of additional breast imaging; 
• Category 4 to 6 or equivalent:  the investigator should contact the medical monitor 
within 24 hours. 
• Patients who have malignant breast lesion(s) or breast carcinoma will be withdrawn 
from study drug treatment (see Section 4.5). 
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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, ECGs, and bone mineral density assessments. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
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: 
− Induces clinical signs or symptoms; 
− Requires active intervention; 
− Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an adverse event; 
• Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• 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); 
• Endometriosis-associated pain is not considered an adverse event in this study 
because it is being quantitatively measured as the primary efficacy endpoint. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
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(CTCAE).  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. 
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 participant 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 admitted to a hospital, 
independent of the duration of that hospitalization.  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) which 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 which 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 Institutional Review Board (IRB) or Independent Ethics Committee 
(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: 
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• “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 eDiary entries, including bleeding and answers to the other patient-reported 
outcome measures, 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 the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for endometriosis, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  Serious adverse events reported to the investigator after the 
safety reporting period should be reported to the sponsor regardless of causal relationship to 
study drug treatment. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
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 
following definitions are to be used for the relationship of the adverse event to study drug: 
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• Probably related:  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 (rechallenge) or withdrawal (dechallenge). 
• Possibly related:  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.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 
Table 7-1 
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 
CTCAE = Common Terminology Criteria for Adverse Events. 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
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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 × 
ULN. 
Any ALT or AST elevation of this degree or greater occurring during the Open-Label Treatment 
Period or the Follow-Up visit should be reported to the sponsor using the Safety Report 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 × ULN may be found in Appendix 7. 
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 × ULN; or 
• ALT or AST > 5 × ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or the INR > 1.5; or 
• ALT or AST > 3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
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 × ULN; AND 
2. Total bilirubin increases to > 2 × ULN or INR > 1.5; AND 
3. Alkaline phosphatase value does not reach 2 × 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); 
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Cli nical St u d y Pr ot o c ol:  M V T -6 0 1 -3 1 0 3  
A me n d me nt 3. 1, 2 5 A u g 2 0 2 0  
M y o v a nt S cie n ces G m b H  
6 3  
C O N FI D E N TI A L  
− E x p os ure t o he pat ot o xic a ge nts/ dr u gs or he pat ot o xi ns, i ncl u di n g her bal a n d 
dietar y s u p ple me nts, pla nts, a n d m us hr o o ms; 
− Alc o h olic he patitis ; 
− N o nalc o h olic steat o he patitis;  
− A ut oi m m u ne he patitis.  
If a n alter nati ve ca use f or he pat ot o xicit y is i de ntifie d, t he n it s h o ul d be deter mi ne d ( base d o n t he 
se verit y of t he he pat ot o xicit y or e ve nt) w het her st u d y dr u g treat me nt s h o ul d be wit h hel d or 
per ma ne ntl y disc o nti n ue d as a p pr o priate f or t he safet y of t he patie nt. 
7. 6.  
Seri o us A d verse E ve nt R e p orti n g  
Usi n g a Safet y Re p ort F or m, all seri o us a d verse e ve nts m ust be re p orte d wit hi n 2 4 h o urs of t he 
st u d y site pers o n nel’s k n o wle d ge of t he e ve nt, re gar dless of t he i n vesti gat or assess me nt of t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g. 
T he c o ntact i nf or mati o n f or s u b missi o n of seri o us a d verse e ve nts, a d verse e ve nts of cli nical 
i nterest ( defi ne d i n Secti o n  7. 5), a n d e ve nts of o ver d ose is a vaila ble o n t he Safet y  Re p ort F or m 
a n d is as f oll o ws: 
Se n d c o m p lete d S afet y Re p ort F or ms t o I Q VI A R D S I nc. (f or merl y Q ui ntilesI M S): 
Site L oc ati o n 
E- m ail 
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber 
( Sec o n d ar y re p orti n g met h o d) 
All st u d y sites  
 
 
F or q uesti o n s o n Seri o us A d verse E ve nt/ A d verse E ve nt of Cli nic al I nterest re p orti n g, 
ple ase c all:  
•  N ort h/ S o ut h A merica:  
 
•  E ur o pe, Asia- Pacific, a n d Africa:  see re gi o n -s pecific p h o ne n u m bers acc o m pa n yi n g 
t he Safet y Re p ort F or m 
T he i nitial re p ort s h o ul d i ncl u de:  
•  St u d y n u m ber ( M V T- 6 0 1- 3 1 0 3); 
•  Site a d dress a n d n u m ber ; 
•  I n vesti gat or na me; 
•  Patie nt I D n u m ber, se x, a n d a ge ; 
•  Details of st u d y dr u g a d mi nistrati o n ; 
•  T he date of t he re p ort; 
•  A descri pti o n of t he seri o us a d verse e ve nt (e ve nt ter m, seri o us ness of t he e ve nt, date 
of o nset, i nte nsit y); 
•  Ca usal relati o ns hi p t o t he st u d y dr u g. 
D o c u Si g n E n v el o p e I D: B 6 0 2 C 9 7 6- C 6 C A- 4 A A 2- 8 F 6 2- 3 3 1 6 9 B A 9 B 0 6 F
P P D
P P D
P P D


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If the patient died, the report should include the cause of death as the event term (with death as 
outcome) and whether or not the event leading to death was related to study drug treatment, 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 > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 × the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose.  
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor within 24 hours; 
• 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 Safety Report Form according to Section 7.6, whether or not the overdose is 
associated with an adverse event; 
• 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 any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  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 
form, as available.  Document the pregnancy in the eCRF as well. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.5.2 details the requirements for measurement of safety parameters including vital 
signs, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on endometriosis-associated pain.  Low-dose hormonal 
add-back therapy with estradiol and norethindrone acetate will be evaluated for maintenance of 
bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 
reproductive toxicity, and metabolic and cardiovascular changes (insulin resistance, 
dyslipidemia, increased weight) with an increased risk of diabetes mellitus and possible 
increased risk of cardiovascular disease.  Additionally, there are potential risks associated with 
the addition of estradiol/norethindrone acetate.  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 strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
Week 52, and 
Week 104/Early Termination 
visits with specified 
discontinuation and follow-
up criteria and all fractures 
will be reported as adverse 
events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52visits, and as 
clinically applicable; 
withdrawal for QTcF 
> 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 × the 
ULN; total bilirubin 
values > 1.5 × ULN. 
Abnormal liver test results 
(AST or ALT > 3 × ULN) 
that develop during the 
Open-Label Treatment 
Period will be reported 
within 24 hours of study 
personnel awareness. 
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, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
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. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each study 
visit;  
A mammogram will be 
performed at Week 52 or at 
the Week 104/Early 
Termination visit for women 
who are or become ≥ 40 
years old during the study, 
with specified 
discontinuation criteria.  
Adverse events will be 
recorded. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; QTc = corrected QT 
interval; QTcF = QT interval by the Fridericia correction; PLD = phospholipidosis; 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 (GCP) 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 GCP.  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 (WHO-DDE), 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. 
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9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  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. 
There will be two analyses:  one at Week 52 and one at Week 104.  A clinical study report will 
be generated from each analysis. 
The study may be closed pending selected contingent safety procedures conducted after the last 
patient’s Week 104/Early Termination or Follow-Up visit.  After the study is closed, any pending 
required follow-up testing of bone mineral density and endometrial biopsies or for menstruation 
recovery beyond the Follow-Up visit will be captured and reported. 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 80 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the Extension Study Population, defined as all 
patients who enrolled into MVT-601-3103 and who have received any amount of randomized 
open-label study drug in MVT-601-3103. 
Safety data analyses will be performed on the Safety Population, defined as all enrolled patients 
who have received any amount of MVT-601-3103 study drug. 
The analysis methods for safety and efficacy endpoints are the same as those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Justification 
Because this is an extension study, the sample size will be determined by the number of patients 
who have completed a parent study and who are eligible and willing to participate in the 
extension study.  It is estimated that approximately 800 patients (67% of the total of 
1200 patients who will be randomized into the parent studies) will participate in this study. 
9.4. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the Extension Study 
Population.  
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
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The point estimates and 2-sided 95% confidence intervals (CI) for the primary efficacy endpoints 
(proportion of responders based on dysmenorrhea NRS scores and use of rescue analgesic 
medications, proportion of responders based on NMPP scores and use of rescue analgesic 
medications) will be calculated. 
A responder at a given time point and for a specific type of pain (dysmenorrhea or NMPP) is 
defined as a patient who had a reduction in that type of pain from Baseline in the parent study 
greater than or equal to a pre-determined threshold and who did not have an increase in the use 
of rescue analgesic medications for endometriosis-associated pain compared with the use at 
Baseline. Patients who had a pain reduction less than the pre-determined threshold or who had an 
increase in the use of analgesics for endometriosis-associated pain will be considered non-
responders.  The pain reduction thresholds will be determined for NMPP and dysmenorrhea 
separately (see the SAP for details) for the parent studies and these same thresholds will be 
applied to this study. 
Baseline values are calculated using the Baseline pain assessment period, which is defined as the 
period from the date of the first dose of placebo in the parent study Run-In Period through the 
day prior to the first dose of randomized study drug.  Patients’ average NRS pain scores and use 
of rescue analgesic medications for endometriosis-associated pain (dysmenorrhea or NMPP) will 
be compared between a given visit-specific pain assessment period (eg, Week 28, Week 32, etc.) 
and the Baseline pain assessment period.  The visit-specific pain assessment period is defined as 
the last 35 calendar days immediately prior to and including the last dose of study drug treatment 
received prior to the visit date. 
For any pain assessment period (Baseline or visit-specific), the average NRS scores will be 
calculated for dysmenorrhea and NMPP separately.  An average NRS score for dysmenorrhea is 
calculated as the average NRS score over the days with menses during a given pain assessment 
period.  An average NRS score for NMPP is calculated as the average NRS score over the days 
without menses during a given pain assessment period.  The analgesic use for a given pain 
assessment period is summarized by total dose count defined as the average daily dose count 
taken during the given pain assessment period multiplied by 35.  Additional details on 
calculating dose counts and on the precise definition of an increase in analgesic use will be 
provided in the SAP. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies at Week 52 and Week 104. 
• Change from the parent study Baseline in the EHP-30 Pain Domain scores; 
• Change from the parent study Baseline to in the mean dysmenorrhea NRS score; 
• Proportion of patients who are better or much better on the PGIC for dysmenorrhea; 
• Change from the parent study Baseline in the mean NMPP NRS score; 
• Change from the parent Baseline in the mean NRS score; 
• Proportion of patients not using opioids; 
• Proportion of patients not using analgesics; 
• Proportion of patients who are better or much better on the PGIC for NMPP; 
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• Change from the parent study Baseline in the mean dyspareunia NRS scores; 
• Proportion of patients who are better or much better on the PGIC for dyspareunia; 
• Change from the parent study Baseline in the mean dyspareunia functional 
impairment on the sB&B scale; 
• Change from the parent study Baseline in severity scores on the PGA for pain; 
• Proportion of responders based on EHP-30 Pain Domain scores; 
• Change from the parent study Baseline in function impairment on the PGA for 
function; 
• Change from the parent study Baseline in each of the non-pain EHP-30 domains 
(Control and Powerlessness, Social Support, Emotional Well-Being, and Self-Image); 
• Change from the parent study Baseline pain assessment period in dysmenorrhea-
related functional effects (sB&B); 
• Change from the parent study Baseline pain assessment period in NMPP-related 
functional effects (sB&B). 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
For endpoint of proportion of responders based on EHP-30 Pain Domain scores, a responder is 
defined using the same within-patient score change threshold determined from the parent studies.  
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, 
mammograms (for patients required to have this procedure, see Section 6.5.2.9), and endometrial 
biopsy.  Safety summaries by treatment group will be performed using treatment groups defined 
based on the actual randomized treatment received in the parent study. 
The treatment-emergent period will be defined as the period of time from the first dose date and 
time of randomized study drug in the parent study through 30 days after the last dose of study 
drug, or the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for endometriosis, whichever occurs 
first.  Safety will be assessed through summaries of adverse events, the frequency of treatment 
discontinuations due to adverse events, laboratory evaluations, and bone densitometry results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute CTCAE.  All adverse events will be coded to preferred term, high level term, 
and system organ class using MedDRA 20.0 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 
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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 to do the 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 
parent study Baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from parent study Baseline to each post-baseline study visit will be presented 
by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  Electrocardiograms will also 
be read centrally.  The distributions of QTc interval will be summarized at each visit.  All data 
will be listed and summarized by visit.  The change from parent study Baseline to each post-
baseline study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for percent change at 
Week 52 from parent study Baseline in bone mineral density will be provided based on mixed 
effects model (assumed missing at random) for each parent study treatment group.  The 95% CI 
for mean percentage change at Week 104/Early Termination from parent study Baseline in bone 
mineral density lumbar spine (L1-L4) will be provided along with descriptive statistics for bone 
mineral density loss at Week 104/Early Termination as supportive analyses. 
All data will be listed and summarized by visit.  The absolute change and percent change from 
parent study Baseline to Weeks 36, 52, and 104/Early Termination and associated 95% CIs will 
be presented by the parent study treatment group for each bone mineral density parameter.  The 
number and percentage of patients meeting a bone mineral density decline of at least 4%, 5%, 
6%, or 7% by body area (lumbar spine, total hip, or femoral neck) will be estimated with 95% 
CIs by the parent study treatment group. 
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Additional analyses will be performed to examine the correlation between bone mineral density 
loss with demographic and baseline characteristics and with treatment exposure.  Details will be 
provided in the SAP. 
9.6. 
Pharmacodynamics Analyses 
The change from the parent study Baseline to Week 52 and to Week 104 in predose 
concentrations of serum estradiol will be summarized.  Percentage of patients with 
concentrations of serum estradiol levels < 10 pg/mL and < 20 pg/mL will be provided. 
9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group will be provided for the following exploratory 
endpoints.  Details on the endpoint analyses including deviations, handling of missing data, and 
statistical methods will be provided in the SAP.  The following exploratory endpoints will be 
assessed at Week 52 and Week 104: 
• Change from Baseline in the EHP-30 scale total score; 
• Change from Baseline in the EHP Work Domain score; 
• Change from parent study Baseline in the EQ-5D-5L. 
9.8. 
Interim Analyses 
An interim analysis will be conducted at Week 52 in which all efficacy and safety endpoints will 
be assessed as described above.  A clinical study report will be generated based on these data to 
support submission of one-year data. 
9.9. 
Steering Committee 
The study will be overseen by a Steering Committee consisting of experts in the field of 
women’s health and staff members of Myovant Sciences GmbH.  The Steering Committee will 
participate in the design, conduct, analyses, and publication of the study. 
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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 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, 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, 1998, 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 1 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 
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 
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signed and dated by the patient or the patient’s legally authorized representative and the person 
obtaining consent. 
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. 
10.1.5. 
Study Files and Retention of Records 
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 two 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 drug (drug dispensing, 
return, and accountability should be documented as well); 
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− 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 indication; and 
− Date of study completion and reason for early termination, 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, decoding procedures for blinded studies, 
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. 
10.1.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed as specified in the Investigator Site File.  
The eCRF casebook for each study patient will be signed by the investigator or sub-investigator 
(as appropriate) listed on the 1572 and/or other appropriate local health authority documents.  
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. 
10.1.7. 
Investigational Product Accountability 
The investigator or investigator’s designee (eg, pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, accountability, and returned or destroyed study 
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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 once the study monitor has reviewed 
and returned used and unused study drug for accountability purposes.  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. 
10.1.8. 
Inspections 
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. 
10.1.9. 
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. 
Safety Reporting 
The sponsor will comply with safety reporting requirements consistent with US FDA, European 
Union (EU) National competent authority, and Health Canada Guidance 2.8.4, Health Canada 
Food and Drugs Act and Regulations, Division 5, Part C.05.014, and applicable ICH and 
regional regulatory safety reporting requirements. 
10.2.2. 
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 appropriate IRB or IEC 
for information and approval in accordance with local requirements and to the appropriate Health 
Authority (eg, FDA, Health Canada, EU National competent authority), if required.  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. 
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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. 
10.2.3. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies) at Week 52 
and a second clinical study report will be prepared at the end of the study (Week 104).  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).  An abbreviated report may be prepared in 
certain cases. 
10.2.4. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
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 GCP 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.  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. 
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: 
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• 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). 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) based on this 
study must be submitted to Myovant for corporate review.  The Clinical Study Agreement 
among the institution, principal investigator, and Myovant will detail the procedures for, and 
timing of, Myovant’s review of publications. 
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11. 
REFERENCES 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 02 October 2017. 
Archer DF, Chwalisz K, Feldman R, et al.  Elagolix for the management of heavy menstrual 
bleeding (HMB) associated with uterine fibroids (UF): Results from a phase 2A proof-of-
concept study. Fertil Steril. 2017 Jul;108(1);152-60.e4. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J 
Obstet Gynec.1992 Feb;166(2):740-5. 
Chwalisz K, Surrey E, Stanczyk FZ. The hormonal profile of norethindrone acetate: rationale for 
add-back therapy with gonadotropin-releasing hormone agonists in women with 
endometriosis. Reprod Sci. 2012 Mar;19(6):563-71. 
Dunselman GA, Vermeulen N, Becker C, et al. European Society of Human Reproduction and 
Embryology. ESHRE guideline: management of women with endometriosis. Hum 
Reprod. 2014 Mar;29(3):400-12. 
Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation. US Dept. of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research, Center for Biologics 
Evaluation and Research. July 2009. 
Franke HR, van de Weijer PHM, Pennings TMM, et al. Gonadotropin-releasing hormone agonist 
plus add-back’ hormone replacement therapy for treatment of endometriosis: a 
prospective, randomized, placebo-controlled, double-blind trial. Fertil Steril. 2000 
Sep;74(3):534-9. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstet Gynecol. 1998 Jan;91(1):16-24. 
Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on hypoestrogenic 
problems by postoperative gonadotropin-releasing hormone agonist treatment in 
endometriosis. Obstet Gynecol Sci. 2016 Jan;59(1):32-8. 
Morris EP, Rymer J, Robinson J, Fogelman I. Efficacy of tibolone as add-back therapy’ in 
conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine 
fibroids. Fertil Steril. 2008 Feb;89(2):421-8. 
Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic 
pain associated with endometriosis: a committee opinion. Fertil Steril. 2014 
Apr;101(4):927-35. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reprod Health. 2015 Mar;21(1):16-23. 
Sinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P. Differences in 
characteristics among 1,000 women with endometriosis based on extent of disease. Fertil 
Steril. 2008 Mar;89(3):538-45. 
Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
therapy in treatment of endometriosis: a meta-analysis. Arch Gynecol Obstet. 2014 
Sep;290(3):513-23. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
in the treatment of endometriosis-associated pain. Fertil Steril. 2004 Nov;82(5):1303-8. 
 
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12. 
APPENDICES 
 
Protocol-Specified Rescue Analgesics 
The medications below are listed based on their dose strength. The prescription (or instructions 
for use) for these medications may allow for use of more than one tablet at any given time. 
Analgesics should be prescribed in accordance with the respective country’s approved product 
labeling.  The subject’s historical use of opioid analgesics should be taken into consideration 
when prescribing these drugs.  
Only one Tier 2 medication should be selected for a given patient to be used throughout the 
study.  
Study-specified analgesics include: 
• Tier 1 
− ibuprofen (200 mg dose strength) 
• Tier 21 
− tramadol (37.5 mg) / paracetamol (325 mg) 
− tramadol (50 mg) 
− codeine (30 mg) 
− codeine (30 mg) / paracetamol (300 mg) 
− codeine (30 mg) / paracetamol (500 mg) 
− codeine 15 mg/ paracetamol (500 mg) 
− hydrocodone (5 mg) / acetaminophen 325 mg 
 
Please consult your site-specific instructions for study-specified analgesics for your country. 
 
 
 
 
 
1All second-tier drugs that contain acetaminophen or paracetamol are fixed-dose combination products (eg, single 
tablet containing both drugs). 
 
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Daily eDiary 
 
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Endometriosis Health Profile-30 
ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. 
Been unable to go to social events 
because of the pain?  
 
 
 
 
 
 
2. 
Been unable to do jobs around the 
house because of the pain?  
 
 
 
 
 
 
3. 
Found it difficult to stand because 
of the pain? 
 
 
 
 
 
 
4. 
Found it difficult to sit because  
of the pain? 
 
 
 
 
 
 
5. 
Found it difficult to walk because  
of the pain? 
 
 
 
 
 
 
6. 
Found it difficult to exercise or do 
the leisure activities you would like 
to do because of the pain? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page. 
 
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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
7. 
Lost your appetite and/or been 
unable to eat because of the pain?  
 
 
 
 
 
8. 
Been unable to sleep properly 
because of the pain? 
 
 
 
 
 
 
9. 
Had to go to bed/lie down because 
of the pain? 
 
 
 
 
 
 
10. Been unable to do the things you 
want because of the pain? 
 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
 
12. Generally felt unwell? 
 
 
 
 
 
 
13. Felt frustrated because your 
symptoms are not getting better? 
 
 
 
 
 
 
14. Felt frustrated because you are not 
able to control your symptoms? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page. 
 
 
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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
15. Felt unable to forget your 
symptoms? 
 
 
 
 
 
 
16. Felt as though your symptoms  
are ruling your life? 
 
 
 
 
 
 
17. Felt your symptoms are taking 
away your life? 
 
 
 
 
 
 
18. Felt depressed? 
 
 
 
 
 
 
19. Felt weepy/tearful? 
 
 
 
 
 
 
20. Felt miserable? 
 
 
 
 
 
 
21. Had mood swings? 
 
 
 
 
 
 
22. Felt bad-tempered or short-
tempered? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question  
before moving on to the next page. 
 
 
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Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
23. Felt violent or aggressive? 
 
 
 
 
 
 
24. Felt unable to tell others how  
you feel? 
 
 
 
 
 
 
25. Felt others do not understand  
what you are going through? 
 
 
 
 
 
 
26. Felt as though others think  
you are whining? 
 
 
 
 
 
 
27. Felt alone? 
 
 
 
 
 
 
28. 
Felt frustrated that you cannot 
always wear the clothes you  
would choose? 
 
 
 
 
 
 
29. Felt your appearance has been 
affected? 
 
 
 
 
 
 
30. Lacked confidence? 
 
 
 
 
 
 
 
Please verify that you have checked one box for each question. 
 
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European Quality of Life Five-Dimension Five-Level Scale 
 
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Amendment 3.1, 25 Aug 2020 
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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 
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Patient Global Impression of Change and Patient Global 
Assessments 
Patient Global Impression of Change (Dysmenorrhea) 
Compared to when you started the treatment in this study, painful periods are  
1. Much better  
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
Patient Global Impression of Change (Nonmenstrual Pelvic Pain) 
Compared to when you started the treatment in this study, your pelvic pain when you are not 
having a period (i.e. not on your period) overall is  
1. Much better 
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly 
button. 
Patient Global Impression of Change (Dyspareunia) 
Compared to when you started the treatment in this study, your pelvic pain when you have 
vaginal sexual intercourse is  
1. Much better 
2. Better 
3. A little better 
4. The same 
5. A little worse 
6. Worse 
7. Much worse 
ϒ Not applicable: I have not had vaginal sexual intercourse since starting the study treatment 
For this study, we define vaginal sexual intercourse as penetration of any duration. 
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Patient Global Assessment (for pain) 
How would you rate your pelvic pain right now? 
Pelvic pain is defined as localized pain in the lower part of the stomach, below the belly button 
Absent 
Mild 
Moderate 
Severe 
Very Severe 
Patient Global Assessment (for function) 
How much were your daily activities limited by endometriosis over the last 4 weeks?  
Not at all 
Minimally 
Moderately 
Significantly  
Very significantly 
Note: PGA for function is administered via a paper questionnaire. 
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Endometriosis Health Profile - Work Domain 
 
Note: EHP Work Domain is administered via a paper questionnaire. 
 
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Assessment of Abnormal Liver Function Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) 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 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]), Alkaline Phosphatase, and INR Tests  
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities improve 
If ALT or AST ≥ 3 × 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 
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; 
• 
CBC 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; 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
CBC = complete blood count; 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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Breast Imaging Reporting and Data System 
Category 
Assessment 
Follow-Up 
0 
Need additional imaging evaluation:  means 
that more studies are necessary to gather more 
information. 
Additional imaging needed before a category can 
be assigned. 
1 
Negative:  means that there is no significant or 
noticeable abnormality to report. 
Continue annual screening mammography (for 
women over age 40). 
2 
Benign (noncancerous) finding:  means that 
there has been a finding, such as benign 
calcifications or fibroadenoma, which is not 
cancerous. 
Continue annual screening mammography (for 
women over age 40). 
3 
Probably benign:  means that there is a finding 
that is most likely benign, but should be 
followed in a shorter period of time to see if the 
area of concern changes. 
Receive a 6-month follow-up mammogram. 
4 
Suspicious abnormality:  means that there are 
suspicious findings that could turn out to be 
cancer. 
May require biopsy. 
5 
Highly suggestive of malignancy (cancer):  
means that there are findings that look like and 
probably are cancer. 
Requires biopsy. 
6 
Known biopsy-proven malignancy (cancer):  
means that any findings on the mammogram 
have already proven to be cancer through a 
biopsy. 
Biopsy confirms presence of cancer before 
treatment begins. 
 
 
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Guidance for Study Conduct during the COVID-19 
Pandemic 
The novel coronavirus 2019 (COVID-19) pandemic has impacted the conduct of clinical trials 
globally.  Regional quarantine laws, travel restrictions, and site closures present challenges to 
normal study conduct and may lead to missed study visits or procedures or an interruption to a 
patient’s study drug supply. 
Myovant Sciences has thoroughly reviewed guidance documents from various country and 
regional regulatory agencies and has put mitigation plans in place to ensure the safety of patients 
is maintained, the study continues to be conducted in compliance with good clinical practice 
(GCP), and risks to the integrity of the study are minimized.  These plans will remain in place 
through the duration of the COVID-19 pandemic. 
Safety During the COVID-19 Pandemic 
Protecting study patients, investigational site staff, and clinical service providers involved in 
Myovant Sciences clinical studies from activities that may unnecessarily increase the risk of 
contracting COVID-19 is of utmost importance.  Regulations and policies instituted for safety 
purposes during the COVID-19 pandemic at the institutional, local, country, and regional level 
should be adhered to. 
Protocol Adherence 
Wherever possible and safe, study visits and procedures must be performed as outlined in the 
protocol to ensure patient safety and to maintain the integrity and interpretability of the study 
data.  While modifications to normal study conduct may, in some cases, be necessary and 
unavoidable, they must be documented and reported where in conflict with the study protocol 
and this guidance.  Deviations from the protocol will be documented, but those resulting 
specifically from the COVID-19 pandemic will be marked as such.  All deviations resulting from 
the COVID-19 pandemic will be summarized in the clinical study report. 
Visit Schedules and Study Procedures 
Local policies, institutional restrictions, and/or patient ability/willingness to make site visits may 
curtail the ability to adhere to the in-person, on-site visit schedule required by the protocol.  
Investigators at clinical sites should evaluate the appropriateness of an on-site study visit during 
the COVID-19 pandemic. 
If a clinical study site remains open for on-site patient visits, patients should be encouraged to 
return for study visits, if willing and able, in the earliest allowable portion of the visit window, 
taking all measures to prevent contracting COVID-19. 
• All protocol required study procedures should be performed whenever possible. 
• Safety assessments should be prioritized if only limited assessments are performed. 
• If assessments are limited, investigators should document whether the assessments 
performed are adequate to ensure it is safe for the patient to continue in the study. 
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Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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CONFIDENTIAL 
• Investigators should use all available information to determine whether 
in-person visits are necessary to fully assure the safety of study patients (for 
example to carry out procedures necessary to assess safety or the safe use of 
the study drug appropriately) or whether alternative means of assessment are 
adequate to assure the safety of continuing patients in the study.  Such 
decisions should be documented.  Investigators can contact the medical 
monitor for consultation as necessary. 
If the clinical study site is closed or the patient is unable/unwilling to attend on-site study 
visits due to the COVID-19 pandemic, alternative methods for completing assessments (eg, 
phone contact or virtual visit) should be implemented. 
• Investigators must assess and evaluate the patient’s continued participation and 
dosing with limited safety assessment. 
• At a minimum, investigational site staff should make every attempt to contact the 
patient via telephone when an expected visit is due or missed to assess for adverse 
events, document concomitant medications, and study drug dosing since the last study 
visit. 
• If the safety blood draws cannot be performed through the central laboratory per 
protocol, the investigator may advise the patient to have blood drawn at a local 
laboratory if there is a safety concern.  If two consecutive study visits are missed and 
the patient is unable to return to the site, the investigator should advise the patient to 
have protocol specified safety labs completed at a local laboratory to assess for any 
safety concerns. In both cases, the local laboratory results should be documented in 
the eCRF. 
• Investigational sites should report all serious adverse events, adverse events of 
clinical interest, overdose, and pregnancy that the patient reports during these calls 
within 24 hours of awareness. 
• Patients should be reminded of the importance of taking study treatment daily, 
adhering to protocol-specified analgesics, and taking non-hormonal contraception. 
• Study patients should continue to complete their daily eDiary, even if they run out of 
study drug, and site staff should motivate them to do so. 
Patients should have the contact details of the investigational site medical staff to report any 
medical issues, including adverse events they may experience in real time. 
As soon as the study patients are able to return to the investigational site for an on-site visit, they 
should return either for their next scheduled visit (if still within protocol window) or for an 
unscheduled visit (if outside of expected protocol visit window). 
Study Participant Study Drug Supply 
If a regional lockdown, travel restrictions, or site closure is imminent due to the COVID-19 
pandemic, sites are encouraged to dispense additional study drug at an expected study visit or 
request patients to return for an unscheduled visit for additional study drug dispensation so 
patients have sufficient supply until their next upcoming visit.  Patients should be instructed to 
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Amendment 3.1, 25 Aug 2020 
Myovant Sciences GmbH 
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CONFIDENTIAL 
contact the site to report any medical issues they may experience and site staff should 
communicate with the patients to determine if it is appropriate for the patient to continue dosing 
with study drug if/when in-person study visits are not possible. 
For cases where study patients are unable to visit the investigational site to pick up study drug, a 
direct-to-patient (DTP) delivery of study drug by site staff or shipment via contracted courier 
may be possible.  Consent authorizing DTP supply will be obtained.  Sites should defer to 
national guidance on how this will occur.  Where permitted by national guidance, verbal consent 
will be taken via telephone or video call and noted in the patient’s source file. Where required, 
by national guidance, this will be followed up with written consent during the next clinic visit.  
Every effort will be made to obtain the patient’s written consent for DTP prior to delivery or 
shipment, where this is required by national guidance. 
In the event that none of the above are possible for participants to continue taking study 
medication, a patient may need to be discontinued per the study protocol.  Such decisions will be 
made on a case-by-case basis in discussion with the investigator and medical monitor. 
Onsite Study Monitoring Restrictions 
In the event study monitors/clinical research associates are not allowed to travel and/or return to 
a clinical site to monitor and source document verify study data, Myovant has developed plans to 
ensure monitors: 
• Remotely verify source documentation as much data as reasonably possible without 
burdening sites, if allowed by the study site and country regulations, focusing on 
pages key to the interpretability of the study and the safety of participants. 
• Remotely monitor study data through cross checking of various systems housing 
patient data against what is captured in the eCRFs. 
Additional guidance on conducting clinical trials during the COVID-19 pandemic may be found 
in the following documents released by Regional Health Authorities, which may be updated 
(updates supersede the versions listed here): 
• FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-
19 Public Health Emergency Guidance for Industry, Investigators, and Institutional 
Review Boards (March 2020 – updated July 2, 2020); 
• European Medicines Agency Guidance on the Management of Clinical Trials during 
the COVID-19 (Coronavirus) Pandemic (Version 3, 28 April 2020). 
 
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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
Myovant Sciences GmbH 
1 
CONFIDENTIAL 
AMENDMENT 3.1:  SUMMARY OF CHANGES 
The MVT-601-3103 clinical study protocol has been amended as described in the table below.  
The primary purpose of the amendment is to include a mammogram at Week 52 or Week 
104/Early Termination for women ≥ 40 years old and to revise the threshold for post-treatment 
follow-up in order to assess the trajectory of BMD recovery in patients with a lesser degree of 
BMD loss. 
 
A detailed list of changes is described below, where deleted text is indicated by strikethrough 
and new text is indicated with bold formatting.  Note that the correction of typos, minor 
clarifications, and minor wording changes to improve readability, understanding, and 
consistency may not be included in this table. 
 


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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
7 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
1.1.  Schedule of 
Activities 
 
Mammogram at Week 52, Week 104/Early 
Termination, and Unscheduled 
 
Xdd 
Added mammogram for 
patients who are ≥ 40 years of 
age. 
1.1.  Schedule of 
Activities 
Footnote r 
 
This procedure is not required at the Early 
Termination visit in patients whose last dose of 
study drug was taken during Week 32 or earlier 
or within 4 weeks after completion of the Week 
36 or Week 52 scan. However, the procedure 
may be done if it will aid in the evaluation of an 
ongoing adverse event. 
See Section 6.5.2.6 for details on the timing 
and follow-up of bone densitometry. 
 
Clarified bone densitometry 
follow-up. 
1.1.  Schedule of 
Activities 
Footnote s 
Determination of bone mineral density by DXA 
at Early Termination and follow-up of findings 
will proceed based on the timing of the Early 
Termination visit.  For Early Termination 
occurring after Week 24 and before Week 36, 
DXA is not required at Early Termination visit 
unless it will aid in the assessment of an adverse 
event, and follow-up DXA required at 6 months 
(± 1 month) if most recent DXA bone mineral 
density loss at lumbar spine (L1-L4) or total hip 
was > 2% relative to the parent study baseline.  
For Early Termination occurring after Week 36 
and before Week 52, DXA is required at Early 
Termination unless a DXA result is available 
from within six weeks prior to Early 
Termination, and follow-up DXA is required at 
6 months (± 1 month) if the most recent DXA 
scan was at Week 24 and bone mineral density 
loss at the lumbar spine (L1-L4) or total hip was 
> 2% or most recent DXA result was after Week 
24 and bone mineral density loss at the lumbar 
spine (L1-L4) or total hip was > 3%, relative to 
the parent study baseline.  For Early Termination 
occurring between Week 52 and Week 104, 
DXA is required at Early Termination unless a 
DXA result is available from within six weeks 
prior to Early Termination, and follow-up DXA 
Determination of bone mineral density by DXA 
at Early Termination and follow-up of findings 
will proceed based on the timing of the Early 
Termination visit (see Section 6.5.2.5).  
 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
8 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
is required at 6 months (± 1 month) if on the 
most recent DXA, bone mineral density loss at 
the lumbar spine (L1-L4) or total hip was > 7%, 
relative to parent study baseline 
1.1.  Schedule of 
Activities 
Footnote t 
Endometrial biopsies are to be done per 
instructions in the parent study.  Procedures for 
handling and shipping biopsy samples to the 
central laboratory for analysis are described in 
the Investigator Site File.  An endometrial biopsy 
will have been performed at the parent study 
Week 24 visit for all patients who participated in 
MVT-601-3101 only (see MVT-601-3101 
protocol for details), at Week 52 for all patients.  
All patients are eligible for a biopsy at Week 
104; however, patients will have the option to 
opt out. 
Endometrial biopsies are to be done per 
instructions in the parent study.  Procedures for 
handling and shipping biopsy samples to the 
central laboratory for analysis are described in 
the Investigator Site File.  An endometrial biopsy 
will have been performed at the parent study 
Week 24 visit for all patients who participated in 
MVT-601-3101 only (see MVT-601-3101 
protocol for details) and at Week 52 and Early 
Termination visit for all patients.  This 
procedure is not required at the Early 
Termination visit in patients whose last dose 
of study drug was taken during Week 32 or 
earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, 
the procedure may be done if it will aid in the 
evaluation of an ongoing adverse event.  An 
endometrial biopsy at Week 104 is 
recommended for all patients who complete 
the open-label extension; however, patients will 
have the option to opt out. 
Added an endometrial biopsy at 
the Early Termination visit to 
assess endometrial safety in 
patients who were on study 
drug for more than 32 weeks. . 
1.1.  Schedule of 
Activities 
Footnote bb 
Patients whose menses have not resumed as of 
the Follow-up visit for whom there is no 
explanation for the lack of resumption (eg, 
medical procedure or medications) will be 
contacted again by telephone 3 (+0.5) months 
after the Follow-Up visit to determine if menses 
has resumed and questioned about factors that 
may affect resumption of menses. 
Patients whose menses have not resumed as of 
the Follow-up visit for whom there is no 
explanation for the lack of resumption (eg, 
medical procedure or medications) will be 
contacted by telephone 3 (+0.5) months after the 
Follow-Up visit to determine if menses has 
resumed and questioned about factors that may 
affect resumption of menses.  If a patient is lost 
to follow-up, three documented attempts 
should be made to contact the patient by 
telephone.  If unable to contact the patient by 
telephone, a certified letter must be sent to the 
patient. 
Revised footnote to clarify 
procedures for when a patient is 
lost-follow-up. 


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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
10 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
contact the patient by telephone, a certified 
letter must be sent to the patient. 
4.5.  Removal of 
Patients from 
Therapy 
 
Evidence of malignant breast lesion(s) or 
breast carcinoma on Week 52 or 
Week 104/Early Termination or most recent 
mammogram or additional breast imaging 
(see Section 6.5.2.9 for more information on 
mammogram at Week 52 or Week 104/Early 
Termination). 
Included removal criteria for 
findings resulting from 
mammogram. 
4.6.  Contraception 
/Pregnancy 
Avoidance 
In this study, medications and devices containing 
hormones for contraception are excluded, and 
patients must agree to use non-hormonal 
contraception throughout the study including 
through 30 days following the last dose of study 
drug, unless any of the following apply: 
All patients should be counseled at every visit 
to adhere to the use of protocol allowed 
contraceptive methods.  In this study, 
medications and devices containing hormones 
for contraception are excluded, and patients must 
agree to use non-hormonal contraception 
throughout the study including through 30 days 
following the last dose of study drug, unless any 
of the following apply: 
Added language for increased 
counselling on contraception. 
4.7.  Novel 
Coronavirus 2019 
Guidance 
 
Guidance for conducting clinical trials during 
the novel coronavirus 2019 (COVID-19) 
pandemic is included in Appendix 9. 
Included COVID-19 pandemic 
guidance to ensure that the 
safety of patients is maintained, 
the study continues to be 
conducted in compliance with 
good clinical practice (GCP), 
and risks to the integrity of the 
study are minimized. 
5.1.  Treatments 
Administered 
Table 5-1 
Description of MVT-601-3003 Study Drugs 
Description of MVT-601-3103 Study Drugs 
Corrected study number. 
5.10.1.  Prohibited 
Medications 
Table 5-2 
Intrauterine devices:  levonorgestrel 
 
copper 
Intrauterine devices:  levonorgestrel 
Removed copper to reduce 
confusion with inclusion 
criterion 6c. 
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 6.5.  Further 
details of the procedures are provided in the 
Investigator Site File. 
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 6.5.  Further 
details of the procedures are provided in the 
Investigator Site File.  Guidelines to address 
Included COVID-19 pandemic 
guidance. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
11 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
the COVID-19 pandemic are included in 
Appendix 9. 
6.2.  Open-Label 
Treatment Period 
(Week 24/Baseline 
to Week 104) 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see MVT-
601-3101 protocol for details), at Week 52 for all 
subjects.  All patients will be eligible for the 
Week 104 biopsy; however, patients will have 
the option to opt out.  Safety monitoring for this 
study includes physical examination, clinical 
laboratory tests, pregnancy tests, and adverse 
event collection at each visit.  Clinical 
chemistries will be collected at each visit.  A 
complete blood count will be collected at Week 
24/Baseline, Week 28, Week 36, Week 52, Week 
65, Week 78, and Week 104.  At the Week 
24/Baseline visit, Week 52 visit, and Week 104 
visit, additional tests include fasting (at least 8 
hours, other than water) glucose, lipid profile, 
and hemoglobin A1c. 
An endometrial biopsy will have been performed 
at the parent study Week 24 visit for all patients 
who participated in MVT-601-3101 (see MVT-
601-3101 protocol for details).  An endometrial 
biopsy is required at Week 52 and the Early 
Termination visit for all patients.  This 
procedure is not required at the Early 
Termination visit in patients whose last dose 
of study drug was taken during Week 32 or 
earlier or within four weeks after completion 
of the Week 52 endometrial biopsy.  However, 
the procedure may be done if it will aid in the 
evaluation of an ongoing adverse event.  An 
endometrial biopsy at Week 104 is 
recommended for all patients who complete 
the open-label extension; however, patients will 
have the option to opt out.  Safety monitoring for 
this study includes physical examination, clinical 
laboratory tests, pregnancy tests, and adverse 
event collection at each visit.  Clinical 
chemistries will be collected at each visit.  A 
complete blood count will be collected at Week 
24/Baseline, Week 28, Week 36, Week 52, Week 
65, Week 78, Week 91, and Week 104.  At the 
Week 24/Baseline visit, Week 52 visit, and 
Week 104 visit, additional tests include fasting 
(at least 8 hours, other than water) glucose, lipid 
profile, and hemoglobin A1c. 
Added endometrial biopsy  at 
the Early Termination visit to 
assess endometrial safety on 
patients who were on study 
drug for more than 32 weeks. 
6.2.  Open-Label 
Treatment Period 
(Week 24/Baseline 
to Week 104) 
Electrocardiograms will be performed at the 
Week 24/Baseline and the Week 52 visits. 
 
Electrocardiograms will be performed at the 
Week 24/Baseline, Week 52, and Week 
104/Early Termination visits. 
 
Added Week 104/early 
termination visit ECG to align 
with Schedule of Activities. 


 
Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
12 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
6.2.  Open-Label 
Treatment Period 
(Week 24/Baseline 
to Week 104) 
 
A mammogram will be performed at Week 52 
or at Week 104/Early Termination for women 
who are or become ≥ 40 years old during the 
study (see Section 6.5.2.9). 
Added mammogram for 
patients who are ≥ 40 years of 
age. 
6.3.  Early 
Termination Visit 
and Follow-up 
Visit 
All patients withdrawing from the study prior to 
Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 104.  Bone 
densitometry may be performed at the 
investigator’s discretion, if it aids in follow-up of 
an ongoing adverse event(s).  Follow-up bone 
densitometry findings for patients who terminate 
from the study early will proceed according to 
the rules provided in Section 6.5.2.6. 
All patients withdrawing from the study prior to 
Week 104 will complete an Early Termination 
visit.  The Early Termination visit procedures are 
identical to those of Week 104.  An endometrial 
biopsy is required for all patients at the Early 
Termination visit except for patients whose 
last dose of study drug was taken during 
Week 32 or earlier or within four weeks after 
completion of the Week 52 endometrial 
biopsy.  However, the endometrial biopsy may 
be obtained if it will aid in the evaluation of an 
ongoing adverse event.  Follow-up bone 
densitometry findings for patients who terminate 
from the study early will proceed according to 
the rules provided in Section 6.5.2.6.   
Added an endometrial biopsy at 
the Early Termination visit to 
assess endometrial safety on 
patients who were on study 
drug for more than 32 weeks. 
6.4.  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 
source documentation.  The following activities 
should be completed at Unscheduled visits:  
recording of reason for the visit, concomitant 
medication review, and evaluation of adverse 
events.  In addition, procedures such as vital 
signs, weight, complete physical examination, 
sign- and symptom-directed physical 
examination, clinical laboratory assessment, 
urinalysis, urine pregnancy testing, 
pharmacodynamic sampling, 12-lead ECG, study 
drug compliance and dispensation, eDiary 
review, dispensation or prescription of protocol-
specified analgesics, etc, may be conducted as 
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 
source documentation.  The following activities 
should be completed at Unscheduled visits:  
recording of reason for the visit, concomitant 
medication review, and evaluation of adverse 
events.  In addition, procedures such as vital 
signs, weight, complete physical examination, 
sign- and symptom-directed physical 
examination, clinical laboratory assessment, 
urinalysis, urine pregnancy testing, 
pharmacodynamic sampling, mammogram (for 
patients required to have this procedure; see 
Section 6.5.2.9), 12-lead ECG, study drug 
compliance and dispensation, eDiary review, 
Added mammogram for 
patients who are ≥ 40 years of 
age. 


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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
18 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
laboratory.  If the Week 52 or Week 104 biopsy 
specimen is inadequate, a transvaginal ultrasound 
for endometrial thickness should be obtained and 
read locally.  The transvaginal ultrasound 
findings will be used to determine if further 
action is required: 
event.  An endometrial biopsy at Week 104 is 
recommended for all patients who complete 
the open-label extension; however, patients will 
have the option to opt out.  Patient participation 
in the Week 104 endometrial biopsy is voluntary 
and refusal to participate will not preclude entry 
into the study or indicate withdrawal from the 
study. 
The Week 52, Week 104, and Early 
Termination endometrial biopsy samples will be 
submitted to the central laboratory.  If the Week 
52, Week 104, or Early Termination biopsy 
specimen is inadequate, a transvaginal ultrasound 
for endometrial thickness should be obtained and 
read locally.  The transvaginal ultrasound 
findings will be used to determine if further 
action is required: 
6.5.2.7.  
Endometrial 
Biopsy 
Patients who have endometrial hyperplasia or 
endometrial carcinoma will be withdrawn from 
study drug treatment and followed per 
instructions in the parent study protocol. 
 
Patients who have endometrial hyperplasia or 
endometrial carcinoma will be withdrawn from 
study drug treatment and followed per 
instructions in the parent and/or extension study 
protocol. 
 
Investigators should contact the medical 
monitor if a patient refuses to have an 
endometrial biopsy at Week 52 or the Early 
Termination visit. 
Changed to reflect existing text 
in Section 4.5. 
 
 
 
 
Clarified investigator role in 
communicating to sponsor 
when a patient refuses the 
endometrial biopsy. 
6.5.2.8.  Status of 
Menstruation 
Recovery 
If the first menstruation after the end of study 
treatment administration is observed before the 
Follow-up visit, the date of onset of the first 
menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted again by 
telephone 3 (+0.5) months after the Follow-Up 
visit to determine if menses has resumed and will 
If the first menstruation after the end of study 
treatment administration is observed before the 
Follow-Up visit, the date of onset of the first 
menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-
Up visit for whom there is no explanation for the 
lack of resumption (eg, medical procedure or 
medications) will be contacted by telephone 3 
months (+ 0.5 months) after the Follow-Up visit 
to determine if menses has resumed and will be 
asked about factors that may affect resumption of 
Clarified procedures for when a 
patient is potentially lost to 
follow-up. 


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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
21 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
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 
form, as available. 
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 
form, as available.  Document the pregnancy in 
the eCRF as well. 
Section 7.10 
Table 7-2 
Risk of Estradiol 
(1.0 mg)/ 
Norethindrone 
Acetate (0.5 mg) 
Monitoring and Withdrawal Criteria 
Clinical chemistries assessing liver tests, fasting 
glucose and lipids, and urine pregnancy tests will 
be performed throughout the study.  Adverse 
events will be recorded at each visit. 
Monitoring and Withdrawal Criteria 
Clinical chemistries assessing liver tests, fasting 
glucose and lipids, and urine pregnancy tests will 
be performed throughout the study.  Adverse 
events will be recorded at each study visit;  
A mammogram will be performed at Week 52 
or at the Week 104/Early Termination for 
women who are or become ≥ 40 years old 
during the study, with specified 
discontinuation criteria.  Adverse events will 
be recorded. 
Added details to correspond 
with the addition of 
mammograms. 
9. Statistical 
Considerations and 
Data Analyses 
 
The study may be closed pending selected 
contingent safety procedures conducted after 
the last patient’s Week 104/Early Termination 
or Follow-Up visit.  After the study is closed, 
any pending required follow-up testing of 
bone mineral density and endometrial 
biopsies or for menstruation recovery beyond 
the Follow-Up visit will be captured and 
reported. 
Added language to provide 
guidance on site closure and 
pending follow up procedures 
9.2.  Analysis 
Population 
Efficacy data analyses will be performed on the 
Modified Intent-to-Treat (mITT) Population, 
defined as all patients who were randomized in a 
parent study (MVT-601-3101 or 
MVT-601-3102) and who have received any 
amount of randomized study drug. 
Efficacy data analyses will be performed on the 
Extension Study Population, defined as all 
patients who enrolled into MVT-601-3103 and 
who have received any amount of randomized 
open-label study drug in MVT-601-3103. 
To clarify the analysis 
populations for efficacy and 
safety data of the extension 
study. 


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Clinical Study Protocol 
MVT-601-3103 Amendment 3.1 
 
Myovant Sciences GmbH 
23 
CONFIDENTIAL 
Section 
Item 
Original 
Amendment 3.1 
Rationale 
COVID-19 
Pandemic 
 

SAP_001.pdf: 
Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
1 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN  
 
Study Titles: 
SPIRIT EXTENSION: An International Phase 3 
Open-Label, Single-Arm, Safety and Efficacy Extension 
Study to Evaluate Relugolix Co-Administered with 
Low-Dose Estradiol and Norethindrone Acetate in Women with 
Endometriosis-Associated Pain  
 
Investigational 
Product: 
 
Relugolix 
Protocol Number: 
MVT-601-3103 
 
Indication: 
Treatment of Endometriosis-Associated Pain  
 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
Regulatory 
Identifier(s): 
IND # 076642 
EudraCT # 2017-004066-10 
 
Version/Effective Date: 
Version 1.0 / 17 Feb 2022 
 
 
 
 
 
 
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. 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
2  
C O N FI D E N TI A L  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L S H E E T  
S PI RI T E X T E N SI O N: A n I nter nati o nal P hase 3 O pe n -La b el, Si n gle -Ar m, L o n g -T er m Efficac y 
a n d Safet y E xte nsi o n St u d y t o E val uat e Rel u g oli x C o-A d mi nistere d wit h L o w -D ose Estr a di ol 
a n d N oret hi n dr o ne Acetate i n W o me n wit h  E n d o metri osis -Ass ociate d Pai n  
T his statistical a nal ysis pla n has bee n a p pr o ve d b y M y o va nt Scie nces G m b H .  T he f oll o wi n g 
si g nat ur es d oc u me nt t his a p pr o val.  
 
 
 
 
 
D ate  
 
 
D ate  
 
D ate  
 
 
 
D ate  
 
 
 
D ate  
 
D ate  
 
 
 
 
 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7
1 8 - F e b - 2 0 2 2  |  7 : 4 7  A M  P S T
1 7 - F e b - 2 0 2 2  |  3 : 5 3  P M  P S T
1 7 - F e b - 2 0 2 2  |  4 : 0 0  P M  P S T
1 7 - F e b - 2 0 2 2  |  3 : 5 9  P M  P S T
1 7 - F e b - 2 0 2 2  |  8 : 0 2  P M  P S T
1 8 - F e b - 2 0 2 2  |  7 : 1 0  A M  P S T
P P D


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
3  
C O N FI D E N TI A L  
 
T A B L E O F C O N T E N T S  
S T A TI S TI C A L A N A L Y SI S  P L A N A P P R O V A L S H E E T  ............................................................2  
T A B L E O F C O N T E N T S  .................................................................................................................3  
LI S T O F T A B L E S  ...........................................................................................................................6  
LI S T O F FI G U R E S  .........................................................................................................................7  
LI S T O F A B B R E VI A TI O N S  ..........................................................................................................8  
1.  
I N T R O D U C TI O N ......................................................................................................1 0  
1. 1.  
St u d y O bjecti ves a n d E n d p oi nts  .................................................................................1 0  
2.  
S T U D Y D E SI G N  .......................................................................................................1 5  
2. 1.  
S u m mar y  of St u d y Desi g n  ..........................................................................................1 5  
2. 2.  
Sa m ple Siz e C o nsi derati o ns  .......................................................................................2 0  
3.  
P L A N N E D A N A L Y S E S  ............................................................................................2 1  
3. 1.  
Fi nal A nal yses  ............................................................................................................2 1  
3. 2.  
Safet y F oll o w -U p A nal yses  ........................................................................................2 1  
4.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D 
H A N D LI N G O F MI S SI N G D A T A  ............................................................................2 2  
4. 1.  
Data Prese nt ati o n C o n ve nti o ns  ...................................................................................2 2  
4. 2.  
A nal ysis P o p ulati o ns  ..................................................................................................2 3  
4. 2. 1.  
E xte nsi o n St u d y P o p ulati o n  ........................................................................................2 3  
4. 2. 2.  
E xte nsi o n Safet y P o p ulati o n  .......................................................................................2 3  
4. 2. 3.  
E x cl usi o n of Site  
 fr o m Efficac y a n d Safet y A nal ys es  .......................................2 3  
4. 3.  
Defi niti o ns, C o m p utati o n, a n d C o n ve nti o n  ................................................................2 4  
4. 3. 1.  
Defi niti o n of Date of First D ose a n d Dat e of La st D ose of Pi v otal p hase 3 
St u d y Dr u g  ..................................................................................................................2 4  
4. 3. 2.  
Defi niti o n of Date of First D ose a n d Dat e of Last D ose of E xte nsi o n St u d y 
Dr u g  ............................................................................................................................2 4  
4. 3. 3.  
St u d y Da y  ...................................................................................................................2 4  
4. 3. 4.  
E xte nsi o n St u d y Da y  ..................................................................................................2 4  
4. 3. 5.  
Defi niti o n of O verall Treat me nt D urati o n  ..................................................................2 5  
4. 3. 6.  
Defi niti o n of E xte nsi o n St u d y Treat me nt D urati o n  ....................................................2 5  
4. 3. 7.  
Defi niti o n of Bas eli ne V al ue a n d P ost -Baseli ne Val ue  ..............................................2 5  
4. 3. 8.  
Visit Wi n d o ws  ............................................................................................................2 5  
4. 4.  
Ge neral R ules f or Missi n g Data  .................................................................................3 0  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7
P P D


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
4 
CONFIDENTIAL 
 
4.4.1. 
By-Visit Endpoints .....................................................................................................30 
4.4.2. 
Adverse Events and Concomitant Medications ..........................................................30 
4.5. 
Handling Multiple Values on the Same Day ..............................................................31 
5. 
STUDY POPULATION .............................................................................................31 
5.1. 
Subject Disposition .....................................................................................................31 
5.2. 
Protocol Deviations ....................................................................................................32 
5.3. 
Demographic and Baseline Characteristics ................................................................32 
5.4. 
Medical History ..........................................................................................................33 
5.5. 
Concomitant Medications ...........................................................................................33 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................34 
7. 
EFFICACY ANALYSES ...........................................................................................35 
7.1. 
General Considerations ...............................................................................................35 
7.1.1. 
Analyses for Categorical Data ....................................................................................35 
7.1.2. 
Analyses for Continuous Data ....................................................................................35 
7.2. 
Primary Efficacy Endpoints ........................................................................................36 
7.2.1. 
Primary Efficacy Analysis ..........................................................................................36 
7.2.2. 
Determination of the Meaningful Change Thresholds for the Primary 
Endpoints ....................................................................................................................36 
7.2.3. 
Data Sources Supporting Derivation of Responder Status .........................................37 
7.2.4. 
Definitions Related to Numerical Rating Scale Pain Scores and Analgesic 
Use ..............................................................................................................................37 
7.2.5. 
Definition of Responder at Week 52 and Week 104/EOT .........................................40 
7.2.6. 
Derivation of Responder Status at Week 52, Week 104/EOT and Missing 
Data Handling Rules ...................................................................................................41 
7.2.7. 
Mixed-Effects Model for Imputing Missing or Partially Missing Pain Scores 
at Week 52 and Week 104/EOT .................................................................................43 
7.2.8. 
Subgroup Analyses .....................................................................................................45 
7.3. 
Secondary Efficacy Endpoints ....................................................................................45 
7.3.1. 
Change from Baseline in EHP-30 Pain Domain Scores .............................................45 
7.3.2. 
Change from Baseline in Numerical Rating Scale Score for Endometriosis-
Associated Pain ...........................................................................................................46 
7.3.3. 
Analgesic use ..............................................................................................................47 
7.3.4. 
Change from Baseline in Patient Global Assessments ...............................................47 
7.3.5. 
Change from Baseline in Functional Impairment on sB&B Scale .............................48 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
5 
CONFIDENTIAL 
 
7.3.6. 
Patient Global Impression of Change .........................................................................49 
7.4. 
Exploratory Efficacy Endpoints .................................................................................49 
7.4.1. 
Exploratory Efficacy Analyses ...................................................................................49 
8. 
PHARMACODYNAMIC ANALYSES .....................................................................50 
9. 
SAFETY ANALYSES ...............................................................................................51 
9.1. 
Adverse Events ...........................................................................................................51 
9.1.1. 
Relationship to Study Drug ........................................................................................53 
9.1.2. 
Severity of Adverse Event ..........................................................................................53 
9.1.3. 
Serious Adverse Event ................................................................................................54 
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug ...............................................54 
9.1.5. 
Adverse Events Leading to Dose Interruption ............................................................54 
9.1.6. 
Adverse Events Resulting in a Fatal Outcome ...........................................................54 
9.1.7. 
Other Safety Parameters of Interest ............................................................................54 
9.1.8. 
Exposure-adjusted Adverse Events ............................................................................55 
9.1.9. 
Adverse Events of Clinical Interest ............................................................................55 
9.2. 
Laboratory Data ..........................................................................................................55 
9.3. 
Other Safety Analyses ................................................................................................57 
9.3.1. 
Electrocardiograms .....................................................................................................57 
9.3.2. 
Vital Signs ..................................................................................................................57 
9.3.3. 
Endometrial Biopsy ....................................................................................................58 
9.3.4. 
Mammogram ...............................................................................................................60 
9.3.5. 
Bone Mineral Density .................................................................................................60 
9.3.6. 
Menstruation Recovery ...............................................................................................62 
9.3.7. 
Analysis of Bleeding Profiles .....................................................................................63 
9.3.8. 
Amenorrhea Rate and Sustained Amenorrhea Rate ...................................................64 
10. 
REFERENCES ...........................................................................................................66 
11. 
REVISION HISTORY ...............................................................................................67 
APPENDICES ...............................................................................................................................68 
Appendix 1. Protocol-Specified Rescue Analgesics ...................................................................68 
Appendix 2. List of pre-defined threshold in selected chemistry and hematology test 
results ..........................................................................................................................69 
 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
6 
CONFIDENTIAL 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................11 
Table 2.  
BMD Requirement by DXA in Protocol and Amendments .......................................16 
Table 3: 
Visit Windows for Monthly and Quarterly Assessments (Monthly and 
Quarterly Visit, Lab and PGA) ...................................................................................26 
Table 4: 
Visit Windows for Bone Mineral Density Assessments.............................................27 
Table 5: 
Visit Windows for ECG Assessments ........................................................................27 
Table 6: 
Visit Windows for EHP-30 Questionnaire Assessments ............................................27 
Table 7: 
Visit Windows for EHP Work Domain and EQ-5D-5L Assessments .......................28 
Table 8: 
Visit Windows for PGIC Assessments .......................................................................28 
Table 9: 
Visit Windows for Endometrial Biopsies Assessments..............................................28 
Table 10: Visit Windows for Mammogram Assessments ..........................................................28 
Table 11: Time Windows for Daily Assessments from eDiary ..................................................29 
Table 12: Categories for Demographic and Baseline Characteristics ........................................32 
Table 13: Effect of Protocol-Specific Analgesic Medication Use for Endometriosis-
Associated Pain on Responder Status at Week 52, Week 104/EOT ..........................39 
Table 14: Missing Data Handling Rules for Average Dysmenorrhea NRS Score at 
Week 52, Week 104/ EOT ..........................................................................................42 
Table 15: Missing Data Handling Rules for Average Non-Menstrual Pelvic Pain NRS 
Score at Week 52, Week 104/EOT .............................................................................43 
Table 16: Planned Subgroup Analyses .......................................................................................45 
Table 17: Endometriosis Health Profile 30-Item Questionnaires Scores ...................................46 
Table 18: Patient Global Assessment Numerical Scores ............................................................47 
Table 19: Subject Modified Biberoglu and Behrman Scales for Dysmenorrhea, Pelvic 
Pain, and Dyspareunia ................................................................................................48 
Table 20: Other Safety Parameters of Interest ............................................................................55 
Table 21: Categories of Liver Test Elevations ...........................................................................57 
Table 22: Categories of Potentially Clinically Significant Abnormalities in Vital Signs ..........58 
Table 23:  Categories of Primary Diagnosis in Endometrial Biopsies ........................................59 
Table 24: Planned Subgroup Analyses .......................................................................................61 
Table 25: Definitions of Bleeding Profile Categories .................................................................63 
Table 26: Summaries of Bleeding Amount and Number of Bleeding Days ...............................64 
 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
7 
CONFIDENTIAL 
 
LIST OF FIGURES 
Figure 1 
MVT-601-3103 Study Schematic ...............................................................................20 
Figure 2: 
Visual Depiction of the Missing Data Handling Rules and Determination of 
Responder Status for the Primary Efficacy Endpoints ...............................................43 
 
 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
8 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS 
Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMD 
bone mineral density 
BMI 
body mass index 
bpm 
beats per minute 
CI 
confidence interval 
CR 
creatinine 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
DXA 
dual-energy x-ray absorptiometry 
E2 
estradiol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
ET 
end of treatment 
early termination 
EHP 
Endometriosis Health Profile  
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
ICH 
International Council on Harmonisation 
LS 
least squares 
MAA 
Marketing Authorization Application 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
msec 
millisecond 
NETA 
norethindrone acetate 
NDA 
New drug application 
NMPP 
non-menstrual pelvic pain 
NRS 
Numerical Rating Scale 
PGA 
Patient Global Assessment 
PGIC 
Patient Global Impression of Change 
PT 
Preferred Term 
QTcF 
corrected QT interval Fridericia 
SAP 
statistical analysis plan 
sB&B 
Subject Modified Biberoglu and Behrman 
SD 
standard deviation 
SMQ 
standard MedDRA query 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
9 
CONFIDENTIAL 
 
Term 
Definition/Explanation 
SOC 
System Organ Class 
ULN 
LLN 
upper limit of normal 
lower limit of normal 
WHO 
World Health Organization 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 0  
C O N FI D E N TI A L  
 
1.  
IN T R O D U C TI O N  
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he efficac y a n d  safet y a nal yses 
pla n ne d f or p h ase 3 st u dy  M V T -6 0 1 -3 1 0 3 , e ntitle d “A n I nter n ati o nal P hase 3  O pe n -La bel, 
Si n gle -Ar m, L o n g -Ter m Efficac y a n d Safet y  E xte nsi o n St u d y t o E val u ate Rel u g oli x C o -
A d mi nistere d wit h  L o w -D ose Estra di ol a n d N oret hi n dr o ne Acet ate i n W o me n wit h  
E n d o metri osis -Ass ociate d Pai n .”  P atie nts w h o c o m plete d st u d y M V T -6 0 1 -3 1 0 1 ( S PI RI T 1) or 
st u d y M V T-6 0 1 -3 1 0 2 ( S PI RI T 2)  i n o n e of t hree treat me nt ar ms:  rel u g oli x 4 0 m g + 
estra di ol/ n oret hi n dr o ne acetate ( E 2 / N E T A) 1 m g/ 0. 5 m g  f or 2 4 wee ks ( Gr o u p A, als o referre d t o 
as t he rel u g oli x + E 2/ N E T A gr o u p ), rel u g oli x 4 0 m g f or 1 2 wee ks f oll o we d b y 1 2 wee ks of 
rel u g oli x 4 0 m g + E 2/ N E T A 1 m g/ 0. 5 m g ( Gr o u p  B , als o referre d t o as t he rel u g oli x + dela ye d 
E 2/ N E T A gr o u p  ), or pl ace b o f or 2 4  wee ks ( Gr o u p C, als o referre d t o as t h e place b o gr o u p) a n d 
meet eli gi bilit y criteria are e nr olle d i n M V T -6 0 1 -3 1 0 3 . 
T his S A P was de vel o pe d i n acc or da nce wit h t he I nter nati o nal C o u ncil o n Har m o nisati o n ( I C H) 
E 9  g ui deli ne s.   
T h is S A P is base d o n:  
 Pr ot oc ol  M V T -6 0 1 -3 1 0 3 , A me n d me nt 4 , date d 1  J ul 2 0 2 1 ; 
 I C H g ui deli nes E3 ( Cli nical St u d y Re p orts) a n d E 9 ( Statistical Pri nci ples f or Cli nical 
Trials) . 
T he met h o ds use d f or a n al ysis of t he M V T -6 0 1 -3 1 0 3 st u d y are c o nsiste nt  wit h  t h ose use d f or t he 
pi v otal p hase 3 st u dies ( M V T-6 0 1 -3 1 0 1 a n d M V T -6 0 1 -3 1 0 2).  T h is d oc u me nt ma y e v ol ve o ver 
ti me (e g, t o reflect t he re q uire me nts of pr ot oc ol a me n d me nts or re g ulat or y re q uests).  T h e S A P is 
t o be fi naliz e d, a p pr o ve d b y t he s p o ns or, a n d place d o n file bef ore t he data base is l oc ke d  f or t he 
fi nal cli nical st u d y re p ort ( CS R ). T he  fi nal S A P ma y b e  a me n de d pri or t o t he data bas e l oc k f or 
t he fi nal C S R. 
1. 1.  
St u d y O bjecti ves a n d E n d p oi nts  
T he o bjecti ves of st u d y M V T-6 0 1 -3 1 0 3  are t o e val uate l o n g -ter m efficac y a n d safet y t hr o u g h u p 
t o 1 0 4 -wee k of treat me nt (i ncl u di n g 2 4 wee ks of treat me nt d uri n g t he pi v ot al p hase 3 st u dies) of 
rel u g oli x 4 0  m g o nce dail y  c o-a d mi nistere d wit h estra di ol a n d n oret hi n dr o n e acetate .  T he st u d y 
o bjecti ves a n d e n d p oi nts are liste d i n Ta ble  1 .  T h e e n d p oi nts i n it alics are n ot liste d i n t he 
pr ot oc ol, b ut t he y h a ve b ee n i de ntifie d as i m p orta nt  f or assess me nt of tr eat me nt effect o n t he 
basis of e mer gi n g dat a a n d cli nical rele va nce t o t h e st u d y o bjecti ves a n d t h eref ore are i ncl u d e d i n 
t his S A P. T he pi v otal p hase 3 st u d y Baseli ne will be i n ge neral use d as t he refere nce p oi nt f or 
t he e xte nsi o n st ud y f or all c ha n ge s fr o m b aseli ne-relate d e n d p oi nts u nless ot her wise s pecifie d.  
 
 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 1  
C O N FI D E N TI A L  
 
T a ble  1 : 
St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ve(s)  
E n d p oi nt(s)  
Pri m ar y Effic ac y  
T o be assesse d at Wee k 5 2  
 
T o e val uate l o n g-ter m efficac y of rel u g oli x 4 0 m g 
o nce dail y c o-a d mi nistere d  wit h l o w -d ose 
estra di ol a n d n oret hi n dr o ne acetate f or u p t o 
5 2  wee ks, a m o n g patie nts w h o pre vi o usl y 
c o m plete d a 2 4 -wee k treat me nt peri o d i n o ne of 
t he pi v otal p hase 3 st u dies ( M V T-6 0 1 -3 1 0 1 or 
M V T 6 0 1 -3 1 0 2), o n e n d o metri osis -ass ociate d 
pai n.  
 
T o be assesse d Wee k 5 2  
 
 
Pr o p orti o n of patie nts w h o meet t he 
d ys me n orr hea re s p o n der criteria at t he 
Wee k 5 2 pai n assess me nt peri o d, 
ac hie vi n g a mea n re d ucti o n i n 
d ys me n orr hea  N R S sc ores of at least 2. 8 
p oi nts a n d n o i ncrease i n use of a nal gesic 
me dicati o ns as rec or de d i n a dail y e Diar y  
 
 
Pr o p orti o n of patie nts w h o meet t he 
N M P P res p o n der criteria at t he Wee k 5 2 
pai n assess me nt peri o d, ac hie vi n g a mea n 
re d ucti o n i n N M P P N R S sc ores of at least 
2. 1 p oi nts a n d n o i ncrease i n use of 
a nal gesic me dicati o ns as rec or de d i n a 
dail y e Diar y  
 
T o be assesse d at Wee k 1 0 4  
 
T o e val uate l o n g -ter m efficac y of rel u g oli x 4 0 m g 
o nce dail y c o -a d mi nistere d wit h l o w -d ose 
estra di ol a n d n oret hi n dr o ne ace tate f or u p t o 
1 0 4  wee ks, a m o n g patie nts w h o pre vi o usl y 
c o m plete d a 2 4 -wee k treat me nt peri o d i n o ne of 
t he pi v otal p hase 3 st u dies ( M V T-6 0 1 -3 1 0 1 or 
M V T -6 0 1 -3 1 0 2), o n e n d o metri osis -ass ociate d 
pai n.  
T o be assesse d at Wee k 1 0 4  
 
 
Pr o p orti o n of patie nts w h o meet  t he 
d ys me n orr hea res p o n der criteria at t he 
Wee k 1 0 4/ E O T pai n assess me nt peri o d, 
ac hie vi n g a mea n re d ucti o n i n 
d ys me n orr hea N R S sc ores of at least 2. 8 
p oi nts a n d n o i ncrease i n use of a nal gesic 
me dicati o ns as rec or de d i n a dail y e Diar y  
 
 
Pr o p orti o n of patie nts w h o meet t he 
N M P P res p o n der criteria at t he Wee k 
1 0 4/ E O T pai n assess me nt peri o d, 
ac hie vi n g a mea n re d ucti o n i n N M P P 
N R S sc ores of at least 2. 1 p oi nts a n d n o 
i ncrease i n use of a nal gesic me dicati o ns 
as rec or de d i n a dail y e Diar y  
 
Sec o n d ar y Effic ac y   
( T o be assess e d at W ee k 5 2 a n d Wee k 1 0 4, u nless ot her wise s pecifie d) 
 T o e val uate l o n g -t er m efficac y of 
rel u g oli x 4 0 m g o nce dail y c o-
a d mi nistere d  wit h l o w -d ose estra di ol a n d 
T o be assesse d o n t h e f oll o wi n g : 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 2  
C O N FI D E N TI A L  
 
O bjecti ve(s)  
E n d p oi nt(s)  
n oret hi n dr o ne acetate, a m o n g patie nts 
w h o pre vi o usl y c o m plete d a 2 4 -wee k 
treat me nt peri o d i n o ne of t he pi v otal p hase 
3 st u dies ( M V T-6 0 1 -3 1 0 1 or M V T 6 0 1 -
3 1 0 2), o n t he f oll o wi n g:  
o  F u ncti o n, as meas ure d b y t he 
E n d o metri osis H ealt h Pr ofile 
Q uesti o n naire  ( E H P-3 0 ) Pai n D o mai n  
 
C ha n ge fr o m t he pi v otal p hase 3 st u d y 
Baseli ne i n t he E H P -3 0 Pai n D o mai n sc ores;  
Pr o p orti o n of patie nts w h o ha ve a re d ucti o n 
of at least 2 0 p oi nts i n t he E H P -3 0 Pai n 
D o mai n sc ores  fr o m t he pi v otal p hase 3 st u d y 
Baseli ne  
o  D ys me n orr hea, as me as ure d b y t he 
N u merical Rati n g Scale ( N R S) f or 
d ys me n orr hea  
C ha n ge a n d perce nt c h a n ge  fr o m t he pi v otal 
p hase 3 st u d y Baseli ne i n t he mea n 
d ys me n orr hea N R S sc ore  
o  Patie nt Gl o bal I m pr essi o n of C ha n ge 
( P GI C) f or d ys me n orr hea 
 
Pr o p orti o n of patie nts w h o are “b etter ” or 
“m uc h better ” o n t he P GI C f or d ys me n orr hea 
(at Wee k 5 2 o nl y)  
o  N o n me nstr ual pel vic pai n ( N M P P), as 
meas ure d b y t he N R S f or N M P P  
C ha n ge a n d perce nt c h a n ge  fr o m t he pi v otal 
p hase 3 st u d y Baseli ne i n t he mea n N M P P 
N R S sc ore  
o  O verall pel vic p ai n, as m eas ure d b y 
t he N R S f or o verall pel vi c pai n 
C ha n ge a n d perce nt c h a n ge  fr o m t he pi v otal 
p hase 3 st u d y Baseli ne i n t he mea n o verall 
pel vic pai n  N R S sc ore  
o  A nal gesic use  
Pr o p orti o n of p atie nts n ot usi n g o pi oi ds ; 
Pr o p orti o n of  p atie nts n ot usi n g a n al gesics  
o  P GI C f or N M P P  
Pr o p orti o n of patie nts w h o are “b etter ” or 
“m uc h better ” o n t he P GI C f or N M P P (at 
Wee k  5 2 o nl y)  
o  D ys p are u nia, as meas ure d b y t he N R S  
C ha n ge a n d perce nt c h a n ge  fr o m t he pi v otal 
p hase 3 st u d y Baseli ne i n t he mea n 
d ys pare u nia N R S sc ores  
o  P GI C f or d ys p are u ni a  
Pr o p orti o n of patie nts w h o are better or m uc h 
better o n t he P GI C f or d ys pare u nia (at 
Wee k  5 2 o nl y)  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 3  
C O N FI D E N TI A L  
 
O bjecti ve(s)  
E n d p oi nt(s)  
o  D ys p are u nia -rel ate d f u ncti o nal effects 
( S u bject M o difie d Bi ber o gl u a n d 
Be hr m a n [s B & B])  
C ha n ge a n d perce nt c h a n ge fr o m t he pi v otal 
p hase 3 st u d y Baseli ne i n t he mea n 
d ys pare u nia f u ncti o nal i m pair me nt o n t he 
s B & B scale 
o  Patie nt Gl o bal Assess me nt ( P G A) f or 
pai n  
C ha n ge fr o m t he pi v otal p hase 3 st u d y 
Baseli ne i n se v erit y sc ores o n t he P G A f or 
pai n ; 
Pr o p orti o n of P atie nts wit h Im pr ove me nt, 
W ors e ni n g , N o c h a n ge  fr o m b aseli ne; 
o  P G A f or f u ncti o n  
C ha n ge fr o m t he pi v otal p hase 3 st u d y 
Baseli ne i n f u n cti o n i m pair me nt o n t he P G A 
f or f u ncti o n; 
Pr o p orti o n of P atie nts wit h I m pr ove me nt, 
W ors e ni n g , N o C h a n ge  fr o m B aseli ne  
o  E n d o metri osis -ass ociate d q ualit y of 
life, as meas ur e d b y t he E H P-3 0 
C o ntr ol a n d P o werless ness, S ocial  
S u p p ort, E m oti o nal W ell -Bei n g, a n d 
Self -I m a ge d o mai ns 
C ha n ge fr o m t he pi v otal p hase 3 st u d y i n eac h 
of t he n o n -pai n E H P -3 0 d o mai ns ( C o ntr ol a n d 
P o werless ness, S ocial S u p p ort, E m oti o nal 
Well -Bei n g, a n d Self -I m a ge) 
o  D ys me n orr hea -relate d f u ncti o nal 
effects (s B & B)  
 
C ha n ge a n d perce nt c h a n ge fr o m t he pi v otal 
p hase 3 st u d y Baseli ne p ai n assess me nt 
peri o d i n d ys me n orr hea -relate d f u ncti o nal 
effects (s B & B)  
o  N M P P -relate d f u ncti o nal effects 
(s B & B) 
C ha n ge a n d perce nt c h a n ge fr o m t he pi v otal 
p hase 3 st u d y Baseli ne p ai n assess me nt 
peri o d i n N M P P -relate d f u ncti o nal effects 
(s B & B) 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 4  
C O N FI D E N TI A L  
 
O bjecti ve(s)  
E n d p oi nt(s)  
S afet y  
 T o e val uate t he s afet y of rel u g oli x 4 0 m g 
o nce dail y c o -a d mi nistere d wit h l o w -d ose 
estra di ol a n d n oret hi n dr o ne acetate f or u p 
t o 1 0 4 wee ks, a m o n g patie nts w h o 
pre vi o usl y c o m plete d a 2 4 -wee k tr eat me nt 
peri o d i n o ne of t he pi v ot al p hase 3 st u dies 
( M V T-6 0 1 -3 1 0 1 or M V T -6 0 1 -3 1 0 2), 
i ncl u di n g: 
o  A d verse e ve nts  
o  C ha n ges i n b o n e mi neral de nsit y  
T o be assesse d at Wee k 5 2 a n d Wee k 1 0 4  
 I n ci de nce of a d v erse e ve nts 
 Perce nt c ha n ge fr o m t he pi v otal p hase 3 
st u d y Baseli ne t o Wee k 5 2 or W ee k 1 0 4 
i n b o ne mi neral de nsit y at t he l u m bar 
s pi ne ( L 1-L 4), fe m oral n ec k, a n d t otal hi p 
as assesse d b y d u al -e ner g y x -ra y 
a bs or pti o metr y ( D X A)  
T o be assesse d at 6 -m o nt hs a n d 1 2 -m o nt hs 
p ost -treat me nt 
 Perce nt c ha n ge fr o m t he pare nt st u d y 
Baseli ne i n B M D at t he l u m b ar s pi ne ( L 1 -
L 4), t otal hi p, a n d fe m or al nec k as 
assesse d b y D X A.  
P h ar m a c o d y n a mi c  
 T o e val uate t he p h ar mac o d y na mic effects 
of rel u g oli x 4 0 m g o nce dail y c o -
a d mi nistere d wit h l o w -d ose estra di ol a n d 
n oret hi n dr o ne acetate f or u p t o 1 0 4 wee ks, 
a m o n g p atie nts w h o pre vi o usl y c o m plete d 
a 2 4-wee k treat me nt peri o d i n o ne of t he 
pi v otal p hase 3 stu dies ( M V T -6 0 1 -3 1 0 1 or 
M V T 6 0 1 -3 1 0 2), o n estr a di ol  
 C ha n ge fr o m pi v otal p hase 3 st u d y 
Baseli ne t o Wee k  5 2 i n pre -d ose 
c o nce ntr ati o ns of ser u m estra di ol  
 C ha n ge fr o m pi v otal p hase 3 st u d y 
Baseli ne t o Wee k  1 0 4 i n pre -d ose 
c o nce ntr ati o ns of ser u m estra di ol  
E x pl or at or y  Effic ac y  
 T o e val uate t he b e nefit of rel u g oli x 4 0 m g 
o nce dail y c o -a d mi nistere d wit h l o w -d ose 
estra di ol a n d n oret hi n dr o ne acetate o n 
e n d o metri osis -ass ociate d q ualit y of life 
( E H P-3 0 t otal sc ore), w or k ( E H P W or k 
D o mai n), patie nt -re p orte d q ualit y of life 
o utc o mes ( E ur o pea n Q ualit y of Life Fi ve -
Di me nsi o n Fi ve -Le v el Scale [ E Q -5 D -5 L]) 
f or u p t o 1 0 4 wee ks a m o n g patie nts w h o 
pre vi o usl y c o m plete d a 2 4 -wee k tr eat me nt 
peri o d i n o ne of t he pi v ot al p hase 3 st u dies 
( M V T-6 0 1 -3 1 0 1 or M V T -6 0 1 -3 1 0 2)  
T o be assess e d at Wee k 5 2 a n d Wee k 1 0 4  
 C ha n ge fr o m pi v otal p hase 3 st u d y Baseli ne 
i n t he E H P-3 0 scale t otal sc ore  
 C ha n ge fr o m pi v otal p hase 3 st ud y  
Baseli ne i n t he E H P W or k D o mai n sc ore . 
 C ha n ge fr o m pi v otal p hase 3 st u d y 
Baseli ne i n t he E Q -5 D -5 L  
 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 5  
C O N FI D E N TI A L  
 
Descri pti ve ass ess me nts of effic ac y a n d safet y will be ma de o n data c ollect e d fr o m t he pi v otal 
p hase 3 st u d y Baseli ne t hr o u g h W ee k 5 2 , a n d fr o m t he pi v otal p hase 3 st u d y Baseli ne t hr o u g h 
t he e n d of t he e xte nsi o n st u d y ( Wee k 1 0 4) o n t he e xte nsi o n st u d y p o p u lati o n, defi ne d as p atie nts 
w h o e nr olle d i n M V T -6 0 1 -3 1 0 3 ( i.e., w h o recei ve d at least o ne d ose of st u d y dr u g i n t he 
e xte nsi o n st u d y), f or t he f oll o wi n g treat me nt gr o u ps  ori gi nall y ra n d o mize d i n t he pi v otal p hase 3 
st u dies: 
 Pi v otal p hase 3 rel u g oli x + E 2/ N ET A gr o u p :  Ra n d o mize d t o 2 4 wee ks of oral 
rel u g oli x 4 0 m g o nce dail y c o -a d mi nistere d wit h 1  m g estr a di ol a n d 0. 5  m g 
n oret hi n dr o ne acetate i n t he pi v otal p hase 3 st u d y; 
 Pi v otal p hase 3 rel u g oli x + dela ye d E 2/ N E T A gr o u p:  Ra n d o mize d t o 1 2 wee ks of 
oral rel u g oli x 4 0  m g o nce dail y f oll o we d b y 1 2 wee ks of oral rel u g oli x 4 0  m g o nce 
dail y c o -a d mi nistere d wit h 1  m g estr a di ol a n d 0. 5  m g n oret hi n dr o ne acetate i n t he 
pi v otal p hase 3 st u d y; 
 Pi v otal p hase 3 place b o gr o u p :  Ra n d o mize d t o 2 4 wee ks t o place b o i n t he pi v ota l 
p hase 3 st u d y. 
 
2.  
S T U D Y  D E SI G N  
2. 1.  
S u m m ar y of  St u d y Desi g n  
T he S PI RI T E X T E N SI O N st u d y is a n i nter nati o nal p hase 3 o pe n -la bel, si n gle-ar m, l o n g-ter m 
effic ac y a n d s afet y e xte nsi o n st u d y t h at will e nr oll eli gi ble patie nts w h o h a ve c o m plete d t heir  
partici pati o n i n o ne of t h e ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d pi v otal p hase 3 st u dies 
( M V T-6 0 1 -3 1 0 1 or M V T -6 0 1 -3 1 0 2) .  All patie nts will recei ve oral rel u g oli x 4 0 m g o nce dail y  
c o-a d mi nistere d wit h estr a di ol 1 m g  a n d n oret hi n dr o ne acetate 0. 5 m g  f or u p t o 8 0 wee ks .  
Patie nts will c o nti n ue t o be f oll o we d u p f or t heir B M D  f or 1 2 m o nt hs after t heir  treat me nt 
peri o d has e n d e d.   
A p pr o xi matel y 8 0 0 w o me n wit h e n d o metri osis-ass ociate d pai n will be  e nr olle d .  T he o bjecti ves 
of t he st u d y are t o e v al uate l o n g-ter m efficac y a n d safet y t hr o u g h u p t o 1 0 4  wee ks of treat me nt 
(i ncl u di n g tr eat me nt d uri n g t he pi v otal p has e 3 st u d y) w hic h will  i ncl u de u p t o 8 0  wee k s of 
treat me nt wit h rel u g oli x c o-a d mi nistere d  wit h l o w -d ose estra di ol/ n oret hi n dr o ne acetate .  Eli gi ble  
patie nts will ha ve c o m plete d partici pati o n i n  o ne of t he pi v otal p hase 3 st u dies ( M V T-6 0 1 -3 1 0 1 
or M V T -6 0 1 -3 1 0 2) a n d c o nse nte d t o partici pate i n t his e xte nsi o n st u d y .   
B aseli ne pr oce d ures will be d o ne at t he sa m e visit (referre d t o as t he “ Wee k 2 4/ Baseli n e visit” i n 
t his st u d y), w hic h c oi nci des wit h t he Wee k 2 4 visit fr o m t he pi v otal p hase 3 st u d y a n d will be 
defi ne d  as t he d ate of c o m pleti o n of t he last W ee k 2 4 pr oce d ure i n t he pi v otal p hase 3 st u d y. T h e 
Wee k 2 4/ Baseli ne visit will i ncl u de vital si g ns, p h ysical e x a mi nati o n, la b orat or y assess me nts, 
1 2 -lea d ele ctr ocar di o gra m ( E C G), b o ne de nsit o metr y, p atie nt-re p orte d o ut c o me assess me nts, a n d 
e n d o metrial bi o ps y (if re q uire d).   W he n Wee k 2 4 pr oce d ures i n t he pi v otal p hase 3 st u d y h a ve 
bee n c o m plete d, t h e i n ves ti gat or will assess patie nt eli gi bilit y f or p artici pati o n i n t he o pe n-la bel 
e xte nsi o n st u d y.  T he eli gi bilit y ass ess me nt will be base d o n dat a a vaila bl e at t he 
Wee k  2 4/ Baseli ne visit.   N o M V T -6 0 1 -3 1 0 3 st u d y pr oce d ures will be perf or me d u ntil t he 
c o nse nt f or m f or t his e xte nsi o n st u d y is si g n e d.  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
16 
CONFIDENTIAL 
 
Patients would have received their last dose of study drug in the pivotal phase 3 study on the day 
prior to the Week 24/Baseline visit and will receive their first dose of study drug for this 
extension study in the clinic after the patient is determined to be eligible for this extension study 
and has provided informed consent to participate.  Therefore, results of testing required for 
eligibility must be available on or prior to the Week 24/Baseline visit.  The administration of the 
first dose of study drug for MVT-601-3103 will define enrollment into this study.  Patients will 
then take the open-label study treatment (relugolix 40 mg co-administered with estradiol 1 mg 
and norethindrone acetate 0.5 mg) orally once daily for 80 weeks.  If necessary, for logistical 
reasons (eg, delayed availability of study drug supply on site, others), and with sponsor/designee 
approval, the first dose of open label study drug for MVT-601-3103 may be administered up to 
10 days following the pivotal phase 3 study Week 24/Baseline visit.  If the first dose of study 
drug is not given during this up to 10-day interval, the pivotal phase 3 study safety follow-up 
procedures should be followed (ie, adverse event reporting, electronic diary [eDiary] completion, 
etc.). 
During the 80-week Open-Label Treatment period and the ~30-day Follow-Up period, patients 
will continue to record study treatment, assessment of pain using the NRS, menstrual bleeding, 
analgesic use, and the functional effects of endometriosis-associated pain (sB&B) in the eDiary 
during the time periods specified in the protocol.  Only study-specific rescue analgesic 
medications should be used starting with the Week 24/Baseline visit and through the Follow-Up 
visit and these medications will be taken for control of pain and not prophylactically.  Health-
related quality of life questionnaires; PGIC for dysmenorrhea, NMPP, and dyspareunia; and 
PGA for pain and function will be completed during the visits on an electronic tablet, according 
to the study protocol Schedule of Activities (Section 1.1). 
Safety will be assessed throughout the study by monitoring adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECGs, mammograms (for 
women who are or become ≥ 40 years old during the study), endometrial biopsies, and bone 
mineral density with DXA.  
At scheduled visits, Early Termination visit, and post-treatment Follow-Up, each patient will 
have an assessment of bone mineral density (BMD) by DXA if required by protocol or protocol 
amendment. 
Determination of BMD by DXA at the Early Termination visit, scheduled visits and post-
treatment Follow-Up of findings will proceed according to the following rules: 
Table 2.  
BMD Requirement by DXA in Protocol and Amendments 
Protocol 
Scheduled Visits and  
Early Termination 
Post-Treatment Follow-Up 
Original  At week 52 visit, DXA is 
required. 
 
DXA at Early Termination (ET) 
visit is required, but DXA is not 
required at the Early Termination 
visit in patients whose last dose of 
Patients with a bone mineral density loss of 
> 3% at the lumbar spine (L1-L4) or total hip 
at their Week 52/ET visit relative to the pivotal 
phase 3 study Baseline measurement will 
undergo another bone densitometry scan at 6 
(±1) months after the last dose of study 
medication. 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 7  
C O N FI D E N TI A L  
 
st u d y dr u g w as ta ke n d uri n g 
Wee k 3 2 or earlier.  H o w e ver, t he 
pr oce d ure ma y be d o n e if it will 
ai d i n t he e val uati o n of a n 
o n g oi n g a d v erse e ve nt.  
  
If t he patie nt e nr olls directl y i nt o a n ot her 
rel u g oli x cli nical st u d y u p o n c o m pleti o n of t he 
Wee k 5 2 visit, t he n t he F oll o w -U p  visit a n d 
t he f oll o w-u p b o ne de nsit o metr y sca n at 6 ( ± 1) 
m o nt hs ma y be wai ve d.  
A M 1. 0  
At t he Wee k 3 6 a n d Wee k  5 2, 
visits, D X A is re q uire d . 
 
D X A at E T visit is re q uir e d, b ut 
D X A is n ot re q uire d at t he Earl y 
Ter mi nati o n visit i n patie nts 
w h ose last d ose of st u d y dr u g was 
ta ke n d uri n g Wee k 3 2 or earlier or 
wit hi n 4 wee ks after c o m pleti o n 
of t he Wee k 3 6 sca n.  H o we ve r, 
t he pr oce d ure ma y b e d o ne if it 
will ai d i n t he e val uati o n of a n 
o n g oi n g a d v erse e ve nt.  
Patie nts wit h a b o ne mi neral de nsit y l oss of 
>  3 % at t he l u m bar s pi ne ( L 1 -L 4) or t otal hi p 
at t heir Wee k 5 2 /E T  visit ( or m ost rece nt sca n, 
if t he Wee k 5 2/E T  sca n was n ot d o ne) relati ve 
t o t he pi v otal p hase 3 st u d y Baseli ne 
meas ure me nt will u n der g o a n ot her b o ne 
de nsit o metr y sca n at 6 ( ± 1) m o nt hs after t he 
last d ose of st u d y me di cati o n. 
  
If t he patie nt e nr olls directl y i nt o a n ot her 
rel u g oli x cli nical st u d y u p o n c o m pleti o n of t he 
Wee k 5 2 visit, t he n t he F oll o w -U p  visit a n d 
t he f oll o w-u p b o ne de nsit o metr y sca n at 6 ( ± 1) 
m o nt hs ma y be wai ve d.  
A M 2. 0  
At t he Wee k 3 6, Wee k 5 2, a n d 
Wee k 1 0 4 visits, D X A is re q uire d . 
 
• F or Earl y Ter mi nati o n occ urri n g 
bef ore Wee k 3 6, D X A is n ot  
re q uire d at Earl y Ter mi nati o n visit 
u nless it will ai d i n t he assess me nt 
of a n a d verse e v e nt  
• F or Earl y Ter mi nati o n occ urri n g 
after Wee k 3 6, D X A is r e q uire d at 
Earl y Ter mi nati o n u nless a D X A 
res ult is a vaila ble fr o m wit hi n si x 
wee ks pri or t o E arl y Ter mi nati o n  
 
P ost -Treat me nt D X A is r e q uire d at 6 m o nt hs 
( ± 1 m o nt h) f or f oll o wi n g:  
• F or Earl y Ter mi nati o n occ urri n g b ef ore 
Wee k 3 6:  
− t he m ost rece nt D X A b o ne mi neral 
de nsit y l oss at l u m bar s pi ne ( L 1 -L 4) or 
t otal hi p was > 2 % rel ati ve t o t he 
pi v otal p hase  3 st u d y b aseli ne. 
• F or Earl y Ter mi nati o n occ urri n g after Wee k 
3 6 a n d bef ore Wee k 5 2:  
− t he m ost rece nt D X A sca n was at Wee k 
2 4 a n d b o ne mi neral d e nsit y l oss at t he 
l u m bar s pi ne ( L 1-L 4) or t otal hi p was  
> 2 %, rel ati ve t o t he pi v otal p hase 3 
st u d y baseli ne; or 
− o n t he m ost rece nt D X A, b o ne mi neral 
de nsit y l oss at t he l u m bar s pi ne ( L 1 -
L 4) or t otal hi p was > 3 %, relati ve t o 
t he pi v otal p hase 3 st u d y baseli ne.  
• F or Earl y Ter mi nati o n occ urri n g b et wee n 
Wee k 5 2 a n d Wee k 1 0 4:  
− o n t he m ost rece nt D X A, b o ne mi neral 
de nsit y l oss  at t he l u m bar s pi ne ( L 1 -
L 4) or t otal hi p was > 7 %, relati ve t o 
pi v otal p hase 3 st u d y b aseli ne. 
  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
1 8  
C O N FI D E N TI A L  
 
If t he patie nt e nr olls directl y i nt o a n ot her 
rel u g oli x cli nical st u d y u p o n c o m pleti o n of t he 
Wee k 1 0 4 visit, t he n t he F oll o w -U p  visit a n d 
t he f ollo w -u p pr oce d ures perf or me d u n der t his 
pr ot oc ol, t he f oll o w -u p b o ne de nsit o metr y sca n 
at 6 ( ± 1) m o nt hs ma y b e wai ve d.  
A M  3. 1  
At t he Wee k 3 6, Wee k 5 2, a n d 
Wee k 1 0 4 visits, D X A is re q uire d . 
 
• F or Earl y Ter mi nati o n occ urri n g 
bef ore Wee k 3 6, D X A is n ot 
re q uire d at t he Earl y T er mi nati o n 
visit u nless it will ai d i n t he 
assess me nt of a n a d vers e e ve nt or 
if t he m ost rece nt D X A b o ne 
mi neral de nsit y l oss at l u m bar 
s pi ne ( L 1-L 4) or t otal hi p was > 
2 % relati ve t o t he pi v otal p hase 3 
st u d y baseli ne.   
  
• F or Earl y Ter mi nati o n occ urri n g 
at or after t he Wee k 3 6 visit, D X A 
is re q uire d at E arl y Ter mi nati o n 
u nless a D X A res ult is a vaila ble 
fr o m wit hi n si x wee ks pri or t o 
Earl y Ter mi nati o n.  
P ost -Treat me nt D X A is r e q uire d at 6 m o nt hs 
( ± 1 m o nt h):  
  
• F or Earl y Ter mi nati o n occ urri n g b ef ore 
Wee k 3 6:  
− t he m ost rece nt D X A b o ne mi neral 
de nsit y l oss at l u m bar s pi ne ( L 1 -L 4) or 
t otal hi p was > 2 % rel ati ve t o t he 
pi v otal p hase 3 st u d y b aseli ne.   
• F or Earl y Ter mi nati o n occ urri n g at or aft er 
t he Wee k 3 6 visit: 
− t he m ost rece nt D X A sca n was at Wee k 
2 4 a n d o n t he m ost rece nt D X A sca n, 
b o ne mi neral de nsit y l oss at t he l u m bar 
s pi ne ( L 1-L 4) or t otal hi p was > 2 %, 
relati ve t o t he pi v otal p hase 3 st u d y 
baseli n e.  
− t he m ost rece nt D X A was after t he 
Wee k 2 4 visit a n d o n t he m ost re ce nt 
D X A sca n, b o n e mi neral de nsit y l oss at 
t he l u m bar s pi ne ( L 1-L 4) or t otal hi p 
was > 3 %, relati ve t o t he pi v otal p hase 
3 st u d y baseli ne. 
• F or patie nts w h o c o m plete t he o pe n-l a bel 
e xte nsi o n st u d y:   
− at t he Wee k 1 0 4 visit or o n t he m ost 
rece nt D X A sca n, b o ne mi neral de nsit y 
l oss at t he l u m bar s pi ne ( L 1-L 4) or 
t otal hi p was > 3 %, rel ati ve t o t he 
pi v otal p hase 3 st u d y b aseli ne. 
  
1 2 -M o nt h P ost -Treat me nt D X A:  
patie nts ha ve 6 -m o nt h p ost -treat me nt f oll o w-
u p sca ns t hat s h o w b o ne l oss of > 1. 5 % at t he 
l u m bar s pi ne a n d/ or > 2. 5 % at t otal hi p 
c o m pare d wit h t he pi v otal p hase 3 st u d y 
baseli ne, patie nts are str o n gl y e n c o ura ge d t o 
c o me bac k t o t he cli nic f or a n a d diti o na l p ost-
treat me nt f oll o w 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
19 
CONFIDENTIAL 
 
AM 4.0 
• For Early Termination occurring 
before Week 36, DXA is not 
required at the Early Termination 
visit unless it will aid in the 
assessment of an adverse event or 
if the most recent DXA BMD loss 
at lumbar spine (L1-L4) or total 
hip was > 2% relative to the 
parent study baseline.    
 
• For Early Termination occurring 
at or after Week 36, DXA is 
required at Early Termination 
unless a DXA result is available 
from within six weeks prior to 
Early Termination. 
6-month and 12-Month Post-Treatment DXA: 
• All ongoing patients, after they complete the 
Week 104 visit or terminate the study early, 
will return for a 6-month PTFU DXA and a 
12-month PTFU DXA 
• All patients who completed treatment or 
terminated from the study early and are within 
6 months from their last day on treatment will 
be requested to return for a 6month PTFU 
DXA and again for a 12-month PTFU DXA.   
• All patients who completed treatment or 
terminated from the study early and are past 6 
months but within 12 months from their last 
day on treatment will be requested to return for 
a 12-month post-treatment DXA. 
• For patients who are outside the PTFU visit 
windows, PTFU DXA is still recommended.  
However, if the patient is beyond 14 months 
from last day on treatment, she does do not 
need to return for 12-month post-treatment 
DXA. 
 
If patients have 6-month or 12-month PTFU 
scans that show bone loss of ≥ 3% at the 
lumbar spine and/or total hip compared with 
the parent study baseline, patients should be 
referred to and strongly encouraged to see a 
bone specialist for further evaluation of the 
bone loss. 
 
The 6-month and 12-month PTFU visits will also measure post-treatment medical and 
gynecological history, concomitant medications, and bone fracture events.  Patients should also 
have the following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous at the 6-month and 12-month PTFU 
visit only if PTFU scans show a bone loss of ≥ 3% at the lumbar spine and/or total hip compared 
with the parent study baseline.   
Status of menstruation recovery will be documented at the Safety Follow-Up visit.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted again by 
telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and will 
be asked about factors that may affect resumption of menses.  If a patient is lost to follow-up, 
three documented attempts should be made to contact the patient by telephone.  If unable to 
contact the patient by telephone, a certified letter must be sent to the patient. A mammogram will 
be performed at Week 52 or at Week 104/Early Termination for women who are or become ≥ 40 
years old during the study 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
20 
CONFIDENTIAL 
 
A schematic of the MVT-601-3103 study is presented in Figure 1.   
Figure 1 
MVT-601-3103 Study Schematic 
 
 
2.2. 
Sample Size Considerations 
It was estimated approximately 800 patients (67% of the total of planned 1200 patients who 
would be randomized to the pivotal phase 3 studies (MVT-601-3101 or MVT-601-3102) and had 
completed either study) were eligible and willing to participate in this extension study. 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
21 
CONFIDENTIAL 
 
3. 
PLANNED ANALYSES 
The final analysis of the data includes data through Week 104 and all post-treatment follow-up 
data. 
3.1. 
Final Analyses 
The final analyses of all efficacy and safety data from MVT-601-3103 will occur after all 
enrolled patients have either completed 80 weeks of open-label treatment with relugolix + 
E2/NETA and the 30-day safety Follow-Up visit or discontinued early from the study.  The 
results of the final analyses will be used for the final CSR for MVT-601-3103.  
3.2. 
Safety Follow-Up Analyses 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-Up visit, the date of onset of the first menstruation is recorded in the eCRF.  Patients 
whose menses has not resumed as of the Follow-Up visit for whom there is no explanation for 
the lack of resumption (eg, medical procedure or medications) will be contacted by telephone 3 
months (+ 0.5 months) after the Follow-Up visit to determine if menses has resumed and will be 
asked about factors that may affect resumption of menses.  If a patient is lost to follow-up, three 
documented attempts should be made to contact the patient by telephone.  If unable to contact 
the patient by telephone, a certified letter must be sent to the patient. 
Bone mineral density by DXA at 6-month and 12-month Post-Treatment will be proceed 
according to the rules mentioned in Section 2.1 Table 2.  The follow-up bone densitometry will 
be submitted for central reading.  
Post-treatment medical and gynecological history, concomitant medications, and bone fracture 
events will be measured at the 6-month and 12-month PTFU visits.  Patients with PTFU scan 
bone loss ≥ 3% at the lumbar spine and/or total hip compared with the pivotal study baseline will 
have the following clinical laboratory evaluations:  vitamin D, thyroid-stimulating hormone, 
parathyroid hormone, creatinine, calcium, and phosphorous.   
Data collected during the additional safety Follow-Up period that are available at the time of 
database lock for final analyses will be summarized and reported in the final clinical study 
report. 
 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
2 2  
C O N FI D E N TI A L  
 
4.  
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S  A N D 
H A N D LI N G  O F  MI S SI N G D A T A  
4. 1.  
D at a Prese nt ati o n C o n ve nti o ns  
All statistical a nal yses will be c o n d ucte d usi n g S A S ® Versi o n 9. 2  or hi g her.   O nl y des cri pti ve 
a nal ys es will be pr o vi de d .  F or mal statistical c o m p aris o n s are n ot pla n ne d.  
A ll c o nfi de nce i nter vals ( Cis) will be re p orte d as t w o -si de d 9 5 %  C is u nless ot her wise state d.  
W here a p pr o pri ate, varia bles will be s u m marize d descri pti vel y b y st u d y visit.  F or t he 
cate g orical varia bl es, t he c o u nt a n d pr o p orti o ns of eac h p ossi ble val u e will be ta b ulate d b y 
pi v otal p hase 3 st u d y tr eat me nt gr o u p.  F or c o nti n u o us varia bles, t he n u m b er of patie nts  wit h 
n o n -missi n g val ues,  me a n, me dia n, sta n dar d de viati o n (S D ), mi ni m u m, a n d ma xi m u m val ues 
will be ta b ulate d . 
U nless ot her wise s pecifie d, t he f oll o wi n g c o n v e nti o ns will be a p plie d t o all a nal ys es:  
 Mea n a n d me dia n v al ues will be f or matte d t o o ne  deci mal place , u nl ess ot her wise 
s pecifie d.  F or B M D D X A, mea n a n d me di a n val ues will be f o r matte d t o t w o deci mal 
place s.  Sta n dar d de viati o n val ues will be f or matt e d t o t w o m ore deci mal places , 
u nless ot her wise s pecifie d.   M i ni m u m a n d ma xi m u m val ues will be prese nt e d t o t he 
sa me n u m ber of d eci mal places as t he m eas ure d v al ue .  If t he m eas ure d val ue is lar ge 
(e g, >  1 0 0), fe w er deci mal place s ma y b e dis pla ye d. 
 Perce nta ges will be r o u n de d t o o ne  deci mal place . 
 P val ue s will be r o u n de d t o f o ur deci mal places .  P  val ue s <  0. 0 0 0 1 will be prese nte d 
as “ < 0. 0 0 0 1 ” a n d p  val u e s >  0. 9 9 9 9 will be pres e nte d as “ > 0. 9 9 9 9 ” . 
 1 m o nt h  =  3 0. 4 3 7 5  da ys .  M o nt h is calc ulate d as ( da ys/ 3 0. 4 3 7 5) r o u n de d t o 
o ne  deci mal place . 
 1 year  =  3 6 5. 2 5  da ys .  Y ear is calc ulate d as ( da ys/ 3 6 5. 2 5) r o u n de d t o o ne  d eci mal 
place . 
 A ge will be cal c ulate d usi n g  t he dat e of ra n d o mizati o n i n pi v otal p hase 3 st u d y.  If 
o nl y year of birt h is c ollecte d, 1 J ul y of t he year of birt h will be use d t o calc ulate a ge. 
 1 p o u n d  =  0. 4 5 4  k g . 
 1 i nc h  =  2. 5 4  c m. 
 Missi n g effi cac y or safet y dat a will n ot be i m p ute d , u nless ot her wise s pecifie d . 
 F or la b orat or y res ults a b o ve or bel o w se nsiti vit y li mits dis pla ye d as “ <”  or “ >”  a 
q ua ntificati o n t hres h ol d, 0. 0 0 0 0 0 0 0 0 0 1 will be s u btracte d or a d de d, res pecti vel y, t o 
t he t hres h ol d t o deri ve a n u meric res ult f or a nal ysis. 
 F or safet y a nal ys es, perce nta ges will be calc ulate d  base d o n  t he n u m ber of patie nts i n 
t he a nal ysis p o p ulati o n i n eac h pi v otal p has e 3 st u d y treat me nt gr o u p. 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
2 3  
C O N FI D E N TI A L  
 
 F or b y -visit o bser v e d dat a a nal yses, p erce nta ges will be calc ulate d  b ase d o n t he 
n u m ber of patie nts wit h n o n -missi n g data as t h e d e n o mi nat or , u nless ot her wise 
s pecifie d; 
 F or ot her c o nti n u o us e n d p oi nts, t he s u m mar y statistics will i ncl u de mea n, S D , 
me dia n,  mi ni m u m , a n d ma xi m u m . 
 F or ti me -t o-e v e nt e n d p oi nts, t he s u m mar y statistics will i ncl u de me di a n ti me t o 
e ve nt-free s ur vi v al, t he 2 5t h a n d 7 5 t h perce ntiles, a n d t he n u m ber of patie nts at ris k at 
s pecifie d ti me p oi nts. 
 F or cate g orical e n d p oi nts, t he s u m mar y statistics will i ncl u de c o u nts a n d perce nt a ges;  
 C o nfi de nce i nter vals  will be c o nstr ucte d at t he 9 5 % le vel .  F or bi n o mial varia bles, 
e x act met h o ds will be e m pl o ye d , u nless ot her wise s pecifie d.  
4. 2.  
A n al ysis P o p ul ati o ns   
T he pr ot oc ol s pecifie d efficac y a n d safet y a nal yses will be perf or me d o n t h e E xte nsi o n St u d y 
P o p u lati o n as defi ne d i n Secti o n 4. 2. 1 a n d Secti o n 4. 2. 2, res pecti vel y.  T h e Wee k 5 2  efficac y 
a nal ys es will i ncl u de effi cac y d ata u p t o 5 2 wee ks of treat me nt o n t he E xte nsi o n St u d y  
p o p ulati o n.  T he Wee k 5 2  safet y a n al ys es  will i ncl u de safet y dat a u p t o 5 2 wee ks  or  s afet y 
F oll o w -U p  if patie nts e arl y ter mi nated  t h e st u d y b ef ore Wee k 5 2 o n t he E xte nsi o n Safet y 
p o p ulati o n .  T h e fi nal a n al ysis  will i ncl u de efficac y d ata u p t o 1 0 4  wee ks of treat me nt  o n t he 
E xte nsi o n St u d y P o p ulati o n a n d safet y d ata u p t o safet y F oll o w -U p  o n t he E xte nsi o n Safet y 
p o p ulati o n .  
4. 2. 1.  
E xte nsi o n St u d y P o p ul ati o n  
T he E xte nsi o n St u d y p o p ulati o n is defi ne d as all p atie nts w h o e nr olle d i nt o M V T -6 0 1 -3 1 0 3 a n d 
w h o ha ve  recei v e d a n y a m o u nt of o pe n -la bel st u d y dr u g i n M V T-6 0 1 -3 1 0 3.  All efficac y  
a nal ys es will be perf or m e d o n t he E xte nsi o n St u d y p o p ulati o n,  u nless ot her wise s pecifi e d .  
Efficac y a nal ys es will be perf or me d b y treat me nt gr o u p as ra n d o mize d  i n t he pi v otal p hase 3 
st u d y.  
4. 2. 2.  
E xte nsi o n S afet y  P o p ul ati o n  
T he E xte nsi o n Safet y p o p ulati o n  is defi ne d as all e nr olle d patie nts w h o recei ve d a n y a m o u nt of 
o pe n -la bel st u d y dr u g i n M V T-6 0 1 -3 1 0 3 .  A n y patie nt w h o recei v e d at least o ne d ose of 
rel u g oli x will be c o nsi dere d as a rel u g oli x patie nt f or p ur p oses of s afet y a n al yses, c o nsiste nt wit h 
a nal ysis i n t he pi v otal p h ase 3 st u dies.  All safet y a nal ys es will be perf or m e d o n t he E xte nsi o n 
Safet y p o p ulati o n , u nless ot her wise s pecifie d .  Safet y d ata will be a n al yze d b y pi v otal p hase 3 
st u d y treat me nt gr o u p acc or di n g t o t he act ual tr eat me nt recei v e d ( n ot  t he ra n d o mize d treat me nt) 
i n pi v otal p hase 3 st u d y.   
4. 2. 3.  
E xcl usi o n of Site  
 fr o m Effic ac y a n d S afet y A n al yses  
D ue t o t he res ults of a n a u dit w hic h f o u n d  e vi de nce of data i nte grit y iss ues at t he Site  
 (i n 
st u d y M V T -6 0 1 -3 1 0 2), t he data of t hr ee p atie nt s e nr olle d i nt o t he o pe n-la bel e xte nsi o n st u d y at 
t hat site will be e x cl u de d fr o m all effi cac y a n d safet y a nal yses.  T he d ata f or t hese t hree patie nts 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7
P P D
P P D


Statistical Analysis Plan  
 
MVT-601-3103 
 
Myovant Sciences GmbH 
24 
CONFIDENTIAL 
 
will be presented in disposition table and listing, and in listing of patients excluded from efficacy 
and safety analyses. 
4.3. 
Definitions, Computation, and Convention 
4.3.1. 
Definition of Date of First Dose and Date of Last Dose of Pivotal phase 3 Study 
Drug 
The date of first dose of pivotal phase 3 study drug is defined as the date when a patient receives 
the first dose of study drug (relugolix/placebo or E2/NETA/placebo) following randomization in 
study MVT-601-3101 or MVT-601-3102.  The date of last dose of pivotal phase 3 study drug is 
defined as the date a patient receives the last dose of study drug in the pivotal Phase 3 study 
MVT-601-3101 or MVT-601-3102, prior to or on the Week 24 visit date.  The exact date of last 
dose of pivotal phase 3 study drug will be known for all patients entering the MVT-601-3103 
study.   
4.3.2. 
Definition of Date of First Dose and Date of Last Dose of Extension Study Drug 
The date of first dose of extension study drug is defined as the date when a patient receives the 
first dose of open-label study drug (relugolix or E2/NETA) in the MVT-601-3103 study.  The 
date of last dose of extension study drug is defined as the date a patient receives the last dose of 
open-label study drug in the MVT-601-3103 study.  If the complete date of last dose of extension 
study drug is unknown, the last date the extension study drug was dispensed will be used.  For 
patients missing only the day of the last dose of extension study drug, either first of the month of 
last dose of extension drug or last date extension study drug was dispensed will be used, 
whichever is later.   
4.3.3. 
Study Day 
Study day will be calculated with respect to the date of the first dose of study drug in the pivotal 
phase 3 study (Study Day 1).  For assessments conducted on or after the date of the first dose of 
pivotal phase 3 study drug, study day will be calculated as: 
(Assessment date – date of first dose of pivotal phase 3 study drug) + 1 
For assessments conducted before the date (and time) of the first dose of pivotal phase 3 study 
drug, study day will be calculated as: 
(Assessment date – date of first dose of pivotal phase 3 study drug) 
4.3.4. 
Extension Study Day 
Extension study day will be calculated with respect to the date of the first dose of open-label 
study drug in the extension study (Extension Study Day 1).  For assessments conducted on or 
after the date of the first dose of extension study drug, extension study day will be calculated as: 
(Assessment date – date of first dose of extension study drug) + 1 
For assessments conducted before the date (and time) of the first dose of extension study drug, 
extension study day will be calculated as: 
(Assessment date – date of first dose of extension study drug) 
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4.3.5. 
Definition of Overall Treatment Duration 
In the final analysis, overall treatment duration is defined as the duration of time from the date of 
the first dose of pivotal phase 3 study drug to the date of the last dose of extension study drug as 
follows:  
(Date of last dose of extension study drug – Date of first dose of pivotal phase 3 study drug) + 1 
For patients missing day and month of the last dose date of extension study drug, the last date 
extension study drug was dispensed will be used to calculate overall treatment duration.  For 
patients missing only day for date of last dose of extension study drug, the later of first of the 
month of last dose of extension drug or last date extension study drug was dispensed will be used 
to calculate treatment duration.   
4.3.6. 
Definition of Extension Study Treatment Duration 
In final analysis, extension study treatment duration is defined as the duration of time from the 
date of the first dose of extension study drug to the date of the last dose of extension study drug 
as follows:  
(Date of last dose of extension study drug – Date of first dose of extension study drug) + 1 
For patients missing day and month for date of last dose of extension study drug, the last date 
extension study drug was dispensed will be used to calculate extension study treatment duration.  
For patients missing only day for date of last dose of extension study drug, the later of first of the 
month of last dose of extension drug or last date extension study drug was dispensed will be used 
to calculate treatment duration.     
4.3.7. 
Definition of Baseline Value and Post-Baseline Value 
Unless otherwise specified, Baseline values are defined as the last measurement before the first 
administration (date and time) of study drug in the pivotal phase 3 study.  A post-Baseline value 
is defined as a measurement taken after the first administration of study drug in the pivotal phase 
3 study.  Change from Baseline is defined as (post-Baseline value – Baseline value).  Both date 
and time of study drug administration and measurement will be considered when calculating 
Baseline value.  If the time is not available, then the date alone will be used.   
4.3.8. 
Visit Windows 
Visit windows, which will be used to associate assessments with a scheduled visit, will be used 
only for summarizing data by visit.  The windows for scheduled assessments are shown in 
Table 3: 
Visit Windows for Monthly and Quarterly Assessments (Monthly and Quarterly 
Visit, Lab and PGA) (Monthly and Quarterly Visit, Lab and PGA), Table 4 (BMD), Table 5 
(electrocardiogram [ECG]), Table 6 (EHP-30), Table 7 (EHP work domain and EQ-5D-5L), 
Table 8 (PGIC), Table 9 (Endometriosis Biopsy), Table 10 (Mammogram), and Table 11 
(eDairy) respectively.  For safety assessments, the study day will be used to determine the 
associated visit window.  There will be no separation of data from the pivotal phase 3 and 
extension study.  For example, if an assessment in the extension study falls in the Week 24 visit 
window, it will be summarized as Week 24. 
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If the results from more than one assessment are within a given visit window, the non-missing 
result from the assessment closest to the target date will be used.  If two assessments are equally 
close to the target day, the earlier assessment will be used.  For summaries of shift from Baseline 
in safety parameters, all values will be considered for these analyses. 
Table 3: 
Visit Windows for Monthly and Quarterly Assessments (Monthly and 
Quarterly Visit, Lab and PGA) 
Visit 
Start Day 
Target Day 
End Day 
Week 4a 
1(2b) 
29 
43 
Week 8 
44 
57 
71 
Week 12 
72 
85 
99 
Week 16 
100 
113 
127 
Week 20 
128 
141 
155 
Week 24 
156 
169 
183 
Week 28 
184 
197 
211 
Week 32 
212 
225 
239 
Week 36 
240 
253 
267 
Week 40 
268 
281 
295 
Week 44 
296 
309 
323 
Week 48 
324 
337 
351 
Week 52 
352 
365 
411 
Week 65 
412 
456 
502 
Week 78 
503 
547 
593 
Week 91 
594 
638 
684 
Week 104 
685 
731 
Date of last dose + 6 
days  
Safety Follow-Upc 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a Start day of Week 4 for study day 1 includes only post-Baseline assessments that occurred after the first dose. 
b   For Patient Global Assessments (PGAs), the start day of the Week 4 visit window begins at Day 2. 
c The safety Follow-Up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑ pituitary‑ gonadal axis or surgical 
intervention for endometriosis-associated pain.  
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Table 4: Visit Windows for Bone Mineral Density Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 36 
197 
253 
308 
Week 52 
309 
365 
421 
Week 104 
647 
731 
815 
6-month post-treatment 
Follow-Up  
Date of last dose + 
150 days 
Date of last dose + 
180 days 
Date of last dose +  
304 days 
12-month post-
treatment Follow-Up  
Date of last dose + 
305 days 
Date of last dose + 
365 days 
Date of last dose + 
425 days 
  
Table 5: 
Visit Windows for ECG Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 52 
309 
365 
421 
Week 104 
675 
731 
787 
 
Table 6: 
Visit Windows for EHP-30 Questionnaire Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 36 
197 
253 
308 
Week 48 
309 
337 
351 
Week 52 
352  
365 
421  
Week 78 
 491 
547 
603 
Week 104  
675 
731 
787 
 
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Table 7: 
Visit Windows for EHP Work Domain and EQ-5D-5L Assessments   
Visit 
Start Day 
Target Day 
End Day 
Week 24 
128 
169 
196 
Week 52 
309 
365 
421 
Week 78 
491 
547 
603 
Week 104 
675 
731 
787 
 
Table 8: 
Visit Windows for PGIC Assessments  
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 36 
197 
253 
308 
Week 52 
309 
365 
421 
 
Table 9: 
Visit Windows for Endometrial Biopsies Assessments   
Visit 
Start Day 
Target Day 
End Day 
Week 24 
128 
169 
196 
Week 52 
309 
365 
421 
Week 104 
675 
731 
787 
Safety Follow-Up a 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a Assessments will be excluded from analysis if they occur on or after the date of initiation of another investigational 
agent or hormonal therapy affecting the hypothalamic‑ pituitary‑ gonadal axis or surgical intervention for 
endometriosis-associated pain.  Assessments after date of last dose of extension study drug + 30 days will also be 
excluded from analysis. 
 
Table 10: 
Visit Windows for Mammogram Assessments  
Visit 
Start Day 
Target Day 
End Day 
Week 52 
309 
365 
421 
Week 104 
675  
731 
787 
For patients who are or become ≥ 40 years old during the study.  
Mammogram assessments are required only by protocol amendment 3.0 and 3.1. 
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Table 11: 
Time Windows for Daily Assessments from eDiary 
Visit 
Target Study Day of Visita 
Days Included in Assessment Period Window 
Week 4 
X1 
1 to X1 
Week 8 
X2 
(X2 – 34) to ≤ X2 
Week 12 
X3 
(X3 – 34) to ≤ X3 
Week 16 
X4 
(X4 – 34) to ≤ X4 
Week 20 
X5 
(X5 – 34) to ≤ X5 
Week 24 
X6 b 
(X6 – 34) to ≤ X6 
Week 28 
X7 
Maximum [OLE start day c, (X7 –34)] to ≤ X7 
Week 32 
X8 
Maximum [OLE start day c, (X8 – 34)] to ≤ X8 
Week 36 
X9 
(X9 – 34) to ≤ X9 
Week 40 
X10 
(X10 – 34) to ≤ X10 
Week 44 
X11 
(X11 – 34) to ≤ X11 
Week 48 
X12 
(X12 – 34) to ≤ X12 
Week 52 
X13 
 (X13 – 34) to ≤ X13 
Week 65g 
X14 
(X14 – 56) to ≤ X14 
Week 78g 
X15 
(X15 – 56) to ≤ X15 
Week 91g 
X16 
(X16  – 48) to ≤ X16 
Week 104g 
X17 
(X17 - 51) to ≤ X17 
Week104/EOTe 
X17 
Maximum [OLE start day c, (X17 – 34)] to ≤ X17 or PAP f 
Abbreviation:  EOT = end of treatment, OLE = open label extension. 
Error! Reference source not found. Refer to Error! Reference source not found.Table 3 for target study day for Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 65, 78, 91, 104 and safety Follow-Up. 
b The target study day for Week 24 is defined as date of last dose of randomized study treatment in pivotal phase 3 
study.  The Week 24 assessment period is defined as the 35 days up to and including the date of last dose of 
randomized study treatment in pivotal phase 3 study, which should occur on the day prior to the Week 24 visit. 
c OLE start day = day of first dose administered of extension study treatment. 
e The target study day for Week 104/EOT for purposes of visit window calculations is defined as date of last dose of 
study treatment in the extension study.   
f If the last 35 calendar days prior to and including date of last dose of study drug are not entirely within an eDiary   
collection period, then days of the pain assessment period (PAP) will be determined as follows: (1) if the date of last 
dose occurs during the eDiary collection period, the PAP will be the last 35 days which are counted during up to  
two eDiary collection periods immediately prior to and including date of last dose of study drug (2) if the date of last 
dose occurs outside of the eDiary collection period, the PAP will be the last 35 days which are counted during up to 
two eDiary collection period(s) immediately prior to but not including date of last dose of study drug.  
g: For Week 65, Week 78, Week 91 and Week 104, only data collected within eDiary cycles required by protocol is 
included in the analysis.  
 
 
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4. 4.  
Ge ner al R ules f or Missi n g D at a  
T he r ules f or ha n dli n g missi n g data f or b y -visit e n d p oi nts a n d i nc o m plete dates ass ociate d wit h 
a d verse e ve nts a n d c o nc o mita nt me dicati o ns are disc usse d i n t his secti o n.  Ha n dli n g of missi n g 
data f or t he pri mar y effic ac y a n al ys es are descri be d i n  Secti o n  7. 2. 4 .  
4. 4. 1.  
B y -Visit E n d p oi nts  
B y -visit e n d p oi nts will be a nal yz e d usi n g o bs er ve d data, u nless ot her wise s pecifie d .  F or 
o bser ve d dat a a nal yses, missi n g data will n ot be i m p ute d a n d o nl y t he o bs er ve d rec or ds will be 
i ncl u de d. 
4. 4. 2.  
A d verse E ve nts a n d C o nc o mit a nt Me dic ati o ns  
T he f oll o wi n g i m p utati o n r ules f or t he s afet y a n al ys es will be us e d t o a d dress t he iss ues wit h 
partial dates .  T he i m p ute d dates will be use d t o deter mi ne t h e treat me nt -e m er ge nt peri o d .  F or 
a d verse e ve nts wit h a partial date, a vaila ble date parts ( year, m o nt h, a n d da y) of t he partial d ate 
will be c o m pare d wit h t h e c orres p o n di n g date c o m p o ne nts of t he start dat e a n d e n d d ate s of t he 
treat me nt-e mer ge nt peri o d  to deter mi ne if t he e v e nt is treat me nt  e mer ge nt .  W he n i n d o u bt, t he 
a d verse e ve nt will be c o nsi dere d treat me nt  e mer ge nt b y defa ult .   
T he f oll o wi n g r ules will be a p plie d t o i m p ute partial dates f or a d v erse e ve nts:  
 If start date of a n a d v erse e ve nt is partiall y missi n g, i m p ute as f oll o ws:  
 If b ot h M o nt h a n d Da y are missi n g a n d Year = Year of e xte nsi o n  st u d y tr eat me nt 
start date, t he n set t o e xte nsi o n st u d y treat me nt start date, as l o n g as a d v erse e ve nt 
e n d date is n ot pri or t o  e xte nsi o n  st u d y treat me nt start date;  
 If b ot h M o nt h a n d Da y are missi n g a n d Year ≠ Year of e xte nsi o n st u d y tr eat me nt 
start date, t he n set t o J a n uar y 1;  
 If Da y is missi n g a n d M o nt h a n d Year = M o nt h a n d Year of e xte nsi o n  st u d y 
treat me nt start date, t h e n set t o e xte nsi o n  st u d y treat me nt start date, as l o n g as 
a d verse e ve nt e n d d ate is n ot pri or t o e xte nsi o n  st u d y treat me nt start date; 
 If Da y is missi n g a n d M o nt h a n d Year ≠ M o nt h a n d Year of e xte nsi o n  st u d y 
treat me nt start date, t h e n set t o first of t he m o nt h; 
 If start date is c o m plet el y missi n g, set t o e xte nsi o n st u d y treat me nt start dat e, as 
l o n g as a d vers e e ve nt e n d date is n ot pri or t o pi v otal p hase 3 st u d y tr eat me nt start 
date.  
 If e n d dat e of a n a d vers e e ve nt is partiall y missi n g, i m p ute as f oll o ws: 
 If b ot h M o nt h a n d Da y are missi n g, the n set t o Dece m ber  3 1;  
 If o nl y Da y is missi n g, t h e n set t o last da y of t he m o nt h; 
 If e n d dat e is c o m pletel y missi n g, d o n ot i m p ute. 
W he n t he start date or e n d date of a me di cati o n is partiall y missi n g, t h e dat e will be i m p ute d t o 
deter mi ne w het h er t he m e d icati o n is pri or or c o n c o mita nt ( or b ot h).   
T he f oll o wi n g r ules will be a p plie d t o i m p ute partial dates f or me dicati o ns:  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
3 1  
C O N FI D E N TI A L  
 
 If start date of a me dicati o n is partiall y missi n g, i m p ute as f oll o ws: 
 If b ot h M o nt h a n d Da y are missi n g, t he n set t o J a n uar y 1;  
 If o nl y Da y is missi n g, t h e n set t o t he first of t he m o nt h.  
 If e n d dat e of a me di cati o n is partiall y missi n g, i m p ute as f oll o ws: 
 If b ot h M o nt h a n d Da y are missi n g, t he n set t o Dece m ber 3 1;  
 If o nl y Da y is missi n g, t h e n set t o last da y of t he m o nt h. 
If start date or e n d dat e of a me dicati o n is c o m plet el y missi n g, d o n ot i m p ut e. 
4. 5.  
H a n dli n g M ulti ple V al ues o n t he S a me D a y  
Q uesti o n n aires  
If a q uesti o n nair e (e g, P G A, P GI C, or E H P-3 0) is c o m plete d m ulti ple ti mes o n t he sa me da y, 
t he n t he q uesti o n naire assess me nt wit h the w orst sc ore will be use d f or a n al ysis.  
e Di ar y E ntries  
If t here are m ulti ple e Diar y e ntries ( N R S, s B & B) o n t he sa me da y f or a patie nt, t he n t he w orst 
sc ore (e g, hi g her p ai n sc ore) will be use d f or a n al ysis.  
If t here are m ulti ple e Diar y e ntries ( a nal gesics) re p orte d o n t he sa me da y b ut at differe nt ti me  f or 
a patie nt, t he n all pills re p orte d  at differe nt ti me will be use d f or a nal ysis . If t here are m ulti ple 
e Diar y e ntries (a n al gesics) o n t he sa me da y a n d at t he sa me ti me, t he n t he rec or d wit h t he last 
m o di fie d ti me will be use d f or t hat ti me.  
 
5.  
S T U D Y P O P U L A TI O N  
5. 1.  
S u bject Dis p ositi o n  
T he n u m ber a n d p erce nta ge of patie nts f or eac h of t he f oll o wi n g cate g ori es will be s u m marize d 
b y pi v otal p hase 3 st u d y treat me nt gr o u p i n fi nal a nal ysis: 
 All patie nts  e nr olle d  defi ne d as ta ki n g t he first d ose of st u d y dr u g  i n t he E xte nsi o n 
S t u d y; 
 Patie nts i ncl u de d i n t he E xte nsi o n St u d y p o p ul ati o n;   
 Patie nts i ncl u de d i n t he E xte nsi o n Safet y p o p ul ati o n .  
I n fi nal a nal ysis, t he n u m ber a n d perce nta ge of patie nts f or eac h of t he f oll o wi n g cate g ories will 
be s u m mariz e d b y pi v otal p hase 3 st u d y tr eat me nt gr o u p: 
 Patie nts w h o c o m plete d 5 2  wee ks treat me nt (2 4 wee ks pi v otal st u d y tr eat me nt peri o d 
a n d 2 8  wee ks o p e n -la b el treat me nt peri o d) 
 Patie nts w h o c o m plete d t he 1 0 4 wee ks of treat me nt  (2 4 wee ks pi v otal st u d y treat me nt 
peri o d a n d 8 0 w ee ks o pe n -la bel treat me nt peri o d); 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
3 2  
C O N FI D E N TI A L  
 
 Patie nts w h o disc o nti n ue d earl y fr o m t he 8 0 wee ks  o pe n -la bel treat me nt p eri o d a n d 
reas o ns f or disc o nti nuati o n ; 
 Patie nts w h o e ntere d t he B M D p ost -treat me nt F oll o w -U p  peri o d . 
5. 2.  
Pr ot oc ol De vi ati o ns  
Pr ot oc ol de viati o ns  t hat occ urre d d uri n g t he e xte nsi o n st u d y will be cate g orize d as i m p orta nt or 
mi n or per t he m ost u p date d versi o n of pr ot o c ol de viati o n pla n .  Im p or t a nt pr ot oc ol de viati o ns 
will i ncl u de, b ut will n ot be li mite d t o, t he f oll o wi n g cate g ories:  
 P atie nt treate d wit h o pe n-la bel st u d y dr u g w h o di d n ot satisf y ke y e ntr y criteria;  
 Patie nt treate d wit h o pe n -la bel st u d y dr u g w h o met wit h dra wal criteria d uri n g t he 
st u d y b ut was n ot wit h dr a w n; 
 Patie nt treate d wit h o pe n -la bel st u d y dr u g w h o recei ve d a pr o hi bite d c o n c o mita nt 
me dicati o n t hat met criteria f or a n i m p ort a nt pr ot oc ol de viati o n . 
I m p ort a nt pr ot oc ol de viati o ns will be s u m marize d b y de vi ati o n cate g or y f or a ll patie nts i n t he 
E xte nsi o n St u d y P o p ulati o n.  A patie nt listi n g of all i m p orta nt pr ot oc ol de viati o ns will be  
pr o vi de d.  
5. 3.  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d Baseli ne  c haracteristics will be s u m marize d b y pi v otal p hase 3 st u d y treat me nt 
gr o u p  in  E xte nsi o n St u d y P o p ulati o n .  Cate g orical data will be s u m marize d usi n g fre q ue n cies 
a n d perce nta ges, b y  pi v ot al p hase 3 st u d y treat me nt gr o u p a n d o verall  (see Ta ble  1 2 le 1 2).  
S u m maries of c o nti n u o us data will dis pla y t he mea n, S D , me dia n, mi ni m u m, a n d ma xi m u m .  
T he n u m bers of missi n g val ues will als o be s u m marize d.  
T a ble  1 2 : 
Cate g ories f or De m o gra p hic a n d Baseli ne C haract eristics   
V ari a ble  
C ate g or y  
A ge ( years)  
<  3 5 , ≥ 3 5   
Ge o gra p hic re gi o n  
N ort h A merica, Rest of W orl d  
Race  
Blac k  or Africa n A merica n , W hite, A merica n 
I n dia n or Alas ka Nati ve, Asia n , Nati ve Ha waiia n or 
Ot her Pacific Isla n der, Ot her   
Et h nicit y  
His pa nic or Lati n o, N ot  His pa nic or Lati n o , or  
N ot re p orte d  
B MI ( k g/ m 2)  
< 1 8. 5, 1 8. 5  t o < 2 5, 2 5 t o < 3 0, 3 0  t o <  3 5,  
3 5  t o <  4 0, ≥ 4 0  
Ti me Si nce S ur gical Dia g n osis of E n d o metri osis 
( years)  
<  5, ≥ 5  
<  2, 2 t o <  5, ≥ 5  
Alc o h ol C o ns u m pti o n Hist or y  
N o ne, M o derate, Hea v y  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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Smoking History 
Never smoker, Former smoker, Current smoker 
Analgesic Use (During Run-In Period in pivotal 
phase 3 study) 
None, Tier 1 only, Tier 2 only,  
Both Tier 1 and Tier 2 
Dysmenorrhea NRS Score  
< 7, ≥ 7  
< 4, 4 to < 7, 7 to 10 
NMPP NRS Score  
< 4, ≥ 4 
< 4, 4 to < 7, 7 to 10 
EHP-30 Pain Domain Score  
0 to < 25, 25 to < 50, 50 to < 75, 75 to 100 
Patient Global Assessments  
 
    Dysmenorrhea 
Absent, Mild, Moderate, Severe, Very Severe 
    NMPP 
Absent, Mild, Moderate, Severe, Very Severe 
    Function 
Not at all, Minimally, Moderately, significantly, 
very significantly 
    Overall Pelvic Pain 
Absent, Mild, Moderate, Severe, Very Severe 
American Fertility Society of Endometriosis 
Stage 
I Minimal; II Mild; III Moderate; IV Severe; 
Unknown/Not Available 
Bone Mineral Density 
 
    Lumbar L1-L4 
Mean (SD), median, min, max 
   Total Hip 
Mean (SD), median, min, max 
    Femoral Neck 
Mean (SD), median, min, max 
Renal Function a  
CrCl: < 60, ≥ 60 to < 90, ≥ 90 mL/min 
Abbreviations:  BMI = body mass index; CrCl = creatinine clearance; EHP-30 = Endometriosis Health Profile 
30-Item Questionnaire; NMPP = non-menstrual pelvic pain; NRS = numerical rating scale; SD = standard deviation. 
a Creatinine clearance by Cockcroft-Gault Equation = 0.85 × {(140 – age(years)) × weight(kg)}/(72 × Serum 
Creatinine(mg/dL)) for women. 
5.4. 
Medical History 
Medical history collected at the time of entry into the pivotal phase 3 study will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by system 
organ class (SOC) and preferred term (PT) for the Extension Study Population.  Additionally, 
summaries of endometriosis–specific medical history, and historic medical and surgical 
treatments collected at the time of entry into the pivotal phase 3 study will be provided.  A 
patient with multiple occurrences of medical history within a PT will be counted only once in 
that PT. 
5.5. 
Concomitant Medications 
Concomitant medications taken during the extension study treatment period and overall 
treatment period will be summarized for all patients in the Extension Safety Population by 
pivotal phase 3 study treatment group.  Medications are considered concomitant during the 
extension study if exposure starts prior to the pivotal phase 3 study and continues in the 
extension treatment period, or exposure starts during the pivotal phase 3 study and continues in 
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the extension treatment period, or exposure starts during the extension study and continues in the 
extension treatment period.  Medications are considered as overall concomitant if exposure starts 
prior to the pivotal phase 3 study, starts during the pivotal phase 3 study, or starts during the 
extension study, with exposure ending in the pivotal phase 3 study period, ending in the 
extension treatment period, or continuing after the extension treatment period.   
A patient who has been administered several medications with the same preferred medication 
name will be counted only once for that preferred medication name.   
Certain medication types will be summarized separately, including Tier 1 analgesics, Tier 2 
analgesics, all analgesics, hormonal contraceptives, estrogens, progestins, other hypothalamic-
pituitary-gonadal axis affecting drugs, calcium supplements, vitamin D supplements, and 
glucocorticoids. 
 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE 
All analyses of study drug exposure and compliance will be summarized by actual treatment 
received in the pivotal phase 3 study.  Extent of exposure to relugolix and E2/NETA during the 
extension study will be summarized for patients in the Extension Safety population.  Overall 
exposure to relugolix (with or without E2/NETA), overall exposure to E2/NETA, and overall 
exposure to any study drug (relugolix [with or without E2/NETA] and placebo) throughout the 
pivotal phase 3 study and extension study will be summarized by pivotal Phase 3study treatment 
group.  Compliance with open-label study drug during the extension study for the Extension 
Safety population will be summarized by pivotal phase 3 study treatment group.  Overall 
compliance with study drug throughout the pivotal phase 3 study and extension study will be 
summarized by pivotal phase 3 study treatment group.  Exposure to and compliance with 
relugolix and E2/NETA will be summarized separately and will be based on the drug 
accountability case report forms. 
Study drug exposure summaries will include the total dosage of relugolix and E2/NETA taken in 
milligrams and treatment duration.  Total dosage of relugolix and E2/NETA taken during the 
extension study and overall, throughout the pivotal phase 3 and extension studies, will be 
summarized by pivotal phase 3 study treatment group.  Treatment duration during the extension 
study and overall with any study drug (relugolix, E2/NETA, or placebo) will be summarized by 
pivotal phase 3 study treatment group. 
Study drug compliance will be summarized for the extension study treatment period and for the 
overall pivotal phase 3 and extension study treatment period, and will be calculated as follows: 
(total tablets taken / total tablets expected to be taken) × 100 
The total tablets taken will be calculated as:   
(total tablets dispensed - total tablets returned) 
The total tablets expected to be taken is calculated as the total number of tablets a patient is 
expected to take each day times the length of time (in days) that the patient was in the extension 
study treatment period, or throughout the pivotal phase 3 and extension study treatment period.  
Tablets that were dispensed and not returned will be assumed to have been taken.  For patients 
without dose interruption, expected number of tablets is calculated as (last dose date of any of 
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the study drug – first dose date of study drug) + 1. In the final analysis, for patients who did not 
return for their last scheduled visit, tablets that were dispensed and not returned will not be 
included in the calculation of study drug compliance.  For patients who did not return for any 
extension study visits after week 24 and did not return dispensed extension study drug, extension 
study drug compliance will not be calculated and will be categorized as “not able to calculate” in 
summaries of extension study drug compliance. 
Summary statistics of study drug compliance (eg, mean, median, etc.) will be presented, along 
with a categorical summary (eg, < 80%, 80% to 100%, > 100%). 
 
7. 
EFFICACY ANALYSES 
7.1. 
General Considerations 
Efficacy analyses will be conducted on the Extension Study Population by pivotal phase 3 study 
treatment group.  No formal treatment comparisons will be performed for this extension study.  
As there are no inferential statistics for these analyses, there is no need for multiplicity 
adjustment.  
The pivotal phase 3 study Baseline will be used as the reference point for this extension study for 
the analyses of change from baseline.  The pain scores during the Baseline Pain Assessment 
Period of the pivotal phase 3 study will establish the patient’s baseline for both the pivotal phase 
3 study and the extension study. 
For the final analyses, efficacy outputs will include all data up to Week 104. Study visits include 
each monthly visit from Week 4 to Week 52 and each quarterly visit after Week 52. 
7.1.1. 
Analyses for Categorical Data 
Qualitative variables will be summarized by frequency counts and percentages.  Unless 
otherwise specified, the calculation of proportions will include the missing category.  Therefore, 
counts of missing observations will be included in the denominator and presented as a separate 
category. 
For efficacy endpoints evaluating proportions, descriptive statistics (point estimates and 
corresponding 95% CIs) will be provided by pivotal phase 3 study treatment group and by visit 
as appropriate. 
7.1.2. 
Analyses for Continuous Data 
Continuous variables will be summarized using descriptive statistics (eg, n, mean, median, SD, 
minimum, and maximum).  For the analyses of change from Baseline, the mean at Baseline will 
be calculated for all patients with at least one post-Baseline value by pivotal phase 3 study 
treatment group.  Additionally, the mean will also be calculated for each visit, including only the 
patients who are in the analysis who have data for that visit by pivotal phase 3 study treatment 
group. 
For endpoints evaluating the change (absolute or percent change) from Baseline to Week 52 or 
Week 104/EOT, mean change as well as least squares (LS) means change and 95% CI will be 
summarized.  LS means and 95% CI will be derived using a mixed-effects model repeated 
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meas ures a p pr oac h wit h pi v otal P hase 3 st u d y ra n d o mizati o n stratificati o n fact ors, visit, 
treat me nt, a n d treat me nt-b y -visit  i nteracti o n i ncl u de d as fi x e d effects.  Here treat me nt r efers t o 
pi v otal P hase 3 st u d y treat me nt gr o u p.  T h e Baseli ne val ue will be i ncl u de d as a c o variate, a n d a n 
u nstr uct ure d varia nce -c o varia nce matri x will be ass u me d.  If t he mi x e d -effects  m o del fails t o 
c o n ver ge, a first -or der a ut ore gressi ve  v aria nce -c o varia nce matri x will be use d.  Calc ulati o n of 
t he de pe n de nt v aria ble (c ha n ge fr o m Bas eli ne) f or eac h p atie nt at eac h visit will be calc ulate d 
base d o n t he visit wi n d o ws s pecifie d i n Secti o n  4. 3. 8 .  I n a d diti o n, s u m mar y statistics ( mea n 
c ha n ge or m ea n % c ha n ge) will be gra p hi call y prese nte d as a p pr o priate.   
7. 2.  
Pri m ar y Effic ac y E n d p oi nt s 
T he pri mar y e n d p oi nts will be referre d t o as res p o n der rat es a n d d eri ve d o n t he basis of re d u cti o n 
o f pai n sc ore a n d n o i ncrease i n use of a nal gesi c me dicati o ns as rec or de d i n a dail y e Diar y  (see 
Secti o n  7. 2. 5  f or details).   
T he pri mar y effic ac y e n d p oi nt s of t he st u d y f or t h e fi nal a nal ys es are f or Wee k 5 2 a n d Wee k 
1 0 4/ E O T . 
T he pri mar y effic ac y e n d p oi nt s of t he st u d y f or t h e Wee k 5 2 a nal yses are:  
 P r o p orti o n of patie nts w h o meet t he D Y S res p o n d er criteria at t he Wee k  5 2  pai n 
assess me nt peri o d, ac hie vi n g a mea n re d u cti o n i n D Y S N R S sc ores of at least 2. 8 p oi nts 
a n d n o i ncrease i n use of a nal gesic me dicati o ns as rec or de d i n a dail y e Diar y ; 
 Pr o p orti o n o f patie nts w h o meet t he N M P P res p o n der criteria at t he Wee k 5 2  pai n 
assess me nt peri o d, ac hie vi n g a mea n re d u cti o n i n N M P P N R S sc ores of at least 2. 1 
p oi nts a n d n o i ncrease i n use of a nal gesic me dicati o ns as rec or de d i n a dail y e Diar y ; 
T he pri mar y effic ac y e n d p oi nt s of t he st u d y f or W ee k 1 0 4/ E O T are:  
 Pr o p orti o n of patie nts w h o meet t he D Y S res p o n d er criteria at t he Wee k  1 0 4/ E O T pai n 
assess me nt peri o d, ac hie vi n g a mea n re d u cti o n i n D Y S N R S sc ores of at least 2. 8 p oi nts 
a n d n o i ncrease i n use of a nal gesic me dicati o ns as rec or de d i n a dail y e Diar y ; 
Pr o p orti o n of patie nts w h o meet t he N M P P res p o n der criteria at t he Wee k  1 0 4/ E O T pai n 
assess me nt peri o d, ac hie vi n g a me a n re d u cti o n i n N M P P N R S sc ores of at least 2. 1 p oi nts 
a n d n o i ncrease i n use of a nal gesic me di cati o ns as rec or de d i n a dail y. 
7. 2. 1.  
Pri m ar y Effic ac y A n al ys is 
T he res p o n der rat e a n d t w o-si de d 9 5 % CI  will be prese nte d b y t he pi v otal p hase 3 st u d y 
treat me nt gr o u p.  N o treat me nt c o m paris o ns will be perf or me d f or t his e xte nsi o n st u d y .  F or t h e 
pri mar y a nal yse s, b ot h pri mar y e n d p oi nts will i nc or p orate t he missi n g data ha n dli n g r ules 
descri be d i n  Secti o n  7. 2. 6 . 
7. 2. 2.  
Deter mi n ati o n of t he Me a ni n gf ul C h a n ge T hres h ol ds f or t he Pri m a r y E n d p oi nts  
T he res p o n der t hres h ol d of D Y S a n d N M P P use d i n pi v otal p hase 3 st u dies will be a p plie d t o 
t his e xte nsi o n st u d y.  F or D Y S, t he res p o n der t hres h ol d was deter mi ne d as a 2. 8 -p oi nt 
i m pr o ve me nt.  F or N M P P, t he res p o n der t hres h ol d was deter mi ned as a 2. 1 -p oi nt i m pr o ve me nt.  
T he deri vati o n of t he pres pecifie d  me a ni n gf ul c ha n ge t hr es h ol ds ( M C Ts) f or t he pri mar y 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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e n d p oi nts was d o ne b y a nc h or-bas e d a nal ys es  (see A p pe n di x 3 of t he pi v otal p hase 3 st u d y 
statistical a nal ysis pla n v ersi o n 1. 2 ).  
7. 2. 3.  
D at a S o u rces S u p p orti n g Deri v ati o n of Res p o n der St at us  
T he data s o urces use d t o deter mi ne t he res p o n der stat us f or t he d ys me n orr hea a n d N M P P 
res p o n der effic ac y e n d p oi nts are liste d bel o w:  
 P atie nt re p ort of N R S pai n sc ores ( d ys me n orr hea a n d N M P P), me nstr uati o n stat us, a n d 
use of pr ot oc ol s pe cifie d a nal gesics f or pel vic pai n as ca pt ur e d i n t he e Diar y;  
 Me nstr uati o n stat us as rec or de d o n t he C R F p a ge at eac h visit.  
F urt her details of t he deri vati o n of t he res p o n der stat us f or t he pri mar y effi cac y e n d p oi nts are 
descri be d i n  t he pi v otal p hase 3 st u d y S A P v ersi o n 1. 2 Secti o n  7. 2. 5 . 
7. 2. 4.  
Defi nit i o ns Rel ate d t o N u meric al R ati n g Sc ale P ai n Sc ores a n d A n al gesic Use 
D ys me n orr he a N R S Sc ores  
D ys me n orr hea N R S pai n sc ores are pai n sc ores re p orte d i n t he e Diar y o n d a ys t hat t he p atie nt 
re p orts s he is blee di n g .  N o n -me nstr ual pel vic pai n N R S pai n sc ores ar e t h ose pai n sc ores 
re p orte d i n t he e Diar y o n da ys t hat t he p atie nt re p orts s he is n ot blee di n g . 
B aseli ne Assess me nt of N R S P ai n Sc ores a n d A n al gesic Use  
Pi v otal p hase 3 st u d y b as eli ne N R S pai n sc ores  will be use d as baseli ne N R S pai n sc ores  i n t he 
e xte nsi o n st u d y a n al ys es .  Baseli ne N R S pai n sc ores f or D Y S  a n d N M P P are t he a vera ges of t he  
res pecti ve e Diar y p ai n sc ores re p orte d d uri n g t he baseli ne pai n assess me nt peri o d .  
Pi v otal p hase 3 st u d y b as eli ne a nal gesic us e f or p el vic pai n will be use d  as baseli ne a nal gesic use 
i n t he e xte nsi o n st u d y a n al yses.  It is t he a vera ge dail y pill c o u nt as re p orte d i n t he e Diar y d uri n g 
t he pi v otal p hase 3 st u d y baseli ne pai n assess me nt peri o d.  T he b as eli ne a vera ge dail y pill c o u nt 
will be calc ulate d s e paratel y f or T ier 1 a n d Tier  2 a nal gesics.  
Wee k 5 2  a n d Wee k 1 0 4 / EO T  Assess me nt of N R S P ai n Sc ores a n d A n al gesic Use  
T he Wee k 5 2 pai n sc ores f or D Y S a n d N M P P are t he a vera ges of t he res pecti ve e Diar y p ai n 
sc ores r e p orte d d uri n g t h e Wee k 5 2 pai n assess me nt peri o d  ( P A P), defi ne d as t he last 
3 5  cale n dar da ys of e xte nsi o n st u d y treat me nt i m me diatel y pri or t o Wee k 5 2 .  F or patie nts wit h  
e xte nsi o n st u d y treat me nt d urati o n less t ha n 3 5 da ys, Wee k 5 2  P A P  is defi ne d as t he da ys 
bet wee n t he first d ose of e xte nsi o n st u d y dr u g a n d  date of last d ose of e xte nsi o n st u d y dr u g . 
Wee k  5 2 a nal gesic us e f or pel vic pai n is t he a v era ge d ail y pill c o u nt as re p orte d i n t he e Diar y 
d uri n g t he Wee k  5 2/  P A P .  T he a vera ge dail y pill c o u nt will be calc ulate d se parat el y f or Tier 1 
a n d Tier 2 a n al gesic s f or Wee k 5 2.  
Si nce e Diar y is n ot re q uire d t o re p ort o ut of t h e e Diar y c ollecti o n c ycle, ie. Wee k 5 3 - 5 7, Wee k 
6 6 - 7 0, Wee k 7 9  - 8 4 a n d Wee k 9 2 - 9 7, st u d y d a ys i n t h ose peri o ds w o ul d n ot be i ncl u de d i n 
t he Wee k 1 0 4/ E O T pai n assess me nt peri o d or a nal ges ic us e f or pri mar y e n d p oi nt s a nal yses.  
T he Wee k 1 0 4/ E O T pai n sc ores f or D Y S  a n d N M P P are t he a vera ges of t he  res pecti ve e Di ar y 
pai n sc ores r e p orte d d uri n g t he Wee k  1 0 4 / E O T P A P , defi ne d as  
 If t he last 3 5 cal e n dar da ys pri or t o a n d i ncl u di n g date of last d ose of  e xte nsi o n  st u d y 
dr u g are e ntirel y wit hi n a n e Diar y c ollecti o n peri o d, t he n t he P A P will be t he last 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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3 5  cale n dar da ys i m me di atel y pri or t o a n d i ncl u di n g t he date of last d ose of st u d y 
dr u g;  
 If t he date of last d ose occ urs o utsi de of t he e Diar y c ollecti o n peri o d  or t here are n ot 
3 5 cale n dar da y s pri or t o t he last d ose of e xte nsi o n st u d y dr u g fr o m t he e Di ar y 
c ollecti o n peri o d  t hat i ncl u des t he last d ose, t he P A P will be t he last 3 5 da ys i n t he 
e Diar y c ollecti o n  da y  o n or  pri or t o t he  last d ose of st u d y dr u g , fr o m t he last o ne or 
t w o e Diar y c ollecti o n peri o ds . 
 If t he last 3 5 cal e n dar da ys pri or t o a n d i ncl u di n g date of last d ose of st u d y dr u g are 
n ot e ntirel y wit hi n a n e Diar y c ollecti o n peri o d :  
o  if t he date of last d ose occ urs d uri n g t he e Diar y c ollecti on peri o d, t he P A P will be 
t he last 3 5 da ys w hic h are c o u nte d d uri n g u p t o t w o e Diar y c ollecti o n peri o ds 
i m me diatel y pri or t o a n d i ncl u di n g date of last d ose of st u d y dr u g 
o  if t he date of last d ose occ urs o utsi de of t he e Diar y c ollecti o n peri o d, t he P A P will 
be t he last 3 5 da ys w hic h are c o u nt e d d uri n g u p t o t w o e Diar y c ollecti o n peri o d(s) 
i m me diatel y pri or t o b ut n ot i ncl u di n g date of l ast d ose of st u d y dr u g 
Wee k  1 0 4/ E O T a nal gesi c use f or p el vic pai n is t he a vera ge d ail y pill c o u nt as re p orte d i n t he 
e Diar y d uri n g t he Wee k  1 0 4/ E O T P A P . T he a vera ge dail y pill c o u nt will be calc ul ate d 
se parat el y f or Tier 1 a n d Tier  2 a nal gesics f or Wee k  1 0 4/ E O T.  
N R S p ai n sc ores a n d an al gesic u s e d uri n g P A P of eac h of ot h er st u d y wee ks will be calc ulate d 
f or efficac y a nal ysis b y visit.  P ai n sc ores f or D Y S  a n d N M P P are t he a v era ges of t he  res p ecti ve 
e Diar y pai n s c ores re p ort e d d uri n g  eac h i n di vi d ual P A P. A nal gesic us e f or pel vic pai n is t he 
a vera ge dail y pill c o u nt as re p orte d i n t he e Di ar y d uri n g eac h i n di vi d ual P A P.  
F or Wee k 6 5, 7 8, 9 1 a n d 1 0 4 , P A P  is defi ne d as t he t otal da ys of e diar y c oll ecti o n peri o d 
i m me diatel y pri or t o res p ecti ve wee k.  F or W ee k 2 8  t o Wee k 4 8 , P A P is defi ne d as t he last 
3 5  cale n dar da ys of e xte nsi o n st u d y treat me nt i m me diatel y pri or t o res p ecti ve wee k. F or patie nts 
wit h e xte nsi o n st u d y treat me nt d urati o n less t ha n 3 5 da ys, P A P  is defi ne d as t he da ys bet w ee n 
t he first d ose of e xte nsi o n st u d y dr u g a n d d ate of l ast d ose of e xte nsi o n st u d y dr u g.Defi niti o n  of 
I ncre ase d Use of A n al gesics 
T he defi niti o n of i ncreas e d a nal gesic us e i n pi v otal p hase 3 st u dies will be a p plie d t o t his 
e xte nsi o n st u d y.  Pr ot oc ol -s pecifie d anal gesic m e dicati o ns f or e n d o metri osis-ass ociate d pai n will 
be a nal yz e d base d o n t h e f oll o wi n g  cate g ories:  
 Tier  1  
o  Ib u pr ofe n ( 2 0 0  m g)  
 Tier  2:  
o  T ra ma d ol ( 3 7. 5 m g)/ P araceta m ol ( 3 2 5  m g)  
o  T ra ma d ol ( 5 0 m g)  
o  C o dei ne ( 3 0  m g)  
o  C o dei ne ( 3 0  m g)/ P aracet a m ol ( 3 0 0  m g)  
o  C o dei ne ( 3 0  m g)/ P aracet a m ol ( 5 0 0  m g)  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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o  C o dei ne ( 1 5  m g)/ P aracet a m ol ( 5 0 0  m g)  
o  H y dr oc o d o ne ( 5  m g)/ P araceta m ol ( 3 2 5  m g)  
T he Tier  2 a n al gesics prescri be d f or us e i n t he st u d y was c o u ntr y s pecific.  Patie nts will rec or d 
t heir use of t hese m e dicati o ns i n an  e Diar y e v er y d a y u ntil Wee k 5 2  a n d aft er Wee k 5 2 , e Di ar y 
sc ores will be e ntere d o v er f o ur e Diar y c ollecti o n c ycle s o n f oll o wi n g sc he d ules: Wee k 5 7 t o t he 
Wee k 6 5 visit, Wee k 7 1 t o t he Wee k 7 8 visit, Wee k 8 5 t o t he Wee k 9 1 visit, a n d Wee k 9 8 t o  t he 
Wee k 1 0 4 visit .  T his will  i ncl u de t he i nf or mati o n o n me dicati o n na me, d os a ge, usa ge of 
me dicati o n (e g, f or e n d o metri osis -ass ociate d pel vic pai n or n ot), a n d t otal n u m ber of pills ta ke n.  
T he perce nt c h a n ge i n a n al gesic use bet w ee n t he pi v otal p hase 3 st u d y b aseli ne a n d Wee k  5 2 will 
be calc ul ate d a s a bs ol ute c ha n ge i n a n al gesic use fr o m pi v otal p hase 3 st u d y bas eli ne t o Wee k  5 2  
di vi de d b y pi v otal p hase 3 st u dy  baseli ne a nal gesi c use. T he p erce nt c ha n ge i n a nal gesic us e 
bet wee n t he pi v otal p h ase 3 st u d y b aseli ne a n d W ee k  1 0 4/ E O T will be calc ulate d as a bs ol ute 
c ha n ge i n a n al gesic use fr o m pi v otal p hase 3 st u d y b as eli ne t o Wee k  1 0 4/ E O T di vi de d b y pi v otal 
p hase 3 st u dy  b aseli ne a n al gesic use.  F or t he pri m ar y e n d p oi nts of D Y S a n d N M P P, patie nts 
will be c o nsi dere d as n o n -res p o n ders if t he y ha v e a n i ncrease i n res c ue a nal gesic us e as s pecifie d 
i n T a ble 1 3 . 
T a ble  1 3 : 
Effect of Pr ot oc ol -S pecific A n al gesic Me dic ati o n Use f or E n d o metri osis -
Ass oci ate d P ai n o n Res p o n der St at us  at Wee k 5 2, Wee k 1 0 4/ E O T  
A n al gesic Use f or E A P at 
Pi v ot al p h ase 3 st u d y 
B aseli ne  
Tier 1 A n al gesic 
Use f or E A P   
 
Tier 2 A n al gesic Use 
f or E A P 
A n al gesic Res p o n der 
St at us a 
Missi n g all e Di ar y d at a d uri n g e xte nsi o n st u d y  
n/a  
n/a  
 
n/a  
Baseli ne/ Wee k 2 4 
a nal gesic res p o n der 
stat us fr o m pi v otal 
p hase 3 st u d y  
A t le ast o ne e D air y d at a d uri n g e xte nsi o n st u d y 
N o a nal gesic use  
A n y use  
O R  
A n y use  
N o n -res p o n der 
 
N o use  
A N D  
N o use  
Res p o n der  
Use d Tier  1 a nal gesic o nl y  
Use i ncrease d >  1 5 % 
fr o m baseli ne 
A N D  
N o use or a n y use  
N o n -res p o n der 
A n y use  or n o use  
A N D  
A n y use  
Use st o p pe d, decrease d , 
or sta ble  
A N D  
N o use  
Res p o n der  
Use d Tier  2 a nal gesic o nl y  
A n y use or n o us e  
A N D  
Use i ncrease d >  1 5 % 
fr o m baseli ne 
N o n -res p o n der 
A n y use  
A N D  
Use is sta ble  
N o us e  
A N D  
Use st o p pe d, 
decrease d , or sta ble  
Res p o n der  
Starte d  use  
A N D  
Use st o p pe d or 
decrease d  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
4 0  
C O N FI D E N TI A L  
 
A n al gesic Use f or E A P at 
Pi v ot al p h ase 3 st u d y 
B aseli ne  
Tier 1 A n al gesic 
Use f or E A P   
 
Tier 2 A n al gesic Use 
f or E A P 
A n al gesic Res p o n der 
St at us a 
Use d Tier  1 a n d Tier  2 
a nal gesics  
Use i ncrease d > 1 5 % 
fr o m baseli ne 
A N D  
Use sta ble or 
i ncrease d > 1 5 % 
fr o m baseli ne 
N o n -res p o n der 
Sta ble use  
A N D  
Use i ncrease d >  1 5 % 
fr o m baseli ne 
Use d ecrease d  
A N D  
Use i ncrease d >  1 5 % 
fr o m baseli ne 
Use st o p pe d  
A N D  
Use i ncrease d >  1 5 % 
fr o m baseli ne 
Use d Tier  1 a n d Tier  2 
a nal gesics  
Use i ncrease d > 1 5 % 
fr o m baseli ne 
A N D  
Use st o p pe d or 
decrease d  
Res p o n der  
S ta ble use  
A N D  
Use st o p pe d , 
decrease d , or sta ble 
Use d ecrease d  
A N D  
Use st o p pe d, 
decrease d , or sta ble 
Use st o p pe d  
A N D  
Use st o p pe d , 
decrease d , or sta ble 
A b bre viati o ns:   E A P  =  e n d o metri osis -ass ociate d pai n; E O T  =  e n d of treat me nt.  
a N o n -res p o n der = patie nt will be c o nsi dere d a n o n-res p o n der f or eac h of t he pri mar y e n d p oi nts; Res p o n der = 
patie nt ma y be classifie d as a r es p o n der f or t he d ys me n orr hea or n o n -me nstr ual pel vic pai n pri mar y e n d p oi nts if 
t here is als o a s ufficie nt re d ucti o n in d ys me n orr hea or n o n -me nstr ual pel vic pai n (as deter mi ne d b y t he a p pr o priate 
res p o n der t hres h ol d), res pecti vel y, fr o m b aseli ne t o Wee k 5 2 , or t o Wee k 1 0 4 / E O T. 
7. 2. 5.  
Defi niti o n of Res p o n der at  Wee k 5 2  a n d  Wee k 1 0 4 /E O T  
A D Y S  res p o n der is defi n e d se paratel y f or Wee k  5 2  a n d Wee k 1 0 4 / E O T.  A D Y S res p o n der is 
defi ne d as a  patie nt wit h data t hat satisfies eac h of t he f oll o wi n g:  
 ha d a re d u cti o n i n a vera ge D Y S N R S pai n sc ore fr o m pi v otal p hase 3 st u d y baseli ne 
of at least 2. 8  p oi nts , or ha d a D Y S N R S pai n sc ore ≤ 0. 1 at Wee k 5 2 or Wee k 
1 0 4/ E O T if t he pi v otal p hase 3 st u d y b aseli ne D Y S pai n sc ore was l ess t ha n 2. 8;  
 di d n ot ha ve a n i ncrease i n t he use of res c ue a nal gesic me dicati o ns f or e n d o metri osis -
ass ociate d pai n c o m pare d wit h pi v otal p hase 3 st u d y bas eli ne use ( T a ble  1 4 ) at Wee k 
5 2 or Wee k 1 0 4/ E O T . 
A n N M P P res p o n der is d efi ne d se p aratel y f or Wee k  5 2 a n d Wee k 1 0 4/ E O T.  A n N M P P 
res p o n der is define d  as a patie nt wit h data t hat satisfies  eac h of t he f oll o wi n g:  
 ha d a re d u cti o n i n a vera ge N M P P N R S pai n sc ore fr o m baseli ne of at least 2. 1  p oi nts , 
or ha d a N M P P N R S pai n  sc ore ≤ 0. 1 at Wee k 5 2 or Wee k 1 0 4/ E O T if t he pi v otal 
p hase 3 st u d y b aseli ne N M P P pai n sc ore was less t ha n 2. 1;  
 di d n ot ha ve  a n i ncrease i n t he use of res c ue a nal gesic me dicati o ns f or e n d o metri osis -
ass ociate d pai n c o m pare d wit h pi v otal p hase 3 st u d y bas eli ne use  (T a ble  1 5 ) at Wee k 
5 2 or Wee k 1 0 4/ E O T . 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
4 1  
C O N FI D E N TI A L  
 
T he re d u cti o n fr o m baseli ne i n D Y S  or N M P P pai n sc ores at Wee k 5 2, or Wee k 1 0 4 / E O T will 
be calc ul ate d  se paratel y as t he a bs ol ute differe n ce bet wee n t he res pecti ve a vera ge p ai n sc ore at 
Wee k 5 2,  or  Wee k 1 0 4 / E O T a n d t he a v era ge pai n sc ore at pi v otal p has e 3 st u d y baseli ne.   
Acc or di n g t o t he des cri pti o n gi ve n a b o v e, patie nts w h o ha ve a n a vera ge b aseli ne D Y S or N M P P 
sc ore s maller t h a n t he c orres p o n di n g mea ni n gf ul c ha n ge t hr es h ol d ma y still be classifie d as a 
res p o n der if t h eir a verage pai n sc ore at Wee k 5 2, or Wee k 1 0 4 / E O T is n o m ore t ha n 0. 1.  T his 
c o n diti o n is strict a n d ca n o nl y be met w he n nearl y all dail y pai n sc ores fr o m t he assess me nt 
peri o d are 0, wit h t he ver y fe w re mai ni n g d ail y p ai n sc ore(s) b ei n g mi ni mal.  
T he res p o n der st at us f or D Y S  or N M P P at Wee k 5 2, Wee k 1 0 4 / E O T will be assesse d b ase d o n 
t he re d ucti o n fr o m pi v otal p hase 3 st u d y b aseli ne i n a vera ge pai n sc ores  (ie, w het her t here is a 
re d ucti o n of at least t he mea ni n gf ul c ha n ge t hres h ol d as descri be d a b o ve), c ha n ge fr o m pi v otal 
p hase 3 st u d y b aseli ne i n use of res c ue a n al gesic me dicati o ns, c o m plia nce wit h e Diar y e ntr y o v er 
t he Wee k 5 2, Wee k 1 0 4 / E O T pai n assess me nt peri o d, a n d me nstr uati o n stat us per t he eC R F.  
F urt her details of t he deri vati o n of res p o n der stat us are gi ve n i n Secti o n  7. 2. 6 . 
7. 2. 6.  
Deri v ati o n of Res p o n der St at us at Wee k 5 2 , W ee k 1 0 4/ E O T  a n d Missi n g D at a 
H a n dli n g R ules  
F or t he pri mar y efficac y a nal ysis, b ot h pri mar y e n d p oi nts will i nc or p orate t he missi n g data 
ha n dli n g r ules at Wee k 5 2, Wee k 1 0 4 / E O T as f oll o ws (Ta ble  1 4 , T a ble  1 5  a n d Fi g ure  2 ): 
 F or p atie nts missi n g e Di ar y f or all visits  i n t he e xte nsi o n st u d y, t heir B aseli ne/Wee k 2 4 
res p o n der stat us fr o m t he pi v otal p hase 3 st u d y will be carri e d o ver as t heir res p o n der 
stat us t o Wee k 5 2,  Wee k 1 0 4/ E O T .     
 F or patie nts w h o h a ve a n y pai n sc or e e ntries i n e Diar y i n t he e xte nsi o n st u d y, res p o n der 
stat us f or D Y S a n d N M P P will be deri ve d as f oll o ws:  
 F or D Y S , t he res p o n der stat us will be defi ne d usi n g t he f oll o wi n g r ul es ta ki n g 
a nal gesic use i nt o c o nsi d erati o n ( Ta bl e  1 4 ): 
 If t here are at least 2 da ys of D Y S  N R S sc ores re p orte d i n t he e Diar y, t he n t he 
a vera ge will be calc ulate d a n d use d i n t he assess me nt of t he D Y S  res p o n d er 
stat us.  Re q uiri n g a mi ni m u m of  2  da ys of D Y S  N R S sc ores is c o nsi dere d 
reas o na bl e si nce a t y pical me nstr ual c ycle h as  blee di n g d a ys ra n gi n g fr o m 3 t o 
7  da ys.  
 If t here are < 2 da ys of N R S sc ores f or D Y S  re p orte d i n t he e Diar y, t he n t h e 
f oll o wi n g sce nari os will be c o nsi dere d: 
 If n o D Y S  sc ores are re p orte d i n t he e Diar y, t he n t he data c ollect e d o n t he 
me nstr uati o n eC R F will  be c o nsi dere d as f oll o ws:  
o  If n o me nstr uati o n is re p orte d o n t he eC R F, t he n t he a vera ge D Y S  sc ore 
will be set as 0;  
o  O t her wise, if a n y me nstr uati o n da ys are re p ort e d o n t he eC R F, t he n t he 
a vera ge D Y S  sc ore will be set as missi n g a n d will be i m p ute d usi n g a 
mi x e d -effects m o del.  
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
4 2  
C O N FI D E N TI A L  
 
 If o nl y  o n e D Y S  sc ore is re p orte d i n t he e Diar y, t h e n t he data c ollecte d o n t he 
me nstr uati o n eC R F will be c o nsi dere d as f oll o ws:  
o  If n o m ore t ha n o ne me nstr uati o n da y is r e p orte d o n t he eC R F, t he n t he 
o bser ve d D Y S  sc ore will be ta ke n as t he a vera ge D Y S  sc ore; 
o  If m ore t ha n o n e me nstr uati o n da y is r e p orte d o n t he eC R F, t he n t he 
a vera ge D Y S  sc ore will be c o nsi dere d missi n g a n d will be i m p ute d usi n g a 
mi x e d -effects m o del.  
 F or N M P P, t he res p o n d er stat us will be defi ne d usi n g t he f oll o wi n g r ules, ta ki n g 
a nal gesic use i nt o c o nsi d erati o n ( Ta bl e  1 5 ): 
 If t here are at least 1 4 da ys of sc ores f or N M P P re p orte d i n t he e Diar y, t he n t he 
a vera ge N M P P sc ore will be use d i n t he assess me nt of t he N M P P res p o n der 
stat us.  Re q uiri n g mi ni m u m 1 4 da ys o f N M P P sc ores is c o nsi dere d reas o n a ble 
si nce t his c orres p o n ds t o at least half of t he n o n-m e nstr ual da ys fr o m a t y pi cal 
2 8 -da y me nstr ual c ycle.  
 If t here are less t ha n 1 4 d a ys of N M P P sc ores i n t h e e Diar y, t h e n t he a v era ge 
N M P P sc ore will be c o nsi dere d miss i n g a n d will be i m p ute d usi n g pre dicte d 
val ues fr o m a mi x e d -effects m o del.  
T a ble  1 4 : 
Missi n g D at a H a n dli n g R ules f or A ver a ge D ys me n orr he a N R S Sc ore at 
Wee k 5 2, Wee k 1 0 4 / E O T  
N u m ber of D a ys 
wit h D Y S  Sc ores 
Re p orte d i n e Di ar y  
M e nstr u ati o n St at us per 
eC R F  
A ver a ge D Y S Sc ore 
St at us  
Res p o n der St at us a 
Missi n g all e Di ar y d at a d uri n g e xte nsi o n st u d y  
n/a  
n/a  
n/a  
Baseli ne/ W ee k 2 4 res p o n der 
stat us fr o m pi v otal p hase 3 st u d y 
H a vi n g a t le ast o ne e Di a r y  d at a d uri n g e xte nsi o n st u d y  
≥ 2 da ys  
n/a  
O bser ve d  
Base d o n o bser ve d c ha n ge fr o m 
baseli ne a n d a nal gesic use  
1 da y  
N o m ore t ha n 1  
me nstr uati o n da y re p orte d  
O bser ve d  
Base d o n o bser ve d c ha n ge fr o m 
baseli ne a n d a nal gesic use  
M ore t ha n 1  me nstr uati o n 
da y re p orte d  
Missi n g (t o be i m p ute d 
fr o m mi xe d-effects 
m o del)  
Base d o n i m p ute d c ha n ge fr o m 
baseli ne a n d a nal gesic use  
0 da ys  
N o me nstr uati o n da ys 
re p orte d 
Assi g ne d as 0  
Base d o n c ha n ge fr o m baseli ne 
a n d a nal gesic use  
At least 1  me nstr uati o n da y 
re p orte d 
Missi n g (t o be i m p ute d 
fr o m mi xe d-effects 
m o del)  
Base d o n i m p ute d c ha n ge fr o m 
baseli ne a n d a nal gesic use  
A b bre viati o ns:   e C R F  =  electr o nic case re p ort f or m; e Diar y  =  electr o nic diar y; n/a  =  n ot a p plica ble.  
a    Deter mi ne d b y c o m pari n g t he o bser ve d ( or i m p ute d) c ha n ge fr o m baseli ne t o t he res p o n der  t hres h ol d a n d b y 
e xa mi nati o n of c ha n ge fr o m baseli ne i n a nal gesic use.  
 
 
 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
 
Table 15: 
Missing Data Handling Rules for Average Non-Menstrual Pelvic Pain NRS 
Score at Week 52, Week 104/EOT 
Number of Days with 
NMPP Scores 
Reported in eDiary 
Average NMPP Score Status 
Responder Statusa 
Missing all eDiary data during extension study 
n/a 
n/a 
Baseline/Week 24 responder status from pivotal 
phase 3 study 
At least one eDiary data during extension study 
≥ 14 days 
Observed 
Based on observed change from baseline and 
analgesic use 
< 14 days 
Missing (to be imputed from 
mixed-effects model) 
Based on imputed change from baseline and 
analgesic use 
Abbreviations:  eDiary = electronic diary; n/a = not applicable; NMPP = non-menstrual pelvic pain. 
a   Determined by comparing the observed (or imputed) change from baseline to the responder threshold and by 
examination of change from baseline in analgesic use. 
Figure 2: 
Visual Depiction of the Missing Data Handling Rules and Determination of 
Responder Status for the Primary Efficacy Endpoints 
 
Abbreviations:  CRF = case report form; DYS = dysmenorrhea; EOT = end of treatment; NMPP = non-menstrual 
pelvic pain. 
T represents the responder threshold (-2.8 for dysmenorrhea and -2.1 for NMPP) determined from the anchor-based 
analyses. 
 
7.2.7. 
Mixed-Effects Model for Imputing Missing or Partially Missing Pain Scores at 
Week 52 and Week 104/EOT 
For the primary analysis in the final analysis, patients with missing pain scores at Week 52, 
Week 104/EOT will be identified separately for DYS and NMPP, per the missing data handling 
rules described above.  For imputing missing data for the primary analysis of each primary 
endpoint, a mixed-effects model approach will be used to derive predicted average pain scores, 
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as the mixed-effects approach may better describe the effects of a hormonal treatment (such as 
suppression of the hypothalamic-pituitary-ovarian axis by gonadotropin-releasing hormone 
(GnRH) receptor antagonists) than other imputation methods, such as multiple imputation. 
Specifically, a mixed-effects model with repeated measures of average pain scores at multiple 
time points will be fitted to predict change in average pain scores from baseline (as a dependent 
variable) through the fixed-effects associated with covariates (ie, stratification factors of years 
since endometriosis diagnosis at pivotal phase 3 study baseline and geographic region, visit, 
treatment,  treatment-by-visit interaction, pivotal phase 3 study baseline average NRS score,) and 
random effects (from the individual patients).  Here treatment refers to pivotal Phase 3 pivotal 
phase 3 study treatment group.  In this model, an unstructured variance-covariance matrix is 
assumed for each patient. If the mixed-effects model fails to converge, a first-order 
autoregressive variance-covariance matrix will be used. Multiple time points at Weeks 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 65, 78, 91, 104 and 104/EOT will be used for the analyses. 
Sample SAS code is provided below for illustration.  The specification of type=UN implements 
unstructured variance-covariance matrix for an individual patient with multiple measures of 
average pain scores.  If the model fails to converge, then variance-covariance matrix structure 
will be specified as first-order autoregressive (ie, AR(1)).  
BASE is the pivotal phase 3 study baseline pain score; CHG_NRS is change in average pain score from pivotal 
phase 3 study baseline to Week 104/EOT as the dependent variable; DXYRS is a randomization stratification factor 
(years since endometriosis diagnosis: < 5 versus ≥ 5); PID is patient identification number; REGION is a 
randomization stratification factor (North America versus rest of world); TRT is pivotal phase 3 study treatment 
group (relugolix + E2/NETA, relugolix + delayed E2/NETA, placebo); VISIT is visit time point. 
Applying this model over the observed longitudinal average NRS score data, the fixed-effects 
will be estimated and the relationship of change in average NRS scores from pivotal phase 3 
study baseline with the covariates will be characterized by the fitted model.  From the fitted 
model, the change in average NRS scores (whether missing or not) will be predicted for each 
patient at each visit and in a particular stratum.  The imputed average NRS scores at Week 52 or 
Week 104/EOT will be obtained by adding the pivotal phase 3 study baseline average NRS 
scores to the difference. 
Since the purpose of using the mixed-effects model is to impute the missing average NRS scores 
identified at Week 52 or Week 104/EOT as described above, the predicted average NRS scores 
from the model at the corresponding Week 52 or Week 104/EOT visit (at which the missing 
average NRS scores are identified) will be used in the determination of responder status.  For 
patients without the need for imputation, their responder status will be derived based on the 
observed data according to the algorithms laid out in Figure 2. 
This imputation approach is consistent with the definition of responder at Week 52, Week 
104/EOT for the primary endpoints. 
proc mixed data=NRS_dataset method=REML covtest; 
class PID DXYRS REGION VISIT TRT; 
model CHG_NRS = DXYRS REGION BASE VISIT TRT VISIT*TRT/ s  outp=emmi_mixed_p covb     
outp=emmi_mixed_p covb; 
repeated VISIT / type=UN subject=PID r; 
lsmeans  VISIT*TRT; 
ods output SolutionF=mixparms CovB=mixcovb; 
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7.2.8. 
Subgroup Analyses 
Subgroup analyses of the dysmenorrhea and NMPP responder analyses at Week  104/EOT will 
be performed to assess whether responder rate is consistent across clinically important 
subgroups.  The responder rate and 95% CI may be displayed for each subgroup.  Subgroups will 
include, but will not be limited to, the subgroups outlined in Table 16. 
Table 16: 
Planned Subgroup Analyses  
Subgroup Name  
Subgroup Level 
Geographic region  
North America, Rest of World 
Age (years) 
< 35, >= 35; 
< 30, 30 to < 35, 35 to < 40, ≥ 40 
Race 
Black or African American, White 
BMI (kg/m2) at Baseline 
< 30, ≥ 30; 
< 18.5, 18.5 to < 25, 25 to < 30, 30 to < 35,  
35 to < 40, ≥ 40; 
<25, 25 to < 30, >=30   
Abbreviations:  BMI = body mass index;  
7.3. 
Secondary Efficacy Endpoints 
All secondary efficacy measures over the course of both the pivotal phase 3 and extension 
studies will be presented by the pivotal phase 3 study treatment group using descriptive statistics.  
No treatment comparisons will be performed for this extension study.    
7.3.1. 
Change from Baseline in EHP-30 Pain Domain Scores 
No imputations will be made for missing values in the EHP-30 Pain Domain scores.  
The score for an EHP-30 domain is calculated by adding the scores for individual items (each 
with five response options scored from 0 to 4) to obtain a total raw score, then dividing by the 
highest possible raw score and multiplying the result by 100 to obtain a normalized score that 
ranges from 0 to 100.  For each domain, the normalized score is: 
Normalized score = (Total raw score / Total raw score range) × 100 
The normalized score is used for analysis.  Higher scores represent a greater (ie, more negative) 
functional impact of endometriosis.   The domains are provided in Table 17.   
The mean change and percent change from pivotal phase 3 study baseline by visit of pivotal 
phase 3 study and extension study will be analyzed for pain domain and each of the non-pain 
domains (Control and Powerlessness, Social Support, Emotional Well-Being, and Self-Image).  
LS means and 95% CI are based on mixed-effects model with visit, treatment, treatment-by-visit 
interaction, region (North America, Rest of World), time since initial surgical diagnosis of 
endometriosis (< 5, >=5 years), and baseline value included as fixed effects.  The multiple visits 
for each patient are the repeated measures as random effects within each patient, and an 
unstructured covariance matrix is assumed. If the mixed-effects model fails to converge, a first-
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order autoregressive variance-covariance matrix will be used. Here treatment refers to pivotal 
phase 3 study treatment group.  
In addition, proportion of patients who are responders of EHP-30 pain domain will be 
determined and summarized by pivotal phase 3 study treatment group.  The prespecified 
clinically meaningful threshold of ≥ 20 points decrease from baseline will be used. 
Responder rate and two-sided 95% CI based on Clopper-Pearson exact binomial will be 
presented for Week 52 and Week 104.  For each question of the EHP-30 Pain Domain, the 
proportion of patients in each category at Week 52 and Week 104 will be described.  The 
percentage of patients shifting from Baseline “often/always” to post-baseline “never/rarely” will 
also be summarized for each question at Week 52 and Week 104. 
Table 17: 
Endometriosis Health Profile 30-Item Questionnaires Scores 
Domain 
Items 
Lowest and Highest Possible 
Total Raw Scores 
Total Raw Score 
Range 
Pain  
1 – 11 
0, 44 
44 
Control and Powerlessness 
12 – 17 
0, 24 
24 
Emotional Well-Being 
18 – 23 
0, 24 
24 
Social Support 
24 – 27 
0, 16 
16 
Self-Image 
28 – 30 
0, 12 
12 
7.3.2. 
Change from Baseline in Numerical Rating Scale Score for Endometriosis-
Associated Pain  
Patients assessed endometriosis-associated pain using an NRS as part of their daily eDiary 
entries.  Patients rated their worst pelvic pain in the past 24 hours on a scale from 0 to 10, with 
0 indicating no pain and 10 indicating pain as bad as you can imagine.  Patients also recorded 
whether they had menstruated in the past 24 hours.  The mean NRS score for DYS during the 
Week 52, Week 104/EOT pain assessment period is calculated as the average of the pain scores 
recorded on days for which patients reported they were menstruating.  The mean NRS score for 
NMPP during the Week 52, Week104/EOT pain assessment period is calculated as the average 
of the pain scores recorded on days on which patients reported they were not menstruating.  The 
mean NRS scores for DYS and NMPP are calculated in a similar manner during the pivotal 
phase 3 studies baseline pain assessment period. 
The mean NRS score of overall pelvic pain for Week 52 and Week 104/EOT pain assessment 
periods will be based on all pain scores recorded without regard for menstruation status.  The 
mean NRS score of dyspareunia for Week 52 and Week 104/EOT pain assessment periods will 
be based on the pain scores recorded on days when the patient reported having vaginal sexual 
intercourse. This analysis will be performed in the subgroup of patients with baseline 
dyspareunia defined as having a non-zero baseline dyspareunia score. 
The mean change and percent change of NRS score from baseline to Week 52, and to Week 
104/EOT will be presented by the pivotal phase 3 study treatment group for DYS, NMPP, 
overall pelvic pain, and dyspareunia separately. LS means and 95% CI are based on mixed-
effects model with visit, treatment, treatment-by-visit interaction, region (North America, Rest of 
World), time since initial surgical diagnosis of endometriosis (< 5, >=5 years), and baseline 
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val ue  as fi x e d effects; T h e m ulti ple visits f or eac h patie nt are t he re peate d meas ures as ra n d o m 
effects wit hi n eac h p atie nt, a n d a n u nstr uct ure d c o varia nce matri x is ass u me d.  Here treat me nt 
refers t o pi v otal p hase 3 st u d y treat me nt gr o u p.  
T he n u m ber a n d p erce nta ge  of patie nts wit h f oll o wi n g N R S cat e g ories will be prese nte d b y visit 
a n d b y t h e pi v otal p hase 3 st u d y treat me nt gr o u p f or D Y S, N M P P se paratel y.  
 < 4 vs > =  4  
 <  4, 4 - <  7, 7 –  1 0  
7. 3. 3.  
A n al gesic  use  
P r ot oc ol-s pecifie d a nal gesics (see secti o n 7. 2. 4 ) f or e n d o metri osis-rel ate d pai n will be a nal yz e d. 
Pr o p orti o n of patie nts n ot usi n g pr ot oc ol -s pecifie d o pi oi ds f or e n d o metri osis -ass ociate d pai n at 
Wee k 5 2, a n d Wee k 1 0 4/ E O T  will be prese nt e d  b y pi v otal p hase 3 st u d y tr eat me nt gr o u p a n d b y 
visit . Pr o p orti o n of patie nts n ot usi n g pr ot oc ol -s p ecifie d a n al gesics f or e n d o metri osis -ass ociate d 
pai n at Wee k 5 2,  a n d Wee k 1 0 4/ E O T  will be pres e nte d  b y pi v otal p hase 3 st u d y treat me nt gr o u p 
a n d b y visit . T w o -si de d 9 5 % CI s f or t he pr op orti o ns will be ge n erat e d base d o n Cl o p per -Pears o n 
e x act bi n o mial.  
7. 3. 4.  
C h a n ge fr o m B aseli ne i n P atie nt Gl o b al Assess me nts  
T he P G As f or o verall pel vic pai n a n d f u ncti o n i m pair me nt use  a 5-p oi nt res p o nse scale.  T o 
calc ulate c ha n ge fr o m pi v otal p hase 3 st u dies b as eli ne t o Wee k 5 2, a n d Wee k 1 0 4 , t he n u meri cal 
sc ores s h o w n i n T a bl e 1 8  Ta ble  1 will be assi g ne d t o eac h res p o nse le vel . 
T a ble  1 8 : 
P ati e nt Gl o b al Assess me nt N u mer ic al Sc o res 
F u ncti o n  
O ver all P el vic P ai n  
N u meric al  Sc ore  
N ot at all  
A bse nt  
0  
Mi ni mall y  
Mil d  
1  
M o deratel y  
M o derate  
2  
Si g nifica ntl y  
Se vere  
3  
Ver y Si g nifica ntl y  
Ver y Se vere  
4  
 
T he n u m ber a n d p erce nta ge of patie nts i n eac h se v erit y of P G A cat e g or y will be prese nte d b y 
pi v otal p hase 3 st u d y tr eat me nt gr o u p. T h e mea n c ha n ge of t otal P G A  sc ore fr o m pi v otal p hase 3 
st u d y Baseli ne will be prese nte d f or o verall pel vic pai n a n d f u ncti o n se p aratel y b y visit a n d b y 
pi v otal p hase 3 st u d y tr eat me nt gr o u p. L S mea ns a n d 9 5 % CI are b ase d o n mi x e d -effects m o del 
wit h visit, pi v otal p hase 3 st u d y treat me nt gr o u p , treat me nt-b y -visit i nteracti o n , re gi o n ( N ort h 
A merica, Rest of W orl d), ti me si nce i nitial s ur gical dia g n osis of e n d o metri osis ( < 5, > = 5 years), 
a n d baseli ne val u e  i ncl u d e d as fi x e d effects; T he m ulti ple visits f or eac h patie nt are t he re peate d 
meas ures as ra n d o m effects wit hi n eac h patie nt, a n d a n u nstr uct ure d c o vari a nce matri x is  
ass u me d.  Here treat me nt refers t o pi v otal p hase 3 st u d y treat me nt gr o u p. Least s q uare s m ea n 
a n d 9 5 % CI will be pres e nte d b y pi v otal p has e 3 st u d y treat me nt gr o u p a n d b y  visit .  T he 
cate g orical c ha n ges of a m o u nt of i m pr o ve me nt of P G A f or o verall pel vic pa i n fr o m baseli ne t o 
Wee k  5 2, a n d t o Wee k  1 0 4 will be s u m marize d b y pi v otal p hase 3 st u d y tr eat me nt gr o u p a n d b y 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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visit. Proportion of patients with PGA for function Improvement, No Change, and Worsening 
from Baseline will be presented by pivotal phase 3 study treatment group and by visit. 
7.3.5. 
Change from Baseline in Functional Impairment on sB&B Scale 
The daily eDiary completed by patients includes assessments of endometriosis-associated pain 
by the sB&B scales for DYS, pelvic pain, and dyspareunia.  The dysmenorrhea and dyspareunia 
scales have possible scores of 0 to 4, while the pelvic pain scale has possible scores of 0 to 3, as 
outlined in Table 19. 
Table 19: 
Subject Modified Biberoglu and Behrman Scales for Dysmenorrhea, Pelvic 
Pain, and Dyspareunia 
Dysmenorrhea 
Pelvic Pain 
Dyspareunia 
Numerical Score 
No pain 
No pain 
No pain 
0 
Mild 
Mild 
Mild 
1 
Moderate 
Moderate 
Moderate 
2 
Severe 
Severe 
Severe 
3 
Did not Menstruate 
-- 
No Intercourse 
4 
 
The mean sB&B for DYS during the Week 52, Week 104/EOT pain assessment period will be 
the average over the days when the DYS response was something other than “Did not 
menstruate.”  If the patient reports “Did not menstruate” for all days of the pain assessment 
period, then the mean sB&B score will be imputed as 0.   
The mean sB&B for NMPP during the Week 52, Week 104/EOT pain assessment period, 
derived from the sB&B for pelvic pain, will be the average of the scores reported for days on 
which a patient reports she did not menstruate.  Mean change of sB&B for NMPP and percent 
change from baseline will be presented by visit by treatment group. 
The mean sB&B for dyspareunia during the Week 52, Week 104/EOT pain assessment period 
will be the average over the days when the dyspareunia response was something other than “No 
intercourse.”  Mean change of sB&B for dyspareunia and percent change from baseline will be 
presented by visit by pivotal phase 3 study treatment group.  Additionally, the following will be 
summarized for patients who reported one or more day on which they had vaginal sexual 
intercourse during a given time interval; the percentage of patients whose maximum 
dysmenorrhea score was severe, moderate, mild, and none during the specified time interval; the 
percentage of patients whose maximum dysmenorrhea score was severe or moderate and mild or 
none during the specified time interval.   
The mean change and percent change of sB&B score from baseline to Week 52, and to Week 
104/EOT will be presented by visit and by the pivotal phase 3 study treatment group for DYS, 
NMPP, and dyspareunia separately.  LS means of mean change and 95% CI are based on mixed-
effects model with visit, pivotal phase 3 study treatment group, treatment-by-visit interaction, 
region (North America, Rest of World), time since initial surgical diagnosis of endometriosis (< 
5, >=5 years), and baseline value included as fixed effects.  The multiple visits for each patient 
are the repeated measures as random effects within each patient, and an unstructured covariance 
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matri x is ass u me d.  Here treat me nt refers t o pi v otal p hase 3 st u d y treat me nt gr o u p.  Least s q uare s 
mea n  a n d 9 5 % CI will be prese nte d b y pi v otal p hase 3 st u d y tr eat me nt gr o u p a n d b y visit .  
7. 3. 6.  
P ati e nt Gl o b al I m pressi o n of C h a n g e 
T he P GI Cs c o m plete d b y patie nts i ncl u des assess me nts of D Y S , N M P P, a n d d ys pare u nia use a 
7 -p oi nt res p o nse scale .  T he  f oll o wi n g p ossi ble res p o nses  are:  M uc h bett er, Better, A little 
better, T he sa m e, A little w orse, W orse, or M uc h w orse .  T he p r o p orti o n of patie nts w h o are 
better or m uc h b etter o n t he P GI C at Wee k 5 2 a n d t w o -si de d 9 5 % CI  b ase d o n Cl o p per -Pears o n 
e x act bi n o mial will be prese nte d b y pi v otal p hase 3 st u d y treat me nt gr o u p f or D Y S , N M P P, a n d 
d ys pare u nia  separ atel y.  N u m ber a n d p erce nta ge of patie nts i n s u m mar y of P GI C cate g or y  will 
be prese nt e d b y pi v otal p hase 3 st u d y treat me nt gr o u p f or D Y S , N M P P, a n d d ys pare u nia 
se parat el y. 
7. 4.  
E x pl or at or y Effic ac y E n d p oi nts  
Descri pti ve s u m maries b y  pi v otal p hase 3 st u d y tr eat me nt gr o u p a n d mea n c ha n ge fr o m baseli ne  
will be pr o vi de d f or t he f oll o wi n g e x pl orat or y e n d p oi nts.   
F or fi nal a nal ysis, t he f oll o wi n g e x pl orat or y e n d p oi nts will be assesse d:  
 C ha n ge fr o m Baseli ne t o Wee k 2 4, Wee k 5 2 , Wee k 1 0 4 i n t he E H P -3 0 scal e t otal 
sc ore 
 C ha n ge fr o m Baseli ne t o Wee k 2 4, Wee k 5 2 , Wee k 1 0 4 i n t he E H P W or k D o mai n 
sc ore 
C ha n ge fr o m Pi v otal p hase 3 St u dies Baseli ne t o Wee k 2 4, Wee k 5 2 , Wee k 1 0 4 i n 
t he E Q -5 D -5 L  
7. 4. 1.  
E x pl or at or y Effic ac y A n al yses  
E H P -3 0 T ot al Sc ore  
T he t otal sc ore f or t he E H P -3 0 q uesti o n naire will be calc ul ate d a n d a n al yz e d as a n or m alize d 
sc ore usi n g t he f or m ula a b o ve.  T o tal sc ore will be s u m marize d b y visit b y pi v otal p hase 3 st u d y 
treat me nt gr o u p.  Sc ore c ha n ge wit h 9 5 % CI fr o m pi v otal p hase 3 st u dies baseli ne t o Wee k 2 4, 
Wee k  5 2, or  Wee k  1 0 4 will be s u m marize d b y  pi v otal p hase 3 st u d y tr eat m e nt gr o u p.  
A mi x e d -effects m o del wit h re peate d meas ures will be use d t o assess t otal sc ore c h a n ge f or t he 
E H P -3 0 at W ee k 2 4, Wee k 5 2 a n d Wee k 1 0 4.  T h e m o del will ha ve baseli n e val ue, visit, 
treat me nt, treat me nt-b y -visit i nteracti o n , re gi o n ( N ort h A merica, Rest of W orl d), ti me si nce 
i nitial s ur gical dia g n osis of e n d o metri osis ( < 5, > = 5 years) i ncl u d e d as fi x e d effects . 
V isit is als o i ncl u de d i n t he m o del  as ra n d o m effect  wit hi n  eac h patie nt a n d a n u nstr uct ure d 
varia nce -c o v aria n ce matri x is ass u me d.  If t he mi xe d-effects m o del f ails t o c o n ver ge, a first -
or der a ut or e gressi ve vari a nce -c o varia nce matri x will be use d. Here treat m e nt refers t o pi v otal 
p hase 3 st u d y treat me nt gr o u p.  Least s q uare s mea n  a n d 9 5 % CI will be  prese nte d b y pi v otal 
p hase 3 st u d y treat me nt gr o u p a n d b y visit .  
E H P W or k D o m ai n  
T he sc ore f or t he 5 -ite m E H P w or k d o mai n q uesti o n naire is cal c ulate d b y a d di n g t he sc ores f or 
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individual items (each with five response options scored from 0 to 4) to obtain a total raw score, 
then dividing by 20 and multiplying the result by 100 to obtain a normalized score that ranges 
from 0 to 100.  The normalized score used for analysis is: 
Normalized score = (Total raw score / 20) × 100 
Higher scores represent a greater (ie, more negative) impact of endometriosis on work-related 
activities.  If one or more items are missing, then the score cannot be calculated for that patient 
and will be set missing. 
The normalized score for the EHP-30 work domain will be summarized by visit and by pivotal 
phase 3 study treatment group. Score change from studies baseline to Week 24, Week 52, and 
Week 104 will be summarized by pivotal phase 3 study treatment group.  
A mixed-effects model with repeated measures will be used to assess total score change for the 
EHP work domain at Week 24, Week 52 and Week 104.  The model will have baseline value, 
visit, treatment, treatment-by-visit interaction, region (North America, Rest of World), time since 
initial surgical diagnosis of endometriosis (< 5, >= 5 years) included as fixed effects.  Visit is 
also included in the model as random effect within each patient and an unstructured variance-
covariance matrix is assumed. If the mixed-effects model fails to converge, a first-order 
autoregressive variance-covariance matrix will be used. Here treatment refers to pivotal phase 3 
study treatment group.  Least square means and associated 95% CIs will be presented by 
treatment and visit. 
For each question, the proportion of patient in each category of the work domain will be 
presented at Baseline, week 24, Week 52 and Week 104 by pivotal phase 3 study treatment 
group.  Additionally, the proportion of patients shifting from “often/always” to “never/rarely” 
from Baseline to Week 24, from Baseline to Week 52, and from Baseline to Week 104 will be 
described by visit and by pivotal phase 3 study treatment group. 
 
European Quality of Life Five-Dimension Five-Level Scale 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcomes. Mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression are each assessed on a 5-level 
categorical scale.  The categorical changes of amount of improvement (1-4 categories), amount 
of deterioration (1-4 categories), or no change from baseline to Week 24, Week 52, and Week 
104 will be summarized by pivotal phase 3 study treatment group.  The EQ-5D-5L also has an 
assessment of overall health status that the patient rates on a 100-point visual analogue scale.  
The change from baseline to Week 24, Week 52, and Week 104 for the visual analogue scale 
scores will be summarized by pivotal phase 3 study treatment group. 
 
8. 
PHARMACODYNAMIC ANALYSES 
For pharmacodynamic assessment, data for the extension study consists of predose 
concentrations of serum estradiol.  The change from the pivotal phase 3 study Baseline to Week 
52 and to Week 104 in predose concentrations of serum estradiol will be summarized.  This data 
will be listed and summarized using descriptive statistics (including raw and change from pivotal 
phase 3 study Baseline to Week 52 and Week 104 by pivotal phase 3 study treatment group, and 
by visit).   
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F or p har mac o d y n a mic assess me nt, t he n u m ber a n d perce nt a ge of patie nts wit h i n di vi d ual E 2 
c o nce ntr ati o n val ues will be s u m marize d b y pi v ot al p hase 3 st u d y treat me nt gr o u p (rel u g oli x + 
E 2/ N E T A, rel u g oli x  + dela ye d E 2/ N E T A, or pl ace b o ) a n d visit acc or di n g t o t he f oll o wi n g 
cate g ories:  
 <  1 0  p g/ m L, 1 0 t o <  2 0  p g/ m L, 2 0 t o <  3 0  p g/ m L , 3 0 t o < 4 0 p g/ m L , 4 0 t o < 5 0  p g/ m L,  
5 0  t o < 6 0 p g/ m L , 6 0 t o < 7 0 p g/ m L, a n d ≥ 7 0  p g/ m L  
 < 2 0 p g/ m L, 2 0 t o < 5 0 p g/ m L, a n d ≥ 5 0  p g/ m L  
 < 2 0  p g/ m L, 2 0 t o < 6 0 p g/ m L, a n d ≥ 6 0 p g/ m L  
9.  
S A F E T Y A N A L Y S E S  
U nless ot her wise s pecifie d, s afet y a n al ys es will be c o n d ucte d usi n g t he E xte nsi o n S afet y 
P o p ulati o n  acc or di n g t o t he  act ual tr eat me nt recei ve d b y t h e patie nts  i n t he e xte nsi o n  st u d y.   
Safet y assess me nts will i ncl u de treat me nt -e mer ge nt a d ver se e ve nts, vital si g ns, cli nical 
la b orat or y tests, 1 2-le a d E C G, b o ne mi neral de nsit y wit h D X A, ma m m o gra ms (f or w o me n w h o 
are or b ec o m e ≥ 4 0 years of a ge  d uri n g t he st u d y ), a n d e n d o metrial bi o ps y.  
9. 1.  
A d verse E ve nts  
A d verse e ve nts will be c ollecte d fr o m t he ti me of t he first d ose of o pe n -la bel st u d y dr u g t hr o u g h 
t he safet y F oll o w u p visit a p pr o xi matel y 3 0 da ys after t he last d ose of o p e n -la bel st u d y dr u g (t he 
e n d of e xte nsi o n treat me nt peri o d), or t he dat e of i nitiati o n of a n ot her i n vesti gati o nal a ge nt or 
h or m o nal t hera p y or s ur gical i nter ve nti o n  affecti n g t he h y p ot hal a mic -pit uitar y -g o na d al a xis  or 
s ur gic al i nter ve nti o n f or e n d o metri osis, w hic he ver occ urs first, as als o s pecifie d i n t he Sc he d ule 
of Acti vities  i n t he st u d y pr ot oc ol Secti o n 1. 1 .  A d diti o nall y, s eri o us a d verse e ve nts r e p orte d t o 
t he i n vesti gat or after t he safet y re p orti n g p eri o d s h o ul d be re p orte d t o t he s p o ns or re gar dless of 
ca usal r elati o ns hi p t o st u d y dr u g tr eat me nt . 
Usi n g a Safet y Re p ort F or m, all seri o us a d verse e v e nts m ust be re p orte d wit hi n  2 4  h o urs of t he 
st u d y site pers o n n el’s k n o wle d ge of t he e ve nt, re gar dless of t he i n vesti gat or assess me nt of t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g.  
T he se verit y of all treat m e nt -e mer ge nt a d verse e v e nts will be e val uate d b y t he i n vesti gat or base d 
o n t he Nati o nal Ca ncer I nstit ute ’s C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E, 
v ersi o n 5. 0 date d  2 7 N o v 2 0 1 7 ), a n d will be c o de d t o preferre d ter m a n d s yste m or ga n class 
usi n g Me d D R A  2 2. 0 or hi g her.  
A t reat me nt-e mer ge nt a d verse e v e nt is defi ne d as a n y a d verse e v e nt  t hat occ urs after 
a d mi nistrati o n of t he first d ose of pi v otal p hase 3 st u d y dr u g. 
A d verse e ve nt s u m maries will be base d o n treat m e nt -e mer ge nt a d verse e v e nts  i n t he pi v otal 
p hase 3 a n d e xte nsi o n st u dies , u nless ot her wise s p ecifie d.  All a d v erse e ve nts i n t he pi v otal 
p hase 3 a n d e xte nsi o n st u dies  will be liste d i n b y -p atie nt listi n gs.  
T he f oll o wi n g t a b ular s u m maries t hat i ncl u de t he n u m ber a n d perce nt a ge of patie nts will be 
pr o vi de d:  
 O ver vie w of a d verse e v e nts ;  
 S afet y p ara meters of i nterest  
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 S afet y p ara meters of i nterest wit h first o nset d uri n g  e xte nsi o n st u d y 
 All a d verse e ve nts;  
 B y S O C  a n d P T ; 
 B y decreasi n g fre q u e nc y of P T ; 
 B y S O C , P T , a n d ma xi m u m se verit y; 
 St u d y dr u g -relate d per i n vesti gat or b y S O C  a n d P T ; 
 B y ti me t o o nset  ( Da y 1 t o Wee k 2 4, >  Wee k 2 4 t o Wee k 5 2, > Wee k 5 2 t o Wee k 
7 8, > Wee k 7 8 t o W ee k 1 0 4 , > Wee k 1 0 4)), S O C  a n d P T ;  
 E x p os ure -a dj uste d A E rate b y S O C a n d P T  
 A d verse eve nts re p orte d i n at least 5 % of p atie nts i n an y treat me nt g r o u p  
 B y decreasi n g fre q u e nc y of P T;  
 Gra de 3 or a b o ve a d verse e ve nts ; 
 B y S O C  a n d P T ; 
 B y decreasi n g fre q u e nc y of P T ; 
 St u d y dr u g -relate d per i n vesti gat or b y S O C  a n d P T ; 
 First o nset e ve nts d uri n g e xte nsi o n st u d y b y decreasi n g fre q ue n c y of P T  
 A d verse e ve nts lea di n g t o st u d y dr u g wit h dr a wal;  
 B y S O C  a n d P T;  
 B y decreasi n g fre q u e nc y of P T ; 
 A d verse e ve nts lea di n g t o d ose wit h dra wal wit h first o nset d uri n g e xte nsi o n st u d y;  
 B y S O C a n d P T;  
 B y decreasi n g fre q u e nc y of P T  
 A d verse e ve nts res ulti n g i n fatal o utc o me ; 
 B y decreasi n g fre q u e nc y of P T ; 
 Seri o us a d verse e ve nts ; 
 B y S O C  a n d P T ; 
 B y S O C, P T a n d ma xi m u m gra d e  
 B y decreasi n g fre q u e nc y of P T ; 
 B y S O C , P T , a n d relati o ns hi p t o st u d y dr u g; 
 A d verse e ve nts  of cli nic al i nterest ( A L T or A S T ≥ 3 ×  U L N) ; 
 B y S O C , P T , a n d ma xi m u m se verit y ; 
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 B y decreasi n g fre q u e nc y of P T . 
 First o nset  e ve nts d uri n g e xte nsi o n st u d y  b y P T  
 Res ol ve d w hile o n st u d y dr u g tr eat me nt (ie, pri or t o t he last d ose date)  
 A d verse e ve nts  wit h first o nset d uri n g t he e xte nsi o n st u d y ; 
 B y S O C  a n d P T;  
 B y decreasi n g fre q u e nc y of P T;  
 Seri o us a d verse e ve nts  wit h first o nset d uri n g t he e xte nsi o n st u d y;  
 B y S O C  a n d P T;  
 M o o d dis or der e ve nt  wit h first o nset d uri n g t he e xte nsi o n st u d y;  
 B y decreasi n g fre q u e nc y of P T;  
 Res ol ve d w hile o n st u d y dr u g tr eat me nt (ie, pri or t o t he last d ose date)  
 Vas o m ot or s y m pt o ms wit h First O nset D uri n g t he E xte nsi o n St u d y  
 B y S O C a n d P T;  
 B y decreasi n g fre q u e nc y of P T;  
 Res ol ve d w hile o n st u d y dr u g tr eat me nt (ie, pri or t o t he last d ose date)  
 B o ne healt h relate d e ve nts  
 B y decreasi n g fre q u e nc y of P T;  
 First o nset e ve nts d uri n g e xte nsi o n st u d y b y P T ; 
 He patic tra ns a mi nase el e vati o ns  
 B y decreasi n g fre q u e nc y of P T;  
 First o nset e ve nts d uri n g e xte nsi o n st u d y b y P T ; 
 Car b o h y drate a n d li pi d meta b olic effects  
 B y decreasi n g fre q u e nc y of P T;  
 First o nset e ve nts d uri n g e xte nsi o n st u d y b y P T ; 
9. 1. 1.  
Rel ati o ns hi p t o St u d y Dr u g  
A d verse e ve nts will be cl assifie d as  “relate d ” t o st u d y treat me nt if t he relati o ns hi p was rate d b y 
t he i n vesti gat or as p ossi bl y rel ate d or pr o ba bl y rel ate d.  A d verse e v e nts rel ate d t o a n y st u d y dr u g  
c o m p o ne nt  (rel u g oli x or place b o a n d E 2/ N E T A or place b o) will be c o nsi dere d as relate d t o st u d y 
dr u g .   
9. 1. 2.  
Se verit y of A d verse E ve nt  
Gra de 2 or hi g h er a d vers e e ve nts will be s u m mari ze d b y S O C , P T , a n d/ or ma xi m u m se verit y, 
relati o ns hi p t o st u d y treat me nt .   
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9. 1. 3.  
Seri o us A d verse E ve nt  
Seri o us a d verse e ve nts t hr o u g h o ut t he pi v otal p has e 3 a n d e xte nsi o n st u dies will be s u m marize d 
b y S O C , P T , a n d/ or ma xi m u m se verit y, relati o ns hi p t o st u d y treat me nt. 
T he data ha n dli n g c o n v e nti o ns f or a n d t he defi niti o n of a seri o us a d v erse e ve nt are disc uss e d i n 
t his secti o n.  All deat hs d uri n g t he st u d ies, i ncl u di n g t he p ost treat me nt F oll o w -U p  peri o d, a n d 
deat hs t hat res ulte d fr o m a pr ocess t hat b e ga n d uri n g t he st u d ies, s h o ul d be i ncl u de d i n t he 
a nal ysis .  F or m ore details , deat hs occ urri n g d uri n g t he f oll o wi n g ti me peri o ds or u n der t he 
f oll o wi n g c o n diti o ns s h o ul d be c o nsi dere d:  
 Deat hs occ urri n g d uri n g partici pati o n i n eit her t he pi v otal p hase 3 st u d y or e xte nsi o n 
st u d y;  
 Deat hs occ urri n g after a patie nt lea ves t he e xte nsio n st u d y, or ot her wise disc o nti n ues 
st u d y dr u g, w h et her or n ot t he patie nt c o m pletes t he st u d y t o t he n o mi nal e n d p oi nt  
will be i ncl u de d i n t he a n al ysis if deat h is re p orte d pri or t o data base l o c k  date . Deat h 
re p orte d after t h at will be sa ve d i n t he data bas e b ut will n ot be a nal yze d .    
9. 1. 4.  
A d verse E ve nt Le a di n g t o Wit h dr a w al of St u d y Dr u g  
A d verse e ve nts lea di n g t o wit h dra wal of st u d y dr u g are t h ose a d verse e ve nt s c ollecte d fr o m t he 
a d verse e ve nt  el ectr o nic case re p ort f or m (e C R F ) pa ges wit h “ dr u g wit h dr a w n”  as t he acti o n 
ta ke n wit h st u d y dr u g.   
A d verse e ve nts wit h “ dr u g wit h dra w n” as acti o n ta ke n d ue t o a n y o ne of t he c o m p o ne nts of 
st u d y dr u g will be c o nsi d ere d as l ea di n g t o wit h dra wal of st u d y dr u g.   
9. 1. 5.  
A d verse E ve nts Le a di n g t o D ose I nterr u pti o n  
A d verse e ve nts lea di n g t o d ose i nterr u pti o n are t h ose a d verse e ve nt s c ollecte d fr o m t he a d v erse 
e ve nt eC R F pa ges wit h “ dr u g i nterr u pte d”  as t heir acti o n ta ke n wit h st u d y dr u g .   
A d verse e ve nt s wit h “ dr u g i nterr u pte d” as acti o n t a ke n d ue t o a n y o n e of t h e c o m p o ne nts o f 
st u d y dr u g will be c o nsi d ere d as l ea di n g t o d ose i nterr u pti o n. 
9. 1. 6.  
A d verse E ve nts Res ulti n g i n a F at al O utc o me  
A d verse e ve nts res ulti n g i n a fatal o utc o me are t h ose a d verse e ve nt s c ollect e d fr o m t he a d v erse 
e ve nt pa ges wit h “fatal ” as t heir o utc o me .   
T he fa tal e ve nts, if a n y, will be pr o vi de d i n  a b y -s u bject listi n g. 
9. 1. 7.  
 Ot her S afet y P a r a meters of Interest  
I n a d diti o n, ot her safet y para meters of i nterest defi ne d i n Ta ble  2 0  will  be s u m marize d b y 
decreasi n g fre q ue nc y of P T  i n t he e xte nsi o n safet y p o p ulati o n.  A d diti o nall y , e v e nt of uteri ne 
blee di n g are s u m marize d i ncl u di n g Me d D R A preferre d t er ms: me n orr h a gia, met r orr ha gia, 
me nstr uati o n irre g ular, v a gi n al hae m orr ha ge, m e n o metr orr ha gia, p ol y me n orr h oea, a n d uteri ne 
hae m orr h a ge.  
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T a ble  2 0 : 
Ot her S afet y P a r a meters of I nterest  
Gr o u pi n g  
Searc h C riteria 
B o ne h ealt h relate d eve nts  Oste o p or osis/ Oste o pe nia S M Q ( br oa d)  
Fract ure (c ust o m S M Q):  All preferre d ter ms i ncl u di n g t he ter m “fract ure,” 
e xcl u di n g “ T o ot h fract ure” a n d “ Fract ure of pe nis”  
He patic tra nsa mi nase 
ele vati o n s 
Dr u g -relate d he patic dis or ders –  c o m pre he nsi ve  S M Q ( narr o w)  
Car b o h y drate a n d li pi d 
meta b olic effects   
D ysli pi de mia S M Q  
H y per gl yce mia/ ne w o nset dia betes mellit us S M Q ( narr o w)  
Vas o m ot or s y m pt o ms 
T he f oll o wi n g fi ve P referre d T er ms will be i ncl u de d:  
 
H y per hi dr osis  
 
Feeli n g h ot  
 
H ot fl us h  
 
Ni g ht s weats  
 
Fl us hi n g  
M o o d dis or ders  
Me d D R A De pressi o n a n d S uici de/ Self -I nj ur y S M Q ( br oa d)   
A b bre viati o ns:  Me d D R A  = Me dical Dicti o nar y f or Re g ul at or y Acti vities ; S M Q  = Sta n dar di ze d Me d D R A Q uer y .   
 
9. 1. 8.  
E x p os ure -a dj uste d A d verse E ve nts  
A d verse e ve nts b y ti me t o o nset a n d a n e x p os ure -adj uste d a d verse e ve nt a nal ysis will be 
pr o vi de d .  T he e x p os ure -a dj uste d a d verse e ve nt rate will be s u m marize d b y s yste m or ga n  class 
a n d preferre d ter m f or eac h  pi v otal p hase 3 st u d y treat me nt gr o u p , w here t h e e x p os ure-a dj uste d 
a d verse e ve nt r ate is calc ulate d as n u m ber of p atie nts wit h a partic ular a d v erse e ve nt b y t otal 
e x p os ure-ti me a m o n g p atie nts at ris k of a n i nitial occ urre nce of t he e v e nt.  E x p os ure -ti me is 
deri ve d as e x p os ure t o a n y st u d y dr u g t hr o u g h o ut t he pi v otal p hase 3  st u dies a n d e xte nsi o n 
st u d y. 
9. 1. 9.  
A d verse E ve nts  of Cli nic al I nterest  
A d verse E v e nt s of cli nic al i nterest i n t he pi v otal p hase 3 st u dies a n d the e xte nsi o n st u d y are 
defi ne d as a n y i ncrease i n A L T or A S T ≥ 3 x  U L N , w hic h are re p orte d as “ Yes” f or a d v erse 
e ve nts of cli nical i nterest i n t he a d verse e ve nt C R F. A d verse e v e nts of cli nical i nterest will be 
s u m marize d b y P T.  
9. 2.  
L a b or at or y D at a  
La b orat or y p ara m eters, i ncl u di n g c h e mistr y a n d h e mat ol o g y p a nels, a n d h or m o nal tests  s pecifie d 
as per pr ot oc ol  f or t he pi v otal p hase 3 a n d e xt e nsi o n st u dies , a n d c ollecte d fr o m t he ce ntr al 
la b orat or y wi ll be ta b ulat e d a n d pres e nte d i n b y-p atie nt listi n gs .  E x ce pt f or t he ta bles usi n g pre -
defi ne d t hres h ol d f or c he mistr y a n d he m at ol o g y  p ara meters , l ocal la b orat ory  para meters will n ot 
be prese nt e d i n ta bles.  T he l ocal la b orat or y para meters will be pres e nte d i n b y -patie nt listi n gs . 
Uri nal ysis a n d he patitis vir us ser ol o gi cal test res ults will be pr o vi de d i n b y -patie nt listi n g o nl y.   
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For patients with incomplete recovery of bone mineral density loss at the 6- and 12-month post-
treatment Follow-Up visit, clinical laboratory tests specified in the protocol should be performed.  
These laboratory assessments will be submitted to the central laboratory.  If these laboratory 
assessments are scheduled to occur after the study database is locked, they will be performed at a 
local laboratory.  
The National Cancer Institute CTCAE Grading Scale with numeric component will be used to 
categorize toxicity grade for laboratory parameters (CTCAE v5.0, dated 27 Nov 2017).  
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 (ie, low and high) if she has laboratory values meeting each 
criterion.  Shift tables will be provided for each parameter gradable by the CTCAE to summarize 
Baseline toxicity grade versus worst post-Baseline toxicity grade throughout the pivotal phase 3 
and extension studies.  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 post-Baseline results throughout the pivotal phase 3 and 
extension studies. A shift table for selected parameters based on predefined categories will be 
provided to summarize baseline category versus post-baseline category at Week 104. The 
parameters include glucose (< 100 mg/dL, 100 - 125 mg/dL, 126 - 200 mg/dl, > 200 mg/dL), 
fasting glucose (< 100 mg/dL, 100 - 125 mg/dL, 126 - 200 mg/dl, > 200 mg/dL), HbA1c (<= 
5.6%, 5.7% - 6.4%, 6.5% - 8.0%, 8.1% - 9.4%, 9.5% - 11%, > 11%), low density cholesterol 
(normal <100 mg/dL, normal high 100 to < 130 mg/dL, borderline high 130 to < 160 mg/dL, 
high 160 to < 190 mg/dL, very high >= 190 mg/dL), high density cholesterol (< 40 mg/dL, 40 - 
59 mg/dL, >= 60 mg/dL), triglycerides (< 150 mg/dL, 150 - 300 mg/dL, 301 - 500 mg/dL, 501 - 
1000  mg/dL, > 1000 mg/dL)  and total cholesterol (<= ULN, > ULN - 300 mg/dL, > 300 - 400 
mg/dL, > 400 - 500 mg/dL, > 500 mg/dL).  
Boxplots of laboratory values over time, including visits in both the pivotal phase 3 study and 
extension study, will be plotted for key laboratory parameters.  These laboratory parameters 
include, but are not limited to, hematology (hemoglobin, platelets, leukocytes, neutrophils), 
creatinine, estimated glomerular filtration rate, and hepatic function panel (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and 
total bilirubin). 
The change from Baseline to each post-Baseline study visit will be presented by pivotal phase 3 
study treatment group for each laboratory test in both tables and figures. 
The number and proportion of patients with liver test elevations will be presented by pivotal 
phase 3 study treatment group.  Liver test elevations are assessed by using post-Baseline results 
for ALT, AST, ALP, and total bilirubin based on the definitions presented in Table 21. The 
number and percentage of patients with concurrent (defined as measurements on the same day) 
ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN, Concurrent ALT or AST ≥ 3  ULN and 
total bilirubin > 2  ULN and ALP < 2  ULN will also be presented. A by-patient listing will 
also be provided, 
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Table 21: 
Categories of Liver 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 < 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 Concurrent ALT or AST ≥ 3  ULN and total bilirubin > 2  ULN  
ALT or AST, total bilirubin, 
and ALP 
Concurrent ALT or AST ≥ 3  ULN and total bilirubin > 2  ULN and 
ALP < 2  ULN 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ULN = upper limit of normal. 
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)Error! Reference source not found. by pivotal phase 3 study treatment 
group. 
9.3. 
Other Safety Analyses 
9.3.1. 
Electrocardiograms 
ECG interval results and changes from Baseline will be summarized descriptively for each 
scheduled visit, including visits in both the pivotal phase 3 studies and extension study, in both 
tables and figures using data provided by and read by central reading. 
A categorical analysis of corrected QT interval using Fridericia’s calculation (QTcF) intervals 
will also be performed for each scheduled visit and for the maximum post-Baseline value.  The 
number and percentage of patients in each QTcF interval category (< 450 msec, 450 to 480 msec, 
481 to 500 msec, and > 500 msec) will be summarized.  Categories of changes from Baseline 
(≥ 30 msec and ≥ 60 msec) will be summarized as well. 
ECG intervals and central reader interpretation and diagnoses will be presented in by-patient 
listings.   
9.3.2. 
Vital Signs 
Blood pressure (systolic and diastolic), heart rate, and BMI will be summarized at pivotal phase 
3 study Baseline and each subsequent scheduled assessment, including visits in both the pivotal 
phase 3 study and extension study, by pivotal phase 3 study treatment group.  Change from 
pivotal phase 3 study Baseline will be calculated and presented for each parameter at all 
scheduled post-Baseline assessment time points in both tables and figures.  All vital sign data 
will also be provided in by-patient listings. 
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Potentially clinically significant abnormalities in vital signs are defined in Table 22, and they 
will be summarized by using post-Baseline values that meet the defined criteria.  Potentially 
clinically significant abnormalities will also be flagged in by-patient listings. 
Table 22: 
Categories of Potentially Clinically Significant Abnormalities in Vital Signs 
Parameter 
Category 
Systolic blood 
pressure 
≥ 140 mmHg over 2 consecutive visits 
≥ 180 mmHg over 2 consecutive visits 
≤ 90 mmHg over 2 consecutive visits 
≥ 140 mmHg and > highest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits; 
≥ 180 mmHg and > highest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
≤ 90 mmHg and < lowest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
Increase of ≥ 20 mmHg from Baseline in pivotal phase 3 studies over 2 
consecutive visits 
Decrease of ≥ 20 mmHg from Baseline in pivotal phase 3 studies over 2 
consecutive visits 
Diastolic blood 
pressure 
≥ 90 mmHg over 2 consecutive visits 
≥ 105 mmHg over 2 consecutive visits 
≤ 50 mmHg over 2 consecutive visits 
≥ 90 mmHg and > highest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits  
≥ 105 mmHg and > highest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
≤ 50 mmHg and < lowest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
Increase of ≥ 15 mmHg from Baseline in pivotal phase 3 studies over 2 
consecutive visits 
Decrease of ≥ 15 mmHg from Baseline in pivotal phase 3 studies over 2 
consecutive visits 
Heart rate 
≥ 120 bpm and > highest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
< 45 bpm and < lowest screening or baseline in pivotal phase 3 studies over 2 
consecutive visits 
Increase of ≥ 15 bpm from Baseline in pivotal phase 3 studies over 2 consecutive 
visits  
Decrease of ≥ 15 bpm from Baseline in pivotal phase 3 studies over 2 consecutive 
visits  
Abbreviations:  bpm = beats per minute; mmHg = millimeters of mercury. 
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9. 3. 3.  
E n d o metri al Bi o ps y  
T he pr ot oc ol -s pecifie d e n d o metrial bi o ps y pr oce d ure wa s p erf or me d at Bas eli ne f or all patie nts 
i n M V T-6 0 1 -3 1 0 1 a n d M V T -6 0 1 -3 1 0 2 , a n d at t he pi v otal p hase 3 st u d y Wee k 2 4/ E T visit f or all 
patie nts w h o partici pate d i n M V T -6 0 1 -3 1 0 1  o nl y .  Starti n g fr o m pr ot o c ol a me n d me nt 2. 0, 
en d o metrial bi o ps y pr oce d ure wa s re q uire d f or all patie nts i n t he e xte nsi o n st u d y at Wee k 5 2  a n d 
Earl y Ter mi nati o n V isit (e x ce pt f or patie nts w h ose last d ose of st u d y dr u g was ta ke n d uri n g 
Wee k 3 2 or earlier or wit hi n f o ur wee ks after c o m pleti o n of t he Wee k 5 2 e n d o metrial bi o ps y ).  
H o we ver, t he pr oce d ure ma y h a ve be e n d o ne if it w o ul d  ai d i n t he e val uati o n of a n o n g oi n g 
a d verse e ve nt.   A n e n d o metrial bi o ps y at Wee k 1 0 4 wa s rec o m me n de d f or all patie nts w h o 
c o m plete t he o pe n -l a bel e xte nsi o n; h o we ver, patie nts ha ve t he o pti o n t o o pt o ut.  C o nse ns us 
rea di n gs b y i n de pe n d e nt pat h ol o gists  were perf or me d o n all e n d o metrial bi o psies .   
T he Wee k 5 2, Wee k 1 0 4, a n d Earl y Ter mi nati o n e n d o metrial bi o ps y sa m pl es will be s u b mitte d 
t o t he ce ntral la b orat or y.  If t he Wee k 5 2, Wee k 1 0 4, or Earl y Ter mi nati o n bi o ps y s peci me n is 
i na de q uate, a tra ns va gi n al ultras o u n d f or e n d o metrial t hic k ness s h o ul d be o btai ne d a n d rea d 
l ocall y.  T h e tra ns va gi n al ultras o u n d fi n di n gs will be use d t o deter mi ne if f urt her acti o n is 
re q uire d.  N o f urt her acti o n is re q uire d f or en d o m etrial t hic k ness ≤ 5 m m . R e peat e n d o metri al 
sa m pli ng  will be c ollect e d f or e n d o metrial t hic k n ess > 5 m m at a n y l o cati o n or a n y ot her 
e n d o metrial a b n or m alit y is prese nt.  U nsc he d ul e d e n d o metrial bi o psies ma y als o be perf or me d 
w he n me dicall y i n dicate d a n d as dee m e d necessar y b y t he i n v esti gat or.   
E n d o metrial  bi o psies will be s u m marize d usi n g fre q ue ncies a n d perce nta ges  acc or di n g t o 
pri mar y dia g n osis a n d sec o n dar y dia g n osis  fr o m t he c o nse ns us r ea di n g (T a ble  2 3 ).  Pri mar y a n d 
sec o n dar y di a g n osis fr o m c o nse ns us rea di n g e val uati o n are s u m marize d Ta ble  2 3   E n d o metrial 
bi o psies perf or me d i n t he pi v otal p hase 3 st u dies a n d e xte nsi o n st u d y will b e s u m marize d b y 
pi v otal p hase 3 st u d y tr eat me nt gr o u p a n d b y visit .  A n y re peat e n d o metrial bi o psies pe rf or me d 
will als o be s u m marize d. Bi o ps y re p ort e d i n t he pi v otal st u d y C S R s will be e x cl u de d fr o m t he 
e xte nsi o n st u d y a n al ys es.  All e n d o metrial bi o ps y fi n di n gs a n d tra ns va gi nal u ltras o u n d data will 
als o be pr o vi de d i n a b y-patie nt listi n g, i ncl u di n g visits  i n b ot h t he pi v otal p hase 3 st u d y a n d 
e xte nsi o n st u d y.   
T a ble  2 3 :  
C ate g ories of Pri m a r y Di a g n osis i n E n d o metri al Bi o psies  
P ri m ar y Di a g n osis C ate g or y  
Sec o n d ar y Di a g n osis  
N or mal -Pr oliferati ve  
 
Wea kl y pr oliferati ve  
 
Pr oliferati ve  
 
Dis or dere d pr oliferati ve  
N or mal -Secret or y/ Me nstr ual/ Mi xe d  
 
Secret or y  
 
Me nstr ual  
 
Pr o gestati o nal/ Deci d ualize d  
 
Mi xe d  
N or mal -Atr o p hic /I n deter mi nate/I nacti ve  
 
Atr o p hic  
 
I n deter mi nate/I nacti ve 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
6 0  
C O N FI D E N TI A L  
 
H y per plasia  
 
Si m ple h y per plasia wit h o ut at y pia  
 
Si m ple h y per plasia wit h at y pia  
 
C o m ple x h y per plasia wit h o ut at y pia  
 
C o m ple x h y per plasia wit h at y pia  
Carci n o ma  
_  
I na de q uate  
_  
Missi n g  
_  
A d diti o nal Dia g n osis ( Ot her re p orte d 
fi n di n gs)  
 
Reacti ve/I nfla m mat or y  
 
P ol y p  
 
Meta plasia  
 
Gla n d ular a n d/ or Str o mal Brea k d o w n  
 
9. 3. 4.  
M a m m o gr a m  
A re q uire m e nt f or p ost -tr eat me nt ma m m o gra m s was a d de d starti n g wit h pr ot oc ol  a me n d me nt 3. 0  
as f oll o ws:   F or w o me n w h o are or bec o m e ≥ 4 0 years ol d at t he ti me of t h e visit , the pr ot oc ol -
s pecifie d l oc al ma m m o gra m  was t o be  perf or me d at Wee k 5 2 or  at Wee k 1 0 4/ Earl y T er mi nati o n .  
If a patie nt h a d a rece nt ma m m o gra m p er sta n dar d of care wit hi n t he si x m o nt hs bef ore Wee k 5 2 
t hat was Breast I ma gi n g Re p orti n g a n d Data S yste m cate g or y 1 or 2 or e q ui vale nt or ha d be ni g n 
fi n di n gs, as d eter mi ne d b y t he i n vesti gat or or me dical m o nit or, a ma m m o gra m is n ot re q uire d at 
Wee k 5 2 b ut s h o ul d be c o m plete d b y Wee k 1 0 4/ E arl y Ter mi nati o n.  If a patie nt t ur ns 4 0 years 
ol d after t he Wee k 5 2 visit has occ urre d, a ma m m o gra m s h o ul d be perf or m e d n o later t ha n t he 
Wee k 1 0 4/ Earl y Ter mi na ti o n visit. All ma m m o gra m res ults will be rea d l ocall y usi n g Breast 
I ma gi n g Re p orti n g a n d Data S yst e m cate g ories or e q ui vale nt a n d rec or de d i n t he e C R F.   
M a m m o gra m s perf or me d i n t he e xte nsi o n st u d y at Wee k 5 2, Wee k 1 0 4 // Earl y Ter mi nati o n will 
be s u m mariz e d.  N u m ber a n d perce nta ge of patie nts i n eac h Breast I m a gi n g Re p orti n g a n d Data 
S yste m cate g or y  or e q ui v ale nt  will be s u m marize d b y visit a n d b y pi v otal p hase 3 st u d y 
treat me nt gr o u p.  M a m m o gra m data will als o be pr o vi de d i n a b y -patie nt listi n g  i n t he e xte nsi o n 
st u d y. 
 
9. 3. 5.  
B o ne Mi ner al De nsit y  
C orrecte d B M D d ata as d eter mi ne d b y t he ce nt ral ra di ol o g y la b orat or y i n t he t hree pres pecifie d 
a nat o mical l ocati o ns  will be use d f or a nal ysis :  l u m bar s pi ne ( L 1– L 4), t otal hi p , a n d fe m oral 
nec k .   
B M D meas ure d at Bas eli ne a n d p ost -bas eli ne visits will be s u m marize d descri pti vel y b y pi v otal 
p hase 3 st u d y treat me nt gr o u p a n d eac h meas ure d a nat o mical l ocati o n  f or all patie nts i n t he 
E xte nsi o n Safet y p o p ul ati o n .  Mea n c ha n ge a n d p erce nt a ge c h a n ges fr o m b aseli ne al o n g wit h 
9 5 %  CIs  will be s u m mari ze d b y pi v otal p hase 3 st u d y treat me nt gr o u p, visit a n d a nat o mical 
l ocati o n.  P erce nta ge c h a n ge fr o m b aseli ne wit h its c orres p o n di n g 9 5 % CI  will be pl otte d b y 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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visit, pivotal phase 3 study treatment group, and anatomical location.  Percentage change from 
Week 12 to subsequent visits along with 95% CIs will be summarized by pivotal phase 3 study 
treatment group, visit and anatomical location.   
A mixed-effects model with repeated measures will be used to assess BMD at each visit.  The 
model will have age at Baseline, treatment, visit, treatment-by-visit interaction, Baseline BMD 
value, stratification factors (geographic region and time since initial surgical diagnosis), body 
mass index at baseline, race (Black/African American versus Other) as fixed effects using an 
unstructured variance-covariance matrix. If the mixed-effects model fails to converge, a first-
order autoregressive variance-covariance matrix will be used. Here treatment refers to pivotal 
phase 3 study treatment group. Least squares mean on each anatomical location will be presented 
and plotted by pivotal phase 3 study treatment group at each visit with associated 95% CIs. 
Specifically for percentage change from Week 12 to subsequent visits, week 12 BMD value is 
considered as a baseline.  
Categorical representation of percentage change from Baseline to post-baseline visits will be 
presented by the number and proportion of patients who had BMD increased (> 0%), no change 
(= 0%) and decreased by < 2%, >= 2% to 3%, > 3% to 5%, > 5% to 8%, and > 8% by pivotal 
phase 3 study treatment group and anatomical location.  The 95% CIs will be provided for the 
respective proportions.  The number and percentage of patients meeting a bone mineral density 
decrease of at least 4%, 5%, 6%, 7%, or 8% by anatomical location (lumbar spine, total hip, or 
femoral neck) will be estimated with 95% CIs by the pivotal phase 3 study treatment group. 
Categorical changes from Baseline in overall BMD (defined as lumbar spine and total hip) also 
will be assessed at post-baseline visits.  Femoral neck evaluates a smaller area of bone mass than 
the total hip and is prone to lower precision in the measurement (Leslie 2007; ISCD Official 
Positions 2015).  Since femoral neck BMD may be associated with discordant readings 
compared with the total hip or lumbar spine due to technical considerations, it is not expected to 
add meaningful interpretation of overall BMD changes in response to treatment, though will be 
included for completeness. 
Z-scores will be summarized by pivotal phase 3 study treatment group, visit, and anatomical 
location with descriptive statistics including 95% CIs. Number and percentage of patients with a 
Z -score < -2.0 will be presented by pivotal phase 3 study treatment group, visit, and anatomical 
location.  Number and percentage of patients with a Z score- change from baseline >= 0, < 0 to -
0.25, < -0.25 to -0.5, < -0.5 to -0.75, < -0.75 to -1.0, < -1.0 to -2.0 and < -2.0 will be presented by 
pivotal phase 3 study treatment group and anatomical location at Week 24, Week 52 and Week 
104.   
BMD change from baseline in the category of decreased, no change, and increased will be 
presented by pivotal phase 3 study treatment group, visit, and anatomical location.   
BMD percentage changes from Baseline will also be summarized by intrinsic factors (eg, age, 
race, body mass index) and extrinsic factors (eg, geographic region).  Subgroups will include, but 
will not be limited to, the subgroups outlined in Table 24.  
Table 24: 
Planned Subgroup Analyses  
Subgroup Name 
Subgroup Level 
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Geographic region 
North America, Rest of World 
Age category (years) 
< 35, ≥ 35  
Race 
Black or African American, Other 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino  
BMI (kg/m2) at Baseline 
< 25, ≥ 25  
Abbreviations:  BMI = body mass index. For patients reporting multiple races, those who reported “Black/African-
American” as one of the races will be included in the “Black or African-American” category. 
 
Post-treatment BMD  
Determination of bone mineral density by DXA at post-treatment follow-up of findings will 
proceed according to the rules defined by original protocol or amendments.  Complete data 
collected during the post-treatment Follow-Up period will be summarized and reported in an 
addendum to the final clinical study report.  
Patients required to have post-treatment follow up for BMD are defined according to the rules 
defined in section 2.1 (Table 2): 
All available 6-month and 12-month post-treatment follow-up BMD data will be summarized to 
display the number and percent of patients who completed post-treatment follow-up, who met 
the threshold for recovery, and who did not meet the threshold for recovery.  Summary statistics 
will be provided for post-treatment DXA by anatomic location at 6 months and 12-months.  
Summary of BMD loss recovery during post treatment follow up will be provided by location 
and by pivotal phase 3 study treatment group. Summaries will be presented of percent change in 
BMD from baseline for patients who entered post-treatment follow-up period by anatomic 
location and by pivotal phase 3 study treatment group. For patients who decline to participate in 
the 6-month and 12-month PTFU, reasons of decline will be summarized in the by-patient 
listing.  
Post-treatment follow-up medical and gynecological history, concomitant medications, and bone 
fracture events will be listed in the by-patient listing. 
For patients with PTFU scans showing a bone loss of ≥ 3% at the lumbar spine and/or total hip at 
the 6-month and 12-month PTFU visit compared with the pivotal study baseline, clinical 
laboratory evaluations including vitamin D, thyroid-stimulating hormone, parathyroid hormone, 
creatinine, calcium, and phosphorous will be listed in the by-patient listings. 
9.3.6. 
Menstruation Recovery 
Status of menstruation recovery will be documented at the Follow-Up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted again by telephone 3 
(+0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
Menstruation recovery data will be presented in the table by pivotal phase 3 study treatment 
group for patients in the Extension Study Population. The table will include menstruation status 
during follow up, number of days to return of menses from last dose of study drug, and 
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explanation for the lack of menstruation resumption. Menstruation recovery data will also be 
provided in a by-patient listing, 
9.3.7. 
Analysis of Bleeding Profiles 
Bleeding profile categories will be determined based on the amount of bleeding experienced by 
patients as reported in the eDiary.  When a patient is menstruating, the amount of bleeding 
during the past 24 hours is captured daily in the eDiary with five response options: spotting, 
light, moderate, heavy, and extremely heavy.  It will be assumed that there is no bleeding on 
days that the patient either uses the eDiary and reports that she is not menstruating, or when the 
patient misses reporting menstruating within eDiary cycle.  The responses to the eDiary question 
about the amount of bleeding will be used to define the bleeding profile categories (Table 25). 
After Week 52, to reduce patient burden, eDiary data were collected over four eDiary collection 
cycles on the following schedule: Week 57 to the Week 65 visit, Week 71 to the Week 78 visit, 
Week 85 to the Week 91 visit, and Week 98 to the Week 104 visit. After the Week 104 visit, 
patients continued daily eDiary entry until the 30-day Follow-Up visit. 
Table 25: 
Definitions of Bleeding Profile Categories 
Bleeding Profile Category 
Category Definition 
Irregular bleeding 
3 to 5 bleeding/spotting episodes and less than 3 bleeding-free intervals 
of least 14 days during a bleeding-profile period 
Prolonged bleeding 
Bleeding/spotting episodes of more than 14 days during a bleeding-
profile period 
Frequent bleeding 
More than 5 bleeding/spotting episodes during a bleeding-profile period 
Infrequent bleeding 
1 or 2 bleeding/spotting episodes during a bleeding-profile period 
No bleeding 
No bleeding during a bleeding-profile period 
Normal bleeding 
None of the above definitions are met 
a Bleeding/spotting episode: at least one day with bleeding or spotting reported, bounded by bleeding-free intervals. 
b Bleeding-free interval: at least two consecutive days with no bleeding or spotting reported, bounded by 
bleeding/spotting episodes. 
The number and percentage of patients belonging to each of the bleeding profile categories 
defined in Table 25 will be summarized by pivotal phase 3 study treatment group over four 
bleeding-profile periods:  Days 1 through 90, Day 91-Day 180, Day 181-Day 270, and Day 271-
365. A patient must have at least 90 days of treatment exposure to be included in the summary of 
each period. No analyses of bleeding profile after Day 365 will be performed because all of the 
eDiary reporting cycles are less than 90 consecutive days.   
Summaries of bleeding intensity and number of bleeding days based on 28-day intervals will be 
provided from the last 28 days starting from the pivotal phase 3 baseline through Day Day 731.  
The following 28-day windows will be used for summaries of bleeding during the randomized 
treatment period:  Week 4 (Days 1 through 28), Week 8 (Days 29 through 56), Week12 (Days 57 
through 84), Week 16 (Days 85 through 112), Week 20 (Days 113 through 140), Week 24 
(Days 141 through 168, Week 28 (Days 169  through 196), Week 32 (Days 197  through 224), 
Week 36 (Days 225  through 252), Week 40 (Days 253  through 280), Week 44 (Days 281  
through 308), Week 48 (Days 309  through 336), Week 52 (Days 338 through 365), Week 65 
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(Days 429 through 456), Week 78 (Days 520 through 547), Week 91 (Days 611 through 638) 
and Week 104 (Days 704 through 731).  Only patients who were on study drug for all days in a 
given 28-day window will be included in the summary for that window.  The specific summaries 
of bleeding that will be provided are described in Table 26. 
Table 26: Summaries of Bleeding Amount and Number of Bleeding Days 
Bleeding outcome 
Type of summary 
Bleeding amount (or intensity), defined 
numerically as: 
Spotting = 1 
Light = 2 
Moderate = 3 
Heavy = 4 
Extremely Heavy = 5 
Mean, SD, median, minimum, maximum; based on all 
eligible patients who report bleeding in the eDiary. 
Number of bleeding days 
Mean, SD, median, minimum, maximum; based on all 
eligible patients, regardless of whether any bleeding is 
reported in the eDiary. 
Number of bleeding days by the 
following bleeding amount (or intensity) 
categories: 
No bleeding 
Spotting 
Light 
Moderate 
Heavy 
Extremely Heavy 
Mean number of days per category. 
9.3.8. 
Amenorrhea Rate and Sustained Amenorrhea Rate 
Determination of amenorrhea will be based on a patient’s daily menstruation status as reported in 
the eDiary.  Amenorrhea for at least 56 consecutive days is defined as the lack of bleeding for at 
least 56 consecutive days after starting randomized study treatment in pivotal phase 3 study until 
Week 52. Amenorrhea for at least 28 consecutive days is defined as the lack of bleeding for at 
least 28 consecutive days after starting randomized study treatment in pivotal phase 3 study until 
Week 104.  The study day when amenorrhea begins is defined as the first study day following 
the last reported day of menstruation.  It will be assumed that there is no menstruation on days 
when menstrual status is not reported in the eDiary. 
A summary of amenorrhea for at least 56 consecutive days will be provided by pivotal phase 3 
study treatment group based on the following 56-day time intervals from pivotal phase 3 baseline 
through Day 365:  Week 8 (Days 1 through 56), Week 12 (Days 29 through 84), Week 16 
(Days 57 through 112), Week 20 (Days 85 through 140), Week 24 (Days 113 through 168), 
Week 28 (Day 141 through 196), Week 32 (Day 169 through 224), Week 36 (Day 197 through 
252), Week 40 (Day 225 through 280), Week 44 (Day 253 through 308), Week 48 (Day 281 
through 336), and Week 52 (Day 310 through 365).  No analyses of 56-day amenorrhea after 
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Week 52 will be performed because some eDiary reporting cycles are less than 56 days.  A 
summary of amenorrhea for at least 28 consecutive days intervals from pivotal study baseline 
through Day 731 will be provided by pivotal phase 3 study treatment group. The number and 
percentage of patients who are amenorrheic (ie, the amenorrhea rate) in each time interval will be 
presented.  In each time interval, the numerator for the amenorrhea rate is the number of patients 
who did not bleed during the time interval; the denominator is the number of patients who 
remained on treatment during the entire time interval. 
Sustained amenorrhea through week 52, defined as lack of bleeding for at least 56 days that 
continues until the Week 52 visit or the date of last dose of extension study treatment for early 
terminated patients who terminated before Week 52, will be summarized by pivotal phase 3 
study treatment group in the time intervals defined above.  No analyses of sustained amenorrhea 
after Week 52 will be performed because some eDiary reporting cycle were less than 56 days.  In 
each time interval, the number and percentage (ie, the sustained amenorrhea rate) of patients with 
sustained amenorrhea will be presented.  In each time interval, the numerator of the sustained 
amenorrhea rate will be the number of patients with sustained amenorrhea beginning on or prior 
to the end of the time interval; the denominator will be the number of patients in the Extension 
Safety population.  For patients who discontinued early, their amenorrhea status at the time of 
discontinuation will be carried forward until Week 104. 
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10. 
REFERENCES 
2015 International Society for Clinical Densitometry (ISCD) Official Positions – Adult 
(https://www.iscd.org/official-positions/2015-iscd-official-positions-adult/; accessed 
30 Apr 2019). 
Leslie WD, Lix LM, Tsang JF, Caetano PA.  Single-site vs Multisite Bone Density Measurement 
for Fracture Prediction.  Arch Intern Med 2007; 167 (15): 1641-7 
 
 
 
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11. 
REVISION HISTORY 
Version 
Effective Date 
Description of Changes  
 
 
 
 
 
 
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Statistical A nal ysis Pla n   
 
M V T -6 0 1 -3 1 0 3  
 
M y o va nt Scie nces G m b H  
6 8  
C O N FI D E N TI A L  
 
A P P E N DI C E S  
A p pe n di x 1.  Pr ot oc ol -S pecifie d Resc ue A n al gesics  
T he me dicati o ns bel o w are liste d base d o n t heir d ose stre n gt h. T he  pr ot oc ol state d t hat t he  
prescri pti o n ( or i nstr ucti o ns f or use) f or t hese me di cati o ns ma y all o w f or use of m ore t ha n o ne 
ta blet at a n y gi ve n ti me. A d diti o nall y, a nal gesics were t o  be  prescri be d i n acc or da nce wit h t he 
res pecti ve c o u ntr y’s a p pr o ve d pr o d uct la beli n g a n d t he s u bject’s hist orical use of o pi oi d 
a nal gesics s h o ul d be ta k e n i nt o c o nsi derati o n w he n prescri bi n g t hese dr u gs.   
O nl y o ne  Tier 2 me dicati o n was all o we d t o be s elec te d f or a gi ve n patie nt t o be use d t hr o u g h o ut 
t he st u d y a n d t his was t o be t he sa me Tier 2 me dicati o n use d i n t he pi v otal p hase 3 st u d y.  
 
St u d y -s pecifie d a nal gesics were as f oll o ws : 
 Tier 1  
 i b u pr ofe n ( 2 0 0 m g d ose stre n gt h)1 
 Tier 2  
 tra ma d ol ( 3 7. 5 m g) / paraceta m ol ( 3 2 5 m g)  
 tra ma d ol ( 5 0 m g) 
 c o dei ne ( 3 0 m g)  
 c o dei ne ( 3 0 m g) / p aracet a m ol ( 3 0 0 m g)  
 c o dei ne ( 3 0 m g) / p aracet a m ol ( 5 0 0 m g)  
 c o dei ne 1 5 m g/ p aracet a m ol (5 0 0  m g ) 
 h y dr oc o d o ne ( 5 m g) / aceta mi n o p he n 3 2 5 m g  
 
Wit hi n a gi ve n c o u ntr y, t he c h oice of Tier 2 a nal gesic was li mite d t o o ne or t w o of t he a b o v e 
Tier 2 a nal gesic me dicati o ns . 
 
 
D o c u Si g n E n v el o p e I D: C E 1 6 1 6 0 4- 3 5 3 F- 4 E 3 C- B 6 5 1- A 8 8 B 2 7 1 F 8 C 2 7


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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 < 3 × ULN 
Total BILI > ULN 
ALT ≥ 3 × ULN and < 5 × ULN 
Total BILI > 2 × ULN 
ALT ≥ 5 × ULN and < 10 × ULN 
 
ALT ≥ 10 × ULN and < 20 × ULN 
ALT or AST ≥ 3 × ULN and  
Total BILI > 2 × ULN 
ALT ≥ 20 × ULN 
ALT or AST ≥ 3 × ULN and 
Total BILI > 2 × ULN and ALP < 2 × ULN 
 
 
AST > ULN and < 3 × ULN 
GGT > ULN and < 3 × ULN 
AST ≥ 3 × ULN and < 5 × ULN 
GGT ≥ 3 × ULN and < 5 × ULN 
AST ≥ 5 × ULN and < 10 × ULN 
GGT ≥ 5 × ULN and < 10 × ULN 
AST ≥ 10 × ULN and < 20 × ULN 
GGT ≥ 10 × ULN and < 20 × ULN 
AST ≥ 20 × ULN 
GGT ≥ 20 × ULN 
 
 
ALT or AST > ULN and < 3 × ULN 
   
ALT or AST ≥ 3 × ULN and < 5 × ULN 
 
ALT or AST ≥ 5 × ULN and < 10 × ULN 
 
ALT or AST ≥ 10 × ULN and < 20 × ULN 
 
ALT or AST ≥ 20 × ULN 
 
 
 
Renal Function 
 
CR > 1.5 mg/dL and > BL 
eGFR < 15 mL/min per 1.73 m2 
CR > 50% increase from BL 
eGFR ≥ 15 to < 30 mL/min per 1.73 m2 
 
eGFR ≥ 30 to < 60 mL/min per 1.73 m2 
 
eGFR ≥ 60 to < 90 mL/min per 1.73 m2 
 
eGFR ≥ 90 mL/min per 1.73 m2 
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Metabolic Parameters 
 
Glucose, Fasting Glucose 
Highest Postbaseline Glucose 
     < 100 mg/dL at BL 
Gluc ≥ 200 mg/dL and > BL 
          < 100 mg/dL  
Gluc ≥ 200 mg/dL and ≥ 126 mg/dL at BL 
          ≥ 100 to < 126 mg/dL  
Gluc ≥ 500 mg/dL and > BL 
          ≥ 126 mg/dL  
Gluc ≥ 500 mg/dL and ≥ 126 mg/dL at BL 
     ≥ 100 to < 126 mg/dL at BL 
 
          < 100 mg/dL 
  
          ≥ 100 to < 126 mg/dL  
 
          ≥ 126 mg/dL  
 
     ≥ 126 mg/dL at BL 
 
         < 100 mg/dL  
 
         ≥ 100 to < 126 mg/dL  
 
         ≥ 126 mg/dL  
 
Lipids 
 
Total CHOL > 200 mg/dL and > BL 
HDL < LLN and < BL 
Total CHOL increase > 30 mg/dL from BL 
 
 
 
Total CHOL Normal < 200 mg/dL 
LDL > ULN and > BL 
Total CHOL Borderline High 200 to < 240 mg/dL 
LDL 100 - < 130 mg/dL and > BL 
Total CHOL High >= 240 mg/dL 
LDL 130 - < 160 mg/dL and > BL 
 
LDL 160 - < 190 mg/dL and > BL 
TRIG > ULN and > BL 
LDL >= 190 mg/dL and > BL 
TRIG 150 - < 200 mg/dL and > BL 
 
TRIG 200 - < 500 mg/dL and > BL 
LDL Normal < 100 mg/dL 
TRIG >= 500 mg/dL and > BL 
LDL Normal high 100 - < 130 mg/dL 
 
LDL Borderline High 130 - < 160 mg/dL 
 
LDL High 160 - < 190 mg/dL 
 
LDL very high >= 190 mg/dL  
Electrolytes and other Chemistry Parameters 
 
ALB < LLN and < BL 
MG < LLN and < BL 
ALB > ULN and > BL 
MG > ULN and > BL 
 
 
ALP > 2 × ULN and > BL 
CK > 2 × ULN and > BL 
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ALP > 5 × ULN and > BL 
CK > 5 × ULN and > BL 
ALP > 10 × ULN and > BL 
CK > 10 × ULN and > BL 
 
 
CA < LLN and < BL 
PHOS < LLN and < BL 
CA > ULN and > BL 
PHOS > ULN and > BL 
 
 
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 × 109/L and < BL 
LYM < LLN and < BL 
PLT > ULN and > BL 
LYM > ULN and > BL 
 
 
 HbA1c ≤ 5.6% and > BL 
MONO < LLN and < BL 
 HbA1c 5.7 - 6.4% and > BL 
MONO > ULN and > BL 
HbA1c ≥ 6.5% and > BL 
 
HbA1c increase > 1.0% from BL 
 
 
HbA1c < 5.7% 
HbA1c < 5.7% 
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Myovant Sciences GmbH 
72 
CONFIDENTIAL 
 
HbA1c 5.7 - 6.4% 
HbA1c 5.7 - 6.4% 
HbA1c 6.5 – 8.0% 
HbA1c ≥ 6.5% 
HbA1c 8.1 - 9.4% 
 
HbA1c 9.5 - 11% 
 
HbA1c > 11% 
 
Abbreviations:  ALB = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BASO = basophils; BILI = bilirubin; BL = baseline; CA = calcium; CHOL = cholesterol; CK = creatine 
kinase; CR = creatinine; E2 = estradiol; EOS = eosinophils; eGFR = estimated glomerular filtration rate; GGT = gamma 
glutamyl transferase; Gluc = glucose; HbA1c = hemoglobin A1c; HCT = hematocrit; HDL = high density lipoprotein 
cholesterol; HGB = hemoglobin; K = potassium; LDL = low density lipoprotein cholesterol; LLN = lower limit of normal; 
LYM = lymphocytes; MCV = mean corpuscular volume; MG = magnesium; MONO = monocytes; NA = sodium; NETA = 
norethindrone acetate; NEUT = neutrophils; PHOS = phosphate; PLT = platelets; TRIG = triglycerides; ULN = upper limit of 
normal; WBC = white blood cell. 
 
DocuSign Envelope ID: CE161604-353F-4E3C-B651-A88B271F8C27


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: C E 1 6 1 6 0 4 3 5 3 F 4 E 3 C B 6 5 1 A 8 8 B 2 7 1 F 8 C 2 7
St at u s: C o m pl et e d
S u bj e ct: Pl e a s e D o c u Si g n: E N D O O L E 2 y e ar S A P fi n al. d o c x
E ntir e d o c u m e nt u pl o a d e d f or r e vi e w a n d si g n at ur e ?: Y e s, I h a v e u pl o a d e d t h e e ntir e d o c u m e nt.
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 7 2
Si g n at ur e s: 6
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 6
I niti al s: 0
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: E n a bl e d
Ti m e Z o n e: ( U T C- 0 8: 0 0) P a cifi c Ti m e ( U S & C a n a d a)
I P A d dr e s s: 
 
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             1 7- F e b- 2 0 2 2 | 1 5: 4 5
H ol d er: 
             
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
 
M y o v a nt S ci e n c e s, I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 8- F e b- 2 0 2 2 | 0 7: 4 6 
Si g n e d: 1 8- F e b- 2 0 2 2 | 0 7: 4 7
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
M y o v a nt S ci e n c e s, I n c - P art 1 1
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 7- F e b- 2 0 2 2 | 1 5: 5 3 
Si g n e d: 1 7- F e b- 2 0 2 2 | 1 5: 5 3
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 7- F e b- 2 0 2 2 | 1 5: 5 7 
Si g n e d: 1 7- F e b- 2 0 2 2 | 1 6: 0 0
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 0 2- D e c- 2 0 2 1 | 1 3: 3 4
      I D: 
S HI O B O M y o v a nt S ci e n c e s, I n c
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I h a v e r e vi e w e d t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 7- F e b- 2 0 2 2 | 1 5: 5 8 
Si g n e d: 1 7- F e b- 2 0 2 2 | 1 5: 5 9
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 1 4- N o v- 2 0 1 9 | 0 8: 2 4
      I D: 
M y o v a nt S ci e n c e s, I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 7- F e b- 2 0 2 2 | 2 0: 0 1 
Si g n e d: 1 7- F e b- 2 0 2 2 | 2 0: 0 2
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      N ot Off er e d vi a D o c u Si g n
M y o v a nt S ci e n c e s, I n c.
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 7- F e b- 2 0 2 2 | 1 5: 5 2
Vi e w e d: 1 8- F e b- 2 0 2 2 | 0 7: 1 0 
Si g n e d: 1 8- F e b- 2 0 2 2 | 0 7: 1 0
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
      A c c e pt e d: 0 1- F e b- 2 0 2 1 | 0 8: 1 5
      I D: 
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
1 7- F e b- 2 0 2 2 | 1 5: 5 2
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
1 8- F e b- 2 0 2 2 | 0 7: 1 0
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
1 8- F e b- 2 0 2 2 | 0 7: 1 0
C o m pl et e d
S e c urit y C h e c k e d
1 8- F e b- 2 0 2 2 | 0 7: 4 7
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e
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E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, S HI I nter nati o nal C or p O B O M y o va nt Scie nces, I n c - Part 1 1 ( we, us or 
C o m pa n y) ma y b e re q uire d b y l a w t o pr o vi de t o y o u certai n writte n n otices or discl os ures. 
Descri be d b el o w are t he t er ms a n d c o n diti o ns f or pr o vi di n g t o y o u s uc h n oti ce s a n d discl os ur es 
electr o nicall y t hr o u g h t h e D oc u Si g n s yste m. Please rea d t h e i nf or mati o n b el o w caref ull y a n d 
t h or o u g hl y, a n d if y o u ca n access t his i nf or mati o n electr o nicall y t o y o ur satisfacti o n a n d a gree t o 
t his Electr o nic Rec or d a n d Si g nat ure Discl os ure ( E R S D), please c o nfir m y o ur a gree me nt b y 
selecti n g t h e c hec k-b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ures’ bef ore clic ki n g 
‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yste m. 
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of  a n y rec or d pr o vi d e d or ma de a v aila ble 
electr o nicall y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n  acc o u nt, y o u ma y access t he d oc u me nts f or a li mite d peri o d of ti me 
( us uall y 3 0 d a ys) after s u c h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fr o m o ur office t o y o u, y o u will be c har ge d  a 
$ 0. 0 0  per -pa ge fee. Y o u ma y re q uest deli ver y of s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w.  
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t hat t hereafter y o u wa nt t o recei v e re q uir e d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nicall y is des cri be d bel o w.  
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u ele ct t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tr a nsacti o ns wit h y o u a n d deli ver i n g s er vices t o 
y o u beca use we will nee d first t o se n d t he re q uir e d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u Si g n s yste m t o 
recei v e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e cr e at e d o n: 0 1- M a y- 2 0 1 9 | 1 1: 0 8
P arti e s a gr e e d t o: P P D


U nless y o u tell us ot her wise i n acc or da nc e wit h t he pr oce d ures des cri be d h erei n, we will pr o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d ur i n g t he c o urse of o ur relati o ns hi p wit h y o u. T o re d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei ve all t he discl os ures a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he para gra p h i m me diatel y a b o ve t hat des cri bes t he 
c o nse q ue nces of y o ur ele cti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us.  
 
H o w t o c o nt act S HI I nter n ati o n al C or p O B O M y o v a nt Scie nces, I nc - P art 1 1:   
Y o u ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fr o m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges t o: 
 
 
T o a d vise S HI I nter n ati o n al C or p O B O M y o v a nt Scie nces, I nc - P art 1 1 of y o ur ne w e m ail 
a d dress   
T o let us k n o w of a c h a n ge i n y o ur e mail a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa g e t o us at  
 a n d i n 
t he b o d y of s uc h re q uest y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail 
a d dress.  We d o n ot re q uire a n y ot her i nf or mati o n fr o m y o u t o c ha n ge y o ur e mail a d dress.   
If y o u create d a D oc u Si g n acc o u nt, y o u may u p d ate it wit h y o ur ne w e mail a d dress t hr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest p a per c o pies fr o m S HI I nter n ati o n al C or p O B O M y o v a nt Scie nces, I nc - P a rt 
1 1   
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u ele ctr o nicall y, y o u m ust se n d us a n e mail t o  
 a n d i n t he 
b o d y of s u c h re q u est y o u m ust state y o ur e m ail a d dress, f ull na me, maili n g a d dress, a n d 
tele p h o ne n u m ber. We will bill y o u f or a n y fees at t hat ti me, if a n y.  
 
T o  wit h dr a w y o ur c o nse nt wit h S HI I nter n ati o n al C or p O B O M y o v a nt Scie nces, I nc - P a rt 
1 1   
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T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 
i. decli ne t o si g n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k-b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y;  
ii. se n d us a n e mail t o 
 a n d i n t he b o d y of s uc h re q uest y o u m ust state 
y o ur e mail, f ull na me, m aili n g a d dress, a n d tele p h o ne n u m ber.  We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h dra w c o nse nt..  T h e c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr o cess..  
 
Re q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s ys te m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me. T h e 
c urre nt s yste m r e q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui de s/si g ner-g ui de -
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will be si milar t o 
ot her electr o nic n otices a n d di scl os ures t hat we will pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve 
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t hat y o u are a ble t o e mail t his E R S D t o a n e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o ur f ut ur e refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k -b o x ne xt t o ‘I a gree t o use electr o ni c rec or ds a n d si g nat ur es’ bef ore 
clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yst e m.  
B y sele cti n g t he c hec k -b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d  
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y  S HI I nt er nati o nal C or p O B O M y o va nt Scie nces, I n c - Part 1 1 
as descri be d a b o ve, y o u c o nse nt t o recei ve e x cl usi vel y t hr o u g h el ectr o nic mea ns all 
n otices, discl os ures, a ut h orizati o ns, ac k n o wle d ge me nts, a n d ot her d oc u me nts t hat are 
re q uire d t o be pr o vi de d or ma de a v aila ble t o y o u b y  S HI I nt er nati o nal C or p O B O 
M y o va nt Scie n ces, I n c - Part 1 1 d uri n g t he c o urse of y o ur relati o ns hi p wit h S HI 
I nter nati o nal C or p O B O M y o va nt Scie nces, I n c - Part 1 1.  
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