Clinical trial NCT03751124
Conditions: Uterine Leiomyoma Uterine Fibroids
Keywords: Heavy menstrual bleeding Menorrhagia Uterine Fibroids Uterine Leiomyoma
Sponsor: Myovant Sciences GmbH
Start date: 2018-10-16; Completion date: 2021-10-20
Enrollment: 229 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this randomized withdrawal study are to evaluate the long-term efficacy and safety of the combination of relugolix, estradiol (E2) and norethindrone acetate (NETA), once daily, for up to 104 weeks in patients with uterine fibroids who have completed a total of 52 weeks of treatment, including a 24-week treatment period in a parent study (study MVT-601-3001 or MVT-601-3002) and a 28-week treatment period in the open-label extension study (MVT-601-3003), and who meet the definition of responder, defined as a patient who demonstrates a menstrual blood loss of \< 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study.

Detailed description:
This randomized withdrawal study is an international phase 3 double-blind, placebo-controlled study that will enroll eligible patients with uterine fibroids who have completed the 24-week treatment period in a parent study (MVT-601-3001 or MVT-601-3002) and the 28-week treatment period of the open-label extension study (MVT-601-3003). When including treatment during the parent study and the extension study, patients completing this randomized withdrawal study will have received up to a total of 104 weeks of treatment with relugolix.

Approximately 360 women with heavy menstrual bleeding associated with uterine fibroids completing the extension study with a response to treatment will be eligible to participate in this study. A responder is defined as a patient who demonstrates a menstrual blood loss of \< 80 mL and at least a 50% reduction from parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine products returned at Week 48 in the extension study.

Screening procedures will be done on the same day as the Week 52 visit for the extension study. This visit will be referred to as the "Week 52/Baseline visit." When the Week 52/Baseline procedures in the extension study have been completed, the investigator will assess patient eligibility for participation in this study. The eligibility assessment will be based on data available at the Week 52/Baseline visit.

Patients will be asked to provide feminine products for alkaline hematin analysis at each visit until the analysis confirms the return of heavy menstrual bleeding. The patients will then be offered retreatment with open-label relugolix with E2/NETA with the onset of the next menses. They will resume collection of feminine products for alkaline hematin analysis until two consecutive analyses confirm resolution of heavy menstrual bleeding (menstrual blood loss of \< 80 mL). Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, and assessments of bone mineral density.

Arms: arm 1: Relugolix 40 mg co-administered with estradiol (1.0 mg) and norethindrone acetate (0.5 mg) for up to 52 weeks. arm 2: * Placebo for relugolix co-administered with placebo for E2/NETA for up to 52 weeks or until heavy menstrual bleeding returns.
* Retreatment with open-label relugolix with E2/NETA will be offered if heavy menstrual bleeding returns.
Interventions: intervention 1: Relugolix intervention 2: Estradiol/norethindrone acetate intervention 3: Placebo for relugolix intervention 4: Placebo for E2/NETA
Intervention descriptions: intervention 1: Relugolix 40 mg tablet administered orally once daily intervention 2: Capsule containing co-formulated tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg administered orally once daily intervention 3: Placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor intervention 4: Placebo capsule administered orally once daily and designed to match the E2/NETA capsule in size, shape, color, and odor

Protocol documents:
Prot_000.pdf: 
MVT-601-035 
Clinical Study Report Appendices 
Myovant Sciences GmbH 
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CONFIDENTIAL 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
Protocol Original 
Protocol Amendment 1 
Protocol Amendment 1 Summary of Changes 


 
 
 
1 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
An International Phase 3 Double-Blind, Placebo-controlled, 
Randomized Withdrawal Study of Relugolix Co-administered 
with Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-035 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
CH-4051 Basel 
Switzerland 
 
Regulatory Identifier(s): 
Eudra CT # 2018-001368-43 
IND # 131161 
Version and 
Effective Date: 
Draft: Original 
Effective: 11-July-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. 


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Clinical Study Protocol: MVT-601-035 
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SPONSOR SIGNATURE PAGE 
An International Phase 3 Double-Blind, Placebo-controlled, Randomized Withdrawal Study of 
Relugolix Co-administered with Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number: MVT-601-035 
This protocol has been approved by Myovant Sciences GmbH. The following signatures 
document this approval. 
 
Date 
 
 
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Date 
 
 
 
Date 
 
 
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Date 
 
 
Myovant Sciences GmbH 
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Clinical Study Protocol:  MVT-601-035 
 
Effective:  11-July-2018 
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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-601-035 
 
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TABLE OF CONTENTS 
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 ....................................................................................................................... 20 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding ..................................................................... 20 
2.2. 
Relugolix ................................................................................................................................... 21 
2.2.1. 
Indication .......................................................................................................................... 21 
2.2.2. 
Pharmacology ................................................................................................................... 21 
3. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 22 
4. 
INVESTIGATIONAL PLAN ..................................................................................................... 24 
4.1. 
Overall Study Design................................................................................................................. 24 
4.2. 
Discussion of Study Design, Including Dosing ......................................................................... 26 
4.3. 
Selection of Study Population ................................................................................................... 28 
4.3.1. 
Inclusion Criteria .............................................................................................................. 29 
4.3.2. 
Exclusion Criteria ............................................................................................................. 29 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number ............................. 30 
4.5. 
Removal of Patients from Therapy ............................................................................................ 31 
4.6. 
Contraception/Pregnancy Avoidance ........................................................................................ 32 
5. 
TREATMENTS ........................................................................................................................... 33 
5.1. 
Treatments Administered .......................................................................................................... 33 
5.2. 
Identity of Investigational Product ............................................................................................ 33 
5.2.1. 
Product Characteristics ..................................................................................................... 34 
5.3. 
Randomization and Stratification .............................................................................................. 34 
5.4. 
Directions for Administration .................................................................................................... 34 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 34 
5.6. 
Storage, Packaging, and Labeling ............................................................................................. 35 
5.7. 
Blinding ..................................................................................................................................... 35 
5.8. 
Study Drug Accountability and Treatment Compliance ........................................................... 36 


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5.9. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 36 
5.9.1. 
Prohibited Medications ..................................................................................................... 36 
5.9.2. 
Permitted Medications ...................................................................................................... 38 
5.9.3. 
Prohibited Non-Drug Therapies ........................................................................................ 39 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 39 
6.1. 
Schedule of Observations and Procedures ................................................................................. 39 
6.2. 
Treatment Period (Week 52/Baseline to Week 104) ................................................................. 39 
6.3. 
Early Termination Visit and Safety Follow-up Visit ................................................................. 40 
6.4. 
Unscheduled Visits .................................................................................................................... 41 
6.5. 
Study Procedures ....................................................................................................................... 41 
6.5.1. 
Efficacy-Related Procedures ............................................................................................. 41 
6.5.2. 
Safety-Related Procedures ................................................................................................ 43 
7. 
SAFETY CONSIDERATIONS .................................................................................................. 46 
7.1. 
Adverse Event Definitions ......................................................................................................... 46 
7.1.1. 
Adverse Event ................................................................................................................... 46 
7.1.2. 
Serious Adverse Event ...................................................................................................... 47 
7.2. 
Adverse Event Reporting........................................................................................................... 48 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 49 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 49 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 50 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 50 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 50 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 51 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 51 
7.7. 
Study Drug Overdose Management .......................................................................................... 52 
7.8. 
Pregnancy Reporting ................................................................................................................. 53 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, Electrocardiograms, and Bone 
Mineral Density Measures ........................................................................................................ 53 
7.10. 
Benefit/Risk Assessment ........................................................................................................... 53 
8. 
DATA QUALITY ASSURANCE ............................................................................................... 56 
8.1. 
Clinical Procedures .................................................................................................................... 56 
8.2. 
Monitoring ................................................................................................................................. 56 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ........................................... 56 
9.1. 
Randomization Methods ............................................................................................................ 57 


Clinical Study Protocol:  MVT-601-035 
 
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9.2. 
Analysis Populations ................................................................................................................. 57 
9.3. 
Efficacy Analyses ...................................................................................................................... 58 
9.3.1. 
Primary Efficacy Endpoint ............................................................................................... 58 
9.3.2. 
Secondary Efficacy Endpoints .......................................................................................... 59 
9.4. 
Pharmacodynamic Analyses ...................................................................................................... 61 
9.5. 
Safety Analyses ......................................................................................................................... 61 
9.6. 
Interim Analyses ........................................................................................................................ 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. 
Steering Committee .......................................................................................................... 64 
10.1.6. 
Study Files and Retention of Records ............................................................................... 64 
10.1.7. 
Electronic Case Report Forms .......................................................................................... 65 
10.1.8. 
Investigational Product Accountability ............................................................................. 65 
10.1.9. 
Inspections ........................................................................................................................ 66 
10.1.10. 
Protocol Compliance ......................................................................................................... 66 
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 ............................................................................... 67 
10.3.1. 
Access to Information Monitoring .................................................................................... 67 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 67 
10.3.3. 
Study Discontinuation ....................................................................................................... 67 
10.3.4. 
Publications ....................................................................................................................... 67 
REFERENCES .......................................................................................................................................... 68 
APPENDICES ........................................................................................................................................... 70 
Appendix 1. 
Health Survey Standard (SF-36v2®) ............................................................................. 70 
Appendix 2. 
Patient Global Assessment (PGA) for Function and Symptoms .................................. 76 
Appendix 3. 
Work Productivity Activity Impairment -Uterine Fibroids (WPAI-UF) ...................... 77 
Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire ...................................... 79 
Appendix 5. 
Assessment of Abnormal Liver Tests ........................................................................... 82 


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LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-035 ............................................................... 17 
Table 5-1 
Description of MVT-601-035 Study Drugs ...................................................................... 33 
Table 5-2 
Prohibited Medications ..................................................................................................... 36 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 44 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 50 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies ....................................................... 54 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury ...................... 82 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests .............................. 83 
 
LIST OF FIGURES 
Figure 4-1 
MVT-601 Uterine Fibroid Program Schematic ................................................................ 26 
 
 
 


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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMD 
Body Mass Data 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
E2/NETA 
estradiol 1.0 mg/norethindrone acetate 0.5 mg 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HMB 
heavy menstrual bleeding 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MBL 
menstrual blood loss 
mITT 
modified Intent-to-Treat 
OLE 
Open-label extension; LIBERTY EXTENSION; MVT-601-3003 
PD 
pharmacodynamic 
PGA  
Patient Global Assessment 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT Interval Corrected by the Fridericia Correction Formula 
RBC 
red blood cell 
SF-36 
Short Form (36) 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
WPAI-UF 
Work Productivity Activity Impairment-Uterine Fibroids 
ULN 
Upper limit of normal 
US 
United States 
WBC 
white blood cells 
WPAI-UF 
Work Productivity Activity Impairment-Uterine Fibroids 
 


Clinical Study Protocol:  MVT-601-035 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
An International Phase 3 Double-Blind, Placebo-controlled, Randomized 
Withdrawal Study of Relugolix with Estradiol and Norethindrone Acetate in 
Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol 
Number 
MVT-601-035 
Location 
Multinational, including North and South America, Europe, and South Africa 
Study Centers 
Approximately 240 sites 
Study Phase 
Phase 3 
Target 
Population 
Women 18 to 51 years old diagnosed with uterine fibroids who complete the 
open-label extension study MVT-601-3003 (OLE study) and who meet the 
definition of responder. A responder is defined as a patient who demonstrates a 
menstrual blood loss of < 80 mL and at least a 50% reduction from Parent study 
baseline menstrual blood loss volume on the alkaline hematin analysis of the 
feminine products returned at Week 48 in the OLE study. 
Number of 
Patients 
Planned 
Approximately 360  
Study 
Objectives 
In women with uterine fibroids who complete the OLE study and are identified as 
responders, the efficacy objectives are as follows: 
 
Primary Efficacy Objective 
• 
To evaluate the long-term effect of relugolix 40 mg with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg (relugolix with E2/NETA) once daily, compared 
with placebo on menstrual blood loss at Week 76 (24 weeks after 
randomization). 
 
Secondary Efficacy Objectives 
• 
To evaluate the long-term effect of relugolix with E2/NETA once daily, 
compared with placebo on menstrual blood loss at 52-weeks after 
randomization. 
• 
To evaluate the effect of retreatment with relugolix with E2/NETA on 
menstrual blood loss in patients whose menstrual blood volume returned to 
≥ 80 mL during the 52-week randomized period. 
• 
To evaluate the long-term effect of relugolix with E2/NETA at 52 weeks after 
randomization on the following: 
• 
Achievement of amenorrhea 
• 
Resumption of menses 
• 
Resumption of heavy menstrual bleeding (HMB) 
• 
Hemoglobin 
• 
Health-related quality of life as measured by the Short Form (36) (SF-36)  
• 
Patient Global Assessment (PGA) for function and symptoms  
• 
Work and productivity impact as measured by the Work Productivity 
Activity Impairment-Uterine Fibroids (WPAI-UF)  


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• 
Disease-specific quality of life as measured by the Uterine Fibroid 
Symptom and Health-Related Quality of Life (UFS-QoL). 
 
Pharmacodynamic Objectives 
• To characterize the pharmacodynamic (PD) effect of withdrawal from relugolix 
with E2/NETA. 
Safety Objectives 
• 
To evaluate the safety and tolerability of relugolix with E2/NETA once daily for 
up to an additional 52 weeks, in patients who previously completed (responders 
and partial responders) the OLE study. 
• 
Adverse events 
• 
Changes in bone mineral density. 
Study Design 
Overall Study Design:  This is an international phase 3 double-blind, placebo-controlled, Randomized 
Withdrawal study that will enroll eligible patients with uterine fibroids who have completed the 
24-week treatment period in a Parent study (study MVT-601-3001 or study MVT-601-3002) and the 
28-week treatment period of the OLE (MVT-601-3003) study. When including treatment during the 
Parent study and the OLE study, patients completing this Randomized Withdrawal study will have 
received up to a total of 104 weeks of treatment. 
Study Population:  All patients who complete the OLE study with a response to treatment, provide 
informed consent, and met all eligibility criteria for study MVT-601-035 will be eligible to participate. 
Approximately 360 women (responders) with heavy menstrual bleeding associated with uterine fibroids 
will be enrolled. A responder is defined as a patient who demonstrates a menstrual blood loss of < 
80 mL and at least a 50% reduction from Parent study baseline menstrual blood loss volume on the 
alkaline hematin analysis of the feminine products returned at Week 48 in the OLE study. 
Objectives:  The objectives of the study are to evaluate long-term efficacy and safety of treatment with 
relugolix with E2/NETA for up to 104 weeks (total treatment duration includes the Parent study, OLE 
study, and Randomized Withdrawal study). 
Treatment Assignment 
Approximately 360 patients completing the OLE study and meeting the definition of responder and 
meeting all other eligibility criteria will be randomized 1:1 to blinded treatment with oral relugolix with 
E2/NETA or placebo, once daily, for up to 52 weeks. Stratification variables will include geographic 
region (North America vs Europe vs Latin America vs Rest of World), duration of relugolix exposure 
prior to randomization (28 weeks vs 52 weeks), and baseline menstrual blood loss volume in the Parent 
study (< 225 mL vs ≥ 225 mL). For patients whose menstrual bleeding returns to ≥ 80 mL (heavy 
menstrual bleeding), treatment with open-label relugolix with E2/NETA (latter also referred to as “add-
back” in context of hormonal “add-back”) will be restarted. A Schedule of Activities is provided in 
Table 1-1. 
Screening and Baseline Procedures:  The study consists of a screening period and a treatment period 
(randomized or open-label) of up to 52 weeks. Screening and baseline procedures will be done at the 
same visit for this Randomized Withdrawal study (referred to as the “Week 52/Baseline visit” in this 
study), which coincides with the Week 52 visit of the OLE study and will be defined as the date of 
completion of the last procedure in the OLE study (see Schedule of Activities; Table 1-1). The 
Week 52/Baseline visit will include vital signs, physical examination, laboratory assessments, a 12-lead 
electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, transvaginal 
ultrasound, and endometrial biopsy (only if required). When Week 52/Baseline procedures in the OLE 
study have been completed, the investigator will assess patient eligibility for participation in this study. 
The eligibility assessment will be based on data available at the Week 52/Baseline visit. No study 


Clinical Study Protocol:  MVT-601-035 
 
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procedures will be performed until the consent form is signed. Patients will receive their last dose of 
study drug in the OLE study on the day of the Week 52/Baseline visit (as per the OLE study protocol). 
Following confirmation that the patient is eligible for this Randomized Withdrawal study and has 
provided informed consent to participate, the patient will be provided blinded study drug to begin 
dosing the following day. The first dose of study drug will be self-administered the next morning 
following the Week 52/Baseline visit. 
Post-baseline Procedures:  Study participants will be randomized to take either blinded study 
treatment (relugolix with E2/NETA or placebo) orally once daily or, when retreatment is indicated, 
open-label relugolix with E2/NETA for up to additional 52 weeks (beyond the 52 weeks of previous 
treatment during the Parent/OLE studies). All post-baseline procedures are provided in the Schedule of 
Activities (Table 1-1). Patients will be contacted on Week 52/Day 1 to confirm initiation of self-
administered dosing. 
Patients will be asked to provide feminine products for alkaline hematin analysis at each visit. If the 
analysis confirms return of heavy menstrual bleeding (defined as menstrual blood loss of ≥ 80 mL) the 
patient will be offered retreatment with open-label relugolix with E2/NETA with the onset of the next 
menses. They will resume collection of feminine products for alkaline hematin analysis until two 
consecutive analyses confirm resolution of heavy menstrual bleeding (menstrual blood loss of < 80 
mL). Patients will complete the bleeding diary daily including compliance with study drug, vaginal 
bleeding, and use of feminine products. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, and bone mineral density with dual-energy x-ray 
absorptiometry (DXA). Quality of life questionnaires will be completed according to the Schedule of 
Activities (Table 1-1). There is a Safety Follow-up visit (approximately 30 days after last dose of study 
drug) for all patients, and additional unscheduled follow-up visit(s) may be arranged at any time during 
the study for patients with study-related safety concerns, as needed. 
The PD effect of withdrawal from relugolix with E2/NETA will be characterized by measuring the pre-
dose concentration of estradiol at Week 56. 
Status of menstruation recovery will be documented at the Safety Follow-up visit (30 days after last 
dose of study drug). Patients whose menses have not resumed as of the Safety Follow-up visit and for 
whom there is no explanation for the lack of resumption (e.g., medical procedure or medications) will 
be contacted again by telephone 12 (± 2) weeks after the Safety Follow-up visit to determine if menses 
have resumed. These patients will be asked about factors that may affect resumption of menses. 
If a patient enrolls directly into another relugolix clinical study upon completion of the Week 104/Early 
Termination visit, then the Safety Follow-up visit, and the follow-up procedures performed under this 
protocol 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 are met at the time of the Week 52/Baseline visit: 
1. Completed the OLE study; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or 
study-specific procedures for MVT-601-035; 
Note:  Procedures conducted as part of the OLE study that also serve as baseline procedures for 
this study may be done under the informed consent for the OLE study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within 
the study period, including the Safety Follow-up period; 


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4. Is a responder:  Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from the 
Parent study baseline based on the results of the alkaline hematin testing performed on the feminine 
products returned at the Week 48 visit of the OLE study. Results from Week 44 may be used if 
Week 48 data is unavailable; 
5. Has a negative urine pregnancy test at the Week 52/Baseline visit; 
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the 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 24 weeks prior to the Week 52/Baseline 
visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at 
least 16 weeks prior to the Week 52/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 (e.g., 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:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study: 
1. Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or any 
other surgical procedure for fibroids, uterine artery embolization, magnetic resonance-guided 
focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding at any time 
during the Parent study or OLE study; 
2. 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 (e.g., bilateral hip 
replacement or spinal hardware in the lumbar spine); 
3. Anticipates use of any prohibited medications as detailed in Section 5.9.1; 
4. Has developed any contraindication to treatment with estradiol or norethindrone acetate including: 
a. Known or suspected breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism; 
d. 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. Porphyria; 
5. Has current active liver disease from any cause; 
6. Has a new diagnosis of a systemic autoimmune disease (e.g., systemic lupus erythematosus, 
Sjogren’s syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 


Clinical Study Protocol:  MVT-601-035 
 
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arthritis, vasculitic syndromes, etc.). Psoriasis not requiring or anticipated to require systemic 
therapy is permitted; 
7. Had any of the following clinical laboratory abnormalities at the OLE study Week 48 visit or any 
subsequent visit: 
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); 
c. Hemoglobin < 8 g/dL despite iron supplementation; 
8. Is currently pregnant or lactating, or intends to become pregnant during the study period or within 
4 weeks after the last dose of study drug, or plans to donate ova during the study period or within 
8 weeks after the last dose of study drug; 
9. 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; 
10. Met a withdrawal criterion in the OLE study. 
Dose and 
Route of 
Administration 
Test Product 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate. The hormonal add-back 
therapy will be over-encapsulated. 
 
Reference Product 
Placebo relugolix manufactured to match relugolix in size, shape, and color 
will be co-administered orally once daily with a placebo capsule designed to 
match the over-encapsulated active hormonal add-back therapy in size, 
shape, and color. 
 
Open-label Product 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate. 
 
Study treatment will be self-administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 52 weeks. 
Criteria for 
Evaluation 
Inferential efficacy assessments will be made on data observed from Week 52 to 
Week 104 between the following two study treatment groups: 
• 
Group A:  52 weeks of oral relugolix with E2/NETA, once daily; 
• 
Group B:  52 weeks of placebo relugolix plus capsule of placebo 
estradiol/norethindrone acetate. 
Week 52 of the OLE study will define the Baseline for this Randomized Withdrawal 
study and will be used as the reference point for all changes from baseline-related 
endpoints. The menstrual blood loss (MBL) volume at the Week 52 period of the 
OLE study will establish the patient’s baseline for evaluation of menstrual blood 
loss during the 52-week randomized treatment period of this Randomized 
Withdrawal study. 
 


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Primary Efficacy Endpoint 
• 
Proportion of women who maintain a menstrual blood loss volume of < 80 mL 
at Week 76 (24 weeks of the randomized treatment period) as measured by the 
alkaline hematin method. 
 
Secondary Efficacy Endpoints 
• 
Proportion of women who maintain a menstrual blood loss volume of < 80 mL 
at Week 104 (Week 52 of the randomized treatment period) as measured by the 
alkaline hematin method; 
• 
Change from Week 52/Baseline to Week 76 and Week 104 in menstrual blood 
volume (during the randomized treatment period); 
• 
Percentage change from Week 52/Baseline to Week 76 and Week 104 in 
menstrual blood volume (during the randomized treatment period); 
• 
Proportion of patients who responded (menstrual blood loss volume of < 80 
mL) to retreatment with relugolix with E2/NETA during the retreatment 
period among placebo patients whose menstrual blood volume had returned to 
≥ 80 mL during the 52-week randomized treatment period. 
The following secondary endpoints will be assessed at Week 76 and at Week 104 
during the randomized treatment period: 
• 
Proportion of women achieving or maintaining amenorrhea; 
• 
Proportion of women whose menses has resumed (among those who were 
amenorrhoeic at Week 52/Baseline); 
• 
Time to resumption of menses; 
• 
Proportion of women with menstrual blood volume ≥ 80 mL at any timepoint 
during the 52-week randomized treatment period; 
• 
Time to resumption of menstrual blood volume ≥ 80 mL; 
• 
Change from Week 52/Baseline in hemoglobin; 
• 
Change from Week 52/Baseline in SF-36 domain and summary component 
scores; 
• 
Change from Week 52/Baseline in PGA for function and symptoms score; 
• 
Change from Week 52/Baseline in the WPAI-UF scores; 
• 
Change from Week 52/Baseline in the Uterine Fibroid Scale Quality of Life 
(UFS-QoL) Symptom Severity scale, and sub-scale scores and total scores. 
 
Pharmacodynamic Endpoint 
• 
Pre-dose concentration of estradiol at Week 56. 
Safety Endpoints 
• 
Incidence of adverse events, change in vital signs and clinical laboratory tests; 
• 
Percent change from Week 52/Baseline to Week 104 in bone mineral density at 
the lumbar spine (L1-L4), femoral neck, and total hip as assessed by DXA. 
Statistical Methods 
Efficacy 
The primary efficacy endpoint of the study is the proportion of women who maintain a menstrual blood 
loss volume of < 80 mL at Week 76 (24 weeks of the randomized treatment period) as measured by the 
alkaline hematin method. 
The primary efficacy analysis is the treatment comparison between the relugolix Group A and the 
placebo Group B performed using a Cochran-Mantel-Haenszel (CMH) test statistic for proportions of 


Clinical Study Protocol:  MVT-601-035 
 
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responders stratified by the Parent study baseline mean menstrual blood loss (< 225 mL vs ≥ 225 mL), 
geographic regions (North America vs Other) and the duration of relugolix exposure at 
Week 52/Baseline (28 weeks vs 52 weeks). 
The study will be considered positive if the treatment effect for the primary endpoint is statistically 
significant with 2-sided p-value < 0.05. The point estimate and 2-sided 95% confidence interval (CI) 
for treatment difference in responder rates for the primary efficacy endpoint will be calculated. 
Efficacy data will be summarized on the modified Intent-to-Treat Population (mITT) defined as all 
randomized patients who took at least one dose of randomized study drug. The analyses methods for 
efficacy endpoints are similar to those used for the Parent studies, unless otherwise specified in the 
Statistical Analysis Plan (SAP). 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, and bone mineral density determined by DXA. Safety data 
analyses will be performed on the Safety Population defined as all randomized patients who receive at 
least one dose of randomized or open-label study drug during the study. 
Drug exposure will be summarized by descriptive statistics. Severity of all treatment-emergent adverse 
events will be evaluated by the investigator based on the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, higher level 
term, and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of patients with adverse events will be presented by MedDRA system organ 
class and preferred term, relationship to study drug, and severity. Laboratory values also will be 
classified by toxicity grade based on the National Cancer Institute’s CTCAE. Laboratory shift tables of 
the study Week52/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 52/Baseline and Week 104/Early Termination visits. The absolute values, change, 
and percent change from the Parent study Baseline, and Z-scores will be summarized by visit and study 
treatment group. The mean percentage change from Week 52/Baseline to Week 104 in bone mineral 
density and corresponding 95% CI will be provided for each treatment group. 
Pharmacodynamics 
Pharmacodynamic estradiol concentration data (pre-dose concentration of estradiol at Week 56) will be 
listed and summarized by treatment arm and visit. 
Sample Size Estimation 
This Randomized Withdrawal study is an extension of the OLE study. The sample size of this study 
will be based on approximately the number of patients who have completed either Parent study (n = 
780 patients in total), and who have participated in the OLE study (approximately n = 600 patients in 
total assuming ~ 20% dropout rate at 6 months from the Parent studies). Assuming the proportion of 
responders at Week 52 in the OLE study is about 60%, it is estimated that approximately 360 patients 
will be responders. 
With 360 patients in the randomized cohort, the study will have at least 90% power to detect a 
difference of 20% or greater between relugolix Group A and placebo Group B for the primary 
endpoint. The following assumptions are used to determine the sample size for this study: 
• 
2-sided type I error rate: 0.05 
• 
Randomization: 1:1 
• 
Responder rate for placebo Group B: 40% 
• 
Responder rate for relugolix Group A: 60% 
• 
Dropout rate: 20%. 


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Stratification factors for Randomization 
• 
Baseline MBL volume in the Parent study (< 225 mL vs ≥ 225 mL) 
• 
Geographic region (North America vs Europe vs Latin America vs Rest of World) 
• 
Duration of exposure to relugolix (28 weeks vs 52 weeks). 
Stratification by the 4 geographic regions (North America vs Europe vs Latin America vs Rest of 
World) will be used for managing the supply of investigational product. For the purpose of stratified 
data analyses, the 4 regions will be pooled into 2 groups (North America vs Other) where Other 
includes Europe, Latin America and Rest of World. 


Clinical Study Protocol:  MVT-601-035 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-035 
PERIOD 
TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/3002) 
Week 52/Baseline 
(Week 52 of OLE 
Study; Baseline of 
Study) 
Wk 
52, 
Day 1 
 
Wks 
56, 60 
Wk 
64 
Wks 
68, 72 
Wk 
76 
Wks 
80, 84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 104 
(or Early 
Termination 
of Study 
Drug) a  
Unsche
duled b 
Follow-up 
(~30 days 
after last 
dose of study 
drug) c 
Visit Window (days) 
OLE Study Day 
365 + 10 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
+ 10 
- 
- 3 to + 18 
Informed Consent 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications e 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
X 
Weight 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
X 
Complete Physical 
Exam 
X f 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Gynecologic Exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Signs and Symptoms-
Directed Physical 
Exam h 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X g 
X 
12-Lead ECG i 
X f 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
Clinical Laboratory 
Tests j 
X f 
 
 
X 
 
X 
 
 
 
 
 
X 
X g 
X 
Urinalysis 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
 
Pregnancy Test 
(Urine) 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X 
Estradiol levels 
X 
 
X k 
 
 
 
 
 
 
 
 
 
 
 
FSHl 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol:  MVT-601-035 
 
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PERIOD 
TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/3002) 
Week 52/Baseline 
(Week 52 of OLE 
Study; Baseline of 
Study) 
Wk 
52, 
Day 1 
 
Wks 
56, 60 
Wk 
64 
Wks 
68, 72 
Wk 
76 
Wks 
80, 84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 104 
(or Early 
Termination 
of Study 
Drug) a  
Unsche
duled b 
Follow-up 
(~30 days 
after last 
dose of study 
drug) c 
Visit Window (days) 
OLE Study Day 
365 + 10 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
+ 10 
- 
- 3 to + 18 
Transvaginal 
Ultrasound m 
X f 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
Bone Densitometry n 
X f 
 
 
 
 
 
 
 
 
 
 
X o p 
X g 
 
Dispense Treatment q 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Take Study Drug Dose 
in Clinic r 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Daily Self-
Administration of 
Study Drugs 
 
X s 
X 
 
X g 
 
Daily Completion of 
Paper Bleeding Diary t 
X 
X g 
 
Dispense Feminine 
Products 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Feminine Product 
Collection and Venous 
Blood Sample u 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Treatment Compliance 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
SF-36 Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGA for function and 
symptoms 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
WPAI-UF 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
UFS-QoL 
Questionnaire 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
Adverse Event 
Collection 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


Clinical Study Protocol:  MVT-601-035 
 
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Abbreviations:  BP, blood pressure; ECG, electrocardiogram; HR, heart rate; PGA, Patient Global Assessment; SF-36, Short Form (36) Health Questionnaire; UFS-QoL, Uterine 
Fibroid Symptom and Health-Related Quality of Life; WPAI-UF, Work Productivity Activity Index-Uterine Fibroid 
a  
The Week 104 visit should occur on or after the 2-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 Safety 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 52/Baseline visit or during the Week 52/Baseline visit. Enrollment in MVT-601-035 is defined by administration of the first 
dose of MVT-601-035 study drug. 
e  
Record all prescription and nonprescription drug and supplements taken from the Week 52/Baseline visit through the Safety Follow-up period. 
f  
This is an MVT-601-3003 (OLE study) Week 52 procedure that serves as the Week 52/Baseline procedure for MVT-601-035 and is covered under the informed consent for 
the OLE study. 
g  
The indicated procedure may be performed at the unscheduled visit based on the purpose of the visit (e.g., follow-up for an adverse event or abnormal laboratory test). 
h  
The exam may include a gynecologic examination, if indicated based on signs and symptoms. 
i  
The 12-lead ECG will be submitted for central reading at the Week 52/Baseline visit. Any subsequent ECGs performed at investigator discretion will be read locally. 
j  
Clinical laboratory tests required include clinical chemistries and a complete blood count. At the Week 52/Baseline visit and Week 104 visit, additional tests include: fasting 
(at least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
k  
Pre-dose specimen drawn at Week 56 only. 
l  
Specimen for FSH will be collected and stored until the study is unblinded. The assay for FSH will be performed after unblinding on amenorrhoeic patients who were 
assigned to placebo. 
m  
Transvaginal ultrasound, with or without transabdominal ultrasound, and with or without saline or gel contrast, is performed to determine uterine and myoma volumes and to 
exclude any other uterine or pelvic pathology. To avoid inter-observer and inter-device variations, a single operator will be assigned to a patient and will perform each of the 
ultrasound scans using the same device as far as possible. Once the transvaginal ultrasound is done, a transabdominal ultrasound may also be done if the uterus cannot be 
adequately imaged on transvaginal ultrasound; for example, due to enlarged size. Results must be submitted to a central reader. 
n  
Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
o  
This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 60 or earlier. However, the procedure may be 
done if it will aid in the evaluation of an ongoing adverse event. 
p  
Patients with a bone mineral density loss of > 7% at their Week 104/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 (estradiol, 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. 
q  
Patients will be dispensed randomized treatment at the Week 52/Baseline visit, for self-administration beginning the following day, Week 52, Day 1. Randomized treatment 
will be dispensed at subsequent visits until HMB (MBL ≥ 80 mL) is documented by alkaline hematin testing. When HMB has been documented, the patient will be invited for 
a visit to begin retreatment with open-label study drug. The timing of that visit should be within 7 days of the onset of the patient’s next menses (Cycle day 1-7 where Cycle 
day 1 is the first day of menstrual bleeding). 
r  
Patients will take the first dose of study drugs for this study once daily starting at Week 52, Day 1 (self-administered with phone follow-up). The last dose of study drug will 
be taken in the clinic during the Week 104/Early Termination visit. 
s  
Site to call patient and confirm first dose of study drug was taken that day. 
t  
Patients enter diary information on menstruation status and feminine product use. 
u  
Patients will collect and return all stained and soiled feminine products to the site with the initiation of randomized study drug treatment until return of heavy menstrual 
bleeding (MBL ≥ 80 mL) is observed. Collection will resume following the initiation of retreatment with open-label relugolix with add back and continue until MBL is 
observed to be < 80 mL on two consecutive collections. When the feminine products are returned, a venous blood sample (for hemoglobin) is to be collected and sent with the 
products to the central laboratory conducting the alkaline hematin assessment. 
 
                                                 


Clinical Study Protocol:  MVT-601-035 
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2. 
INTRODUCTION 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding 
Uterine leiomyomas (often referred to as fibroids or myomas) are common benign, estrogen-
dependent tumors that grow in the muscular wall of the uterus and occur in approximately 75% 
of women by the onset of menopause. While the majority of uterine fibroids are asymptomatic, 
approximately 25% of women with fibroids develop symptoms requiring treatment 
[Stewart, 2001; Stewart, 2017]. The most problematic symptom for women with uterine fibroids 
is heavy menstrual bleeding, with menstrual periods of increased duration and volume. In 
women with uterine fibroids, menstrual periods can last as long as 10 to 14 days rather than the 
usual 5 to 7 days, and blood loss can be as high as 300 to 500 mL, with anything more than 
80 mL during a given cycle considered abnormal. The heavy menstrual bleeding associated with 
uterine fibroids is likely caused by the increase in surface area of the uterine cavity, poor uterine 
contraction due to the myoma, and increased circulation, congestion, or impaired hemostasis due 
to hypertrophy of the endometrium near the myoma [Hapangama, 2016]. Persistent heavy 
menstrual bleeding can induce iron-deficiency anemia and associated fatigue and loss of energy. 
Heavy menstrual bleeding is a primary reason for the deterioration in the health-related quality of 
life assessed in patients with uterine fibroids and is a major cause of elective hysterectomy. Other 
symptoms include bulk symptoms, such as pain or pressure in the abdomen and pelvis due to 
large myoma(s), low back pain, urinary frequency or urinary tract obstruction, constipation, and 
pregnancy loss. 
The incidence of uterine fibroids increases as women grow older, and risk factors include 
nulliparity, obesity, family history, black race, and hypertension. Fibroids typically arise during 
the reproductive years, tend to enlarge during pregnancy, and regress after menopause as these 
tumors are dependent upon estrogen and progesterone for their growth. Transvaginal ultrasound 
is used most commonly to diagnose these benign tumors, and magnetic resonance imaging, 
sonohysterography, and hysteroscopy are used to evaluate their size and position. The type of 
treatment recommended for uterine fibroids typically depends upon their size, location, the 
patient’s age, reproductive plans, and obstetrical history. Few medical options are available for 
women with heavy menstrual bleeding associated with uterine fibroids, and approximately 60% 
of women who received medical therapy in one study underwent a surgical procedure within 
2 years [Marjoribanks, 2006], suggesting many women are inadequately treated with the 
currently available medical therapies. 
Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide acetate (also known as 
leuprorelin) are effective in lowering estrogen and progesterone levels, decreasing menstrual 
bleeding, and decreasing fibroid size. However, they cannot be used for more than 6 months due 
to bone mineral density loss from the resulting hypoestrogenic state. The GnRH agonists, which 
are administered by injection at 1- or 3-month intervals, first stimulate secretion of luteinizing 
hormone (LH) and follicle-stimulating hormone (FSH), which, in turn, increase estradiol and 
progesterone levels resulting in a flare of clinical symptoms. This initial rise in hormonal levels 
is followed by a gradual decline in levels over 4 weeks as the pituitary becomes desensitized to 
the chronic stimulation of the GnRH agonist and LH and FSH levels fall. Other medical 
treatments are used but have limited clinical effectiveness, including tranexamic acid, aromatase 
inhibitors, nonsteroidal anti-inflammatory medications, and danazol. 


Clinical Study Protocol:  MVT-601-035 
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The current mainstay of treatment for women with heavy menstrual bleeding associated with 
uterine fibroids is surgery. Several surgical procedures are frequently performed including 
myomectomy by various techniques, endometrial ablation, endometrial uterine artery 
embolization, and magnetic resonance-guided focused-ultrasound surgery. Each of these 
procedures has complications. For example, abdominal myomectomy results in complications 
requiring hysterectomy in up to 3 to 4% of cases, along with the frequent development of 
intraoperative adhesions [Gliklich, 2011]. Furthermore, recurrence of heavy menstrual bleeding 
after myomectomy is common, with at least 25% of women requiring additional treatment 
[Stewart, 2015; Marret, 2012; ACOG Practice Bulletin No. 96, 2008]. Hysterectomy is the 
definitive procedure with more than 200,000 hysterectomies performed annually in the United 
States (US) for uterine fibroids [Farquhar, 2002; Wu, 2007]. Major complications have been 
reported to occur in up to 25% of women undergoing hysterectomy, including infection, severe 
bleeding, and injuries to the urethra, bowel, or bladder. One study showed that among women 
with Medicaid insurance who underwent abdominal hysterectomy, there was a 10% risk of 
transfusion and up to a 28% risk of medical or surgical complications including major blood loss, 
wound infection, and febrile episodes [Gliklich, 2011]. 
Approximately 3 million women in the US suffer from symptomatic uterine fibroids that are 
inadequately treated with medical therapy, and related US health care costs for uterine fibroids 
exceeds $34 billion [Stewart, 2015; Cardozo, 2012; Gliklich, 2011]. There is a great need for a 
safe and efficacious medicine that can decrease the symptoms of uterine fibroids so women have 
an alternative to myomectomy and hysterectomy. 
2.2. 
Relugolix 
The current relugolix Investigator’s Brochure summarizes the nonclinical toxicology and 
previous human experience with relugolix. The previous human experience with relugolix 
includes results of phase 1 and phase 2 studies evaluating relugolix monotherapy in women with 
uterine fibroids or endometriosis and in men with prostate cancer, and phase 3 studies in women 
with uterine fibroids. The Investigator’s Brochure also provides a full discussion of the safety 
profile of relugolix. 
2.2.1. 
Indication 
Relugolix 40 mg with estradiol 1.0 mg/norethindrone acetate 0.5 mg (relugolix with E2/NETA) 
is being developed as a once-daily oral medication for the treatment of heavy menstrual bleeding 
associated with uterine fibroids. 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. 
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. 


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Relugolix antagonizes human GnRH receptors present on 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 LH 
and FSH 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 when 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 
The objectives of this Randomized Withdrawal study are to evaluate the long-term efficacy and 
safety of relugolix with E2/NETA, once daily, for up to 104 weeks in patients with uterine 
fibroids who have completed a total of 52 weeks of treatment including 24-week treatment 
period in a Parent study (study MVT-601-3001 or study MVT-601-3002) and 28-week treatment 
period of the OLE study and who meet the definition of responder. A responder is defined as a 
patient who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from 
Parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the 
feminine products returned at Week 48 in the OLE study. 
Primary and secondary assessment of efficacy and safety assessments will be made in the 
following two study treatment groups: 
• Group A:  52 weeks of relugolix with E2/NETA, once daily; 
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo 
estradiol/norethindrone acetate. 
Week 52 of the OLE study will define the baseline for this Randomized Withdrawal study and 
will be used as the reference point for all changes from baseline-related endpoints. The Week 48 
blood loss volume establishes responder status. Menstrual blood loss volume in this study will be 
compared to the threshold of 80 mL. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA, once daily, compared with 
placebo on menstrual blood loss at Week 76 
(24 weeks after randomization). 
• 
Proportion of women who maintain a 
menstrual blood loss volume of < 80 mL at 
Week 76 (24 weeks of the Randomized 
treatment period) as measured by the alkaline 
hematin method. 


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Objective(s) 
Endpoint(s) 
Secondary Efficacy 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA, once daily compared with 
placebo on menstrual blood loss at 52 weeks 
after randomization. 
• 
Proportion of women who maintain a 
menstrual blood loss volume of < 80 mL at 
Week 104 (52 weeks of the randomized 
treatment period) as measured by the alkaline 
hematin method; 
• 
Change from Week 52/Baseline to Week 76 
and Week 104 in menstrual blood volume 
(during the randomized treatment period); 
• 
Percentage change from Week 52/Baseline to 
Week 76 and Week 104 in menstrual blood 
volume (during the randomized treatment 
period). 
• 
To evaluate the effect of retreatment with 
relugolix with E2/NETA on menstrual blood 
loss in patients whose menstrual blood 
volume returned to ≥ 80 mL during the 52-
week randomized period. 
• 
Proportion of patients who responded 
(menstrual blood loss volume of < 80 mL) to 
retreatment during the retreatment period 
among placebo patients whose menstrual 
blood volume returns to ≥ 80 mL during the 
52-week randomized treatment period. 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA at 52 weeks after 
randomization on the following: 
• 
Achievement of amenorrhea 
• 
Resumption of menses 
• 
Resumption of heavy menstrual bleeding 
(HMB) 
• 
Hemoglobin 
• 
Health-related Quality of Life as 
measured by the Short Form (36) Health 
(SF-36) questionnaire 
• 
Patient Global Assessment (PGA) for 
function and symptoms  
• 
Work and Productivity impact as 
measured by the Work Productivity 
Activity Impairment-Uterine Fibroids 
(WPAI-UF) questionnaire 
• 
Disease-specific quality of life as assessed 
by the Uterine Fibroid Symptom and 
Health-Related Quality of Life (UFS-
QoL) questionnaire 
The following secondary endpoints will be 
assessed at Week 76 and Week 104 during the 
randomized treatment period: 
• 
Proportion of women achieving or 
maintaining amenorrhea; 
• 
Proportion of women whose menses has 
resumed (among those who were 
amenorrhoeic at Week 52/Baseline); 
• 
Time to resumption of menses; 
• 
Proportion of women with menstrual blood 
volume ≥ 80 mL at any timepoint during the 
52-week randomized treatment period; 
• 
Time to resumption of menstrual blood 
volume ≥ 80 mL; 
• 
Change from Week 52/Baseline in 
hemoglobin; 
• 
Change from Week 52/Baseline in SF-36 
domain and summary component scores; 
• 
Change from Week 52/Baseline in PGA for 
function and symptoms score; 
• 
Change from Week 52/Baseline in the WPAI-
UF scores; 
• 
Change from Week 52/Baseline in the UFS-
QoL scale and sub-scale scores as well as the 
total score. 


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Objective(s) 
Endpoint(s) 
Pharmacodynamic 
• To characterize the pharmacodynamic (PD) 
effect of withdrawal from relugolix with 
E2/NETA 
• 
Pre-dose concentration of estradiol at 
Week 56 
Safety 
• 
To evaluate the safety and tolerability of 
relugolix with E2/NETA, once daily, for up to 
an additional 52 weeks, in patients who 
previously completed (responders and partial 
responders) the OLE study 
• 
Adverse events 
• 
Changes in bone mineral density 
• 
Incidence of adverse events, change in vital 
signs and clinical laboratory tests; 
• 
Percent change from Week 52/Baseline to 
Week 104 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by DXA. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This Randomized Withdrawal study (MVT-601-035) is an international phase 3 double-blind, 
placebo-controlled study that will enroll eligible patients with uterine fibroids who have 
completed the 24-week treatment period in a Parent study (study MVT-601-3001 or study 
MVT-601-3002) and the 28-week treatment period of the OLE study. When including treatment 
during the Parent study and the OLE study, patients completing this Randomized Withdrawal 
study will have received up to a total of 104 weeks of treatment with relugolix. 
Study Population:  All patients completing the OLE study with a response to treatment and 
consenting will be eligible to participate. Approximately 360 women with heavy menstrual 
bleeding associated with uterine fibroids will be enrolled. A responder is defined as a patient 
who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from Parent 
study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine 
products returned at Week 48 in the OLE study. 
Objectives:  The objectives of the study are to evaluate long-term efficacy and safety of 
treatment with relugolix with E2/NETA for up to 104 weeks (total treatment duration includes 
the Parent study, OLE study, and Randomized Withdrawal study). 
Approximately 360 patients completing the OLE study and meeting the definition of responder 
and all other eligibility criteria will be randomized 1:1 to blinded treatment with oral relugolix 
with E2/NETA, once daily or placebo for up to 52 weeks. For patients whose menstrual bleeding 
returns to ≥ 80 mL (heavy menstrual bleeding), treatment with open-label relugolix with 
E2/NETA will be restarted. A Schedule of Activities is provided in Table 1-1. 
Screening and Baseline Procedures:  Screening procedures will be done on the same day as the 
Week 52 visit for OLE. This visit will be referred to as the “Week 52/Baseline visit”. The Week 
52/Baseline visit will include vital signs, physical examination, laboratory assessments, a 12-lead 
electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, 


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transvaginal ultrasound, and endometrial biopsy (only if required). When Week 52/Baseline 
procedures in the OLE study have been completed, the investigator will assess patient eligibility 
for participation in this study. The eligibility assessment will be based on data available at the 
Week 52/Baseline visit. No study procedures will be performed until the consent form is signed. 
Patients will receive the last dose of study drug in the OLE study on the day of the 
Week 52/Baseline visit (per the OLE protocol) and will be dispensed study drug for this 
Randomized Withdrawal study in the clinic after the patient is determined to be eligible for this 
study and has provided informed consent to participate. The first dose of study drug for the 
Randomized Withdrawal study will be self-administered the next morning following the 
Week 52/Baseline visit. Dosing will be confirmed by telephone. 
Post-baseline Procedures:  All post-baseline procedures are provided in the Schedule of 
Activities (Table 1-1). 
Patients will be asked to provide feminine products for alkaline hematin analysis at each visit 
until the analysis confirms the return of heavy menstrual bleeding (defined as menstrual blood 
loss of ≥ 80 mL). The patients will then be offered retreatment with open-label relugolix with 
E2/NETA (latter also referred to as “add-back” in context of hormonal “add-back”) with the 
onset of the next menses. They will resume collection of feminine products for alkaline hematin 
analysis until two consecutive analyses confirm resolution of heavy menstrual bleeding 
(menstrual blood loss of < 80 mL). Patients who experience a return of heavy menstrual bleeding 
(or terminate early because they have a return of heavy menstrual bleeding) but decline 
retreatment with open-label study drug will complete an Early Termination visit and a 30-day 
Safety Follow-up visit. 
At the Week 104/Early Termination visit, all other patients will have an assessment of bone 
mineral density via dual-energy x-ray absorptiometry (DXA). Patients will complete the bleeding 
diary daily including compliance with study drug, vaginal bleeding, and use of feminine 
products. 
The pharmacodynamic effect of withdrawal from relugolix with E2/NETA will be characterized 
by measuring the pre-dose concentration of estradiol at Week 56. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, and bone mineral density with DXA. 
Quality of life questionnaires will be completed according to the Schedule of Activities (Table 
1-1). 
Status of menstruation recovery will be documented at the Safety Follow-up visit (30 days after 
last dose of study drug). Patients whose menses have not resumed as of the Safety Follow-up 
visit and for whom there is no explanation for the lack of resumption (e.g., medical procedure or 
medications) will be contacted again by telephone 12 (± 2) weeks after the Safety Follow-up 
visit to determine if menses have resumed. These patients will be asked about factors that may 
affect the resumption of menses. 
If a patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104/Early Termination visit, then the Safety Follow-up visit and the follow-up procedures 
performed under this protocol may be waived. 
A schematic of the MVT-601 Uterine Fibroid Program including the MVT-601-035 Study is 
provided in Figure 4-1. 


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Figure 4-1 
MVT-601 Uterine Fibroid Program Schematic  
 
 
4.2. 
Discussion of Study Design, Including Dosing 
This Randomized Withdrawal study (MVT-601-035) is an extension of the 2 replicate, 24-week 
phase 3 Parent studies (MVT-601-3001 and MVT-601-3002) and subsequent 28-week open-
label extension study (MVT-601-3003). The Parent studies and open-label extension study were 
designed to establish the efficacy and safety of relugolix with E2/NETA, once daily, for up to 52 
weeks. This subsequent 52-week Randomized Withdrawal study provides additional efficacy and 
safety data for up to 104 weeks of treatment. The primary objective is to assess the long-term 
efficacy of relugolix with E2/NETA, once daily, for up to 104 weeks on reduction of heavy 
menstrual bleeding, the most common and burdensome symptom of uterine fibroids. Because 
heavy menstrual bleeding due to uterine fibroids is a chronic condition in premenopausal 
women, this investigation is clinically relevant since patients are anticipated to require ongoing 
therapy. 
In this design, the long-term efficacy of relugolix with E2/NETA will be assessed by comparing 
the maintenance of response in patients receiving continuous treatment to that in patients who are 
withdrawn from therapy. Patients who responded to open-label relugolix with E2/NETA in the 
OLE will be randomly assigned to continued active treatment or placebo in this study. Upon 
relapse, i.e., the return of heavy menstrual bleeding (MBL ≥ 80 mL), retreatment with open-label 
relugolix with E2/NETA, once daily, will be permitted. This design allows for placebo-
controlled assessment of maintenance of efficacy while minimizing the duration of time in which 
symptomatic patients are without treatment. The effect of active treatment will be demonstrated 
by observing the difference in response between continued active treatment and placebo groups. 
This design also affords the opportunity to assess the effectiveness of retreatment. This is 
important because, in clinical practice, interruption of treatment for variable lengths of time may 
occur due to circumstances such as poor compliance, desire to conceive, reimbursement issues, 
or intercurrent illness or surgery. Patients in this Randomized Withdrawal study who are given 
retreatment will be assessed to evaluate whether improvement in heavy menstrual bleeding can 
be recaptured. 
The dose of relugolix for this Randomized Withdrawal study 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 


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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 demonstrated the 40 mg dose provided the greatest reduction in menstrual blood loss and 
was the optimal dose to move forward into phase 3 development. 
The 40 mg dose has been used in two phase 3 studies in Japan. One study demonstrated that 
relugolix 40 mg administered once daily to women experiencing heavy menstrual bleeding due 
to uterine fibroids reduced menstrual blood loss similar to leuprolide. The second study 
compared 40 mg relugolix to placebo in women having pain symptoms associated with uterine 
fibroids. The study included women with a Numerical Rating Scale (NRS) of score of ≥ 4 in the 
menstrual cycle prior to randomization. The proportion of subjects without pain symptoms 
(NRS = 0) during the 28 days before the final dose of study drug was higher in the relugolix 
40 mg group (48.5%) than in the placebo group (3.1%). 
However, data on bone mineral density from DXA scanning in both the phase 2 and phase 3 
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 limits dosing of relugolix 
to short term use only. To mitigate this known adverse consequence of estrogen suppression, 
relugolix is given with E2/NETA in phase 3 clinical studies, including this study. Estradiol 1.0 
mg with norethindrone acetate 0.5 mg 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 led to less bone mineral density loss, these doses did not 
provide adequate relief from heavy menstrual bleeding in a high enough percentage of women to 
move forward into phase 3 clinical development.  Additionally, based on the DXA data from the 
phase 2 study, these lower doses 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 with 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 heavy menstrual blood loss. It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of supplemental 
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, 2017]. 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, 2015; Lee, 2016; Franke, 2000]. The estradiol/norethindrone 
acetate combination proposed for evaluation in combination with relugolix in this Randomized 
Withdrawal phase 3 study is currently approved in the US as long-term hormone replacement 


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therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal women 
[Activella US Prescribing Information, 2017]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix with E2/NETA demonstrated that this dose of add-back therapy maintains 
serum estradiol in the 25 to 50 pg/mL range, a 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 hormonal 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, 2017]) 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 Randomized Withdrawal study 
(1.0 mg and 0.5 mg, respectively) are also used in the Parent studies (MVT-601-3001 and MVT-
601-3002) and the OLE study (MVT-3003). This 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 marked decrease in the heavy 
menstrual bleeding associated with uterine fibroids in a majority of women in well-designed 
phase 2 and phase 3 studies. However, its administration was associated with a degree of bone 
mineral density loss unacceptable for long-term treatment. This phase 3 double-blind, placebo-
controlled Randomized Withdrawal study will assess long-term efficacy and safety of relugolix 
with E2/NETA, once daily, for the reduction of heavy menstrual bleeding associated with uterine 
fibroids, and for mitigation of bone mineral density loss and other side effects associated with a 
hypoestrogenic state such as hot flushes. 
This Randomized Withdrawal study will provide information on long-term efficacy and safety 
data for an additional 52 weeks of treatment, providing approximately 2 years of efficacy and 
safety data from the women with uterine fibroids treated with relugolix in the Parent studies 
(MVT-601-3001 and MVT 601-3002) and the OLE (MVT 601-3003) study. 
4.3. 
Selection of Study Population 
The study population will include approximately 360 responders who have completed the 
24-week treatment period in a Parent study (Study MVT-601-3001 or Study MVT-601-3002) 
and the 28-week treatment period of the OLE study with a response to treatment and meet all 
eligibility criteria for this study. 
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. 


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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 Criteria 
A woman will be eligible for enrollment in this study only if all of the following inclusion 
criteria are met at the time of the Week 52/Baseline visit: 
1. Completed the OLE study (MVT-601-3003); 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures for MVT-601-035; 
Note:  Procedures conducted as part of the OLE study that also serve as baseline procedures 
for this study may be done under the informed consent for the OLE study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids 
within the study period, including the Safety Follow-up period; 
4. Is a responder:  Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from 
the Parent study baseline based on the results of the alkaline hematin testing performed on 
the feminine products returned at the Week 48 visit of the OLE. Results from Week 44 may 
be used if Week 48 data is unavailable; 
5. Has a negative urine pregnancy test at the Week 52/Baseline visit; 
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the 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 24 weeks prior to the 
Week 52/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 16 weeks prior to the Week 52/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 (e.g., 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. 
4.3.2. 
Exclusion Criteria 
None of the following criteria may be true for a patient to be eligible for enrollment into this 
study: 
1. Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or 
any other surgical procedure for fibroids, uterine artery embolization, magnetic resonance-


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guided focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding 
at any time during the Parent study or OLE study; 
2. 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 (e.g., 
bilateral hip replacement or spinal hardware in the lumbar spine); 
3. Anticipates use of any prohibited medications as detailed in Section 5.9.1; 
4. Has developed any contraindication to treatment with estradiol or norethindrone acetate, 
including: 
a. Known or suspected breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism; 
d. 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. Porphyria; 
5. Has current active liver disease from any cause; 
6. Has a new diagnosis of a systemic autoimmune disease (e.g., 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; 
7. Had any of the following clinical laboratory abnormalities at the OLE study Week 48 visit or 
any subsequent visit: 
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); 
c. Hemoglobin < 8 g/dL despite iron supplementation; 
8. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 4 weeks after the last dose of study drug, or plans to donate ova during the study 
period or within 8 weeks after the last dose of study drug; 
9. 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. 
10. Met a withdrawal criterion in the OLE study. 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number 
Eligible patients who sign consent will be identified with the same Patient Identification Number 
assigned to the patient during the OLE study. All patients completing the OLE study with a 


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response to treatment and consenting will be eligible to screen. Once eligibility is confirmed, 
they will be randomized 1:1 to blinded treatment with oral relugolix with E2/NETA, once daily 
or placebo for up to 52 weeks. 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 104 visit with appropriate safety follow-up 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; Table 1-1) and will have a follow-up 
visit to assess safety approximately 30 days after the end of study drug treatment (i.e., after the 
patient’s last dose of study drugs). 
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 an 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%); 
• If an iron deficiency anemia related to heavy menstrual bleeding develops with a 
hemoglobin < 8g/dL and is unresponsive to iron supplementation; 
• 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 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 OLE 
study Week 52 DXA assessment of bone mineral density; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements. This may include < 75% compliance with 
the study drug for at least 2 months; not returning any feminine products despite having 
menstrual bleeding for > 2 consecutive cycles; or missing multiple study visits; 
• 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 make at least 3 documented attempts to contact the 
subject by telephone, or if necessary by certified letter 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. 
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 52/Baseline visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™) at least 4 months prior to the Week 52/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 (e.g., 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 whom none of the above methods 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 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). 


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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Approximately 360 patients completing the OLE study and meeting the definition of responder 
and meeting all other eligibility criteria will be randomized 1:1 to blinded treatment with oral 
relugolix with E2/NETA (relugolix with add-back) or placebo for up to 52 weeks. 
• Group A:  52 weeks of oral relugolix with E2/NETA, once daily; 
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo 
estradiol/norethindrone acetate. 
The placebo relugolix tablet is manufactured to match the relugolix tablet in size, shape, and 
color. The placebo capsule is designed to match the over-encapsulated estradiol/norethindrone 
acetate active product in size, shape, color, and odor. 
After randomization, if the alkaline hematin analysis confirms the return of heavy menstrual 
bleeding (defined as menstrual blood loss of ≥ 80 mL) the patient will be offered retreatment at 
their next visit with open-label relugolix with add-back for the remainder of the treatment period. 
Descriptions of all study drugs are provided in Table 5-1. 
Table 5-1 
Description of MVT-601-035 Study Drugs 
Name of 
Investigational 
Product 
Blinded and 
Open-Label 
Relugolix 
Relugolix 
Placebo 
Blinded 
Estradiol / 
Norethindrone 
Acetate 
Estradiol / 
Norethindrone 
Acetate Placebo 
Open-Label 
Estradiol / 
Norethindrone 
Acetate 
Formulation 
Description 
Round film-
coated pink 
tablet 
Round film-
coated pink 
tablet 
A Swedish 
orange, over-
encapsulated 
round film-
coated white 
tablet with 
back-fill 
material 
A Swedish 
orange capsule 
with placebo 
back-fill 
material 
Round, white, 
biconvex, film-
coated tablet 
Dosage Form 
Tablet 
Tablet 
Capsule 
Capsule 
Tablet 
Unit Dose 
Strength 
40 mg 
0 mg 
Estradiol 1.0 mg 
/ Norethindrone 
acetate 0.5 mg 
0 mg 
Estradiol 1.0 mg 
/ Norethindrone 
acetate 0.5 mg 
Route of 
Administration/ 
Duration 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
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)/norethindrone acetate (0.5 mg) is a fixed-dose combination product. 


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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/norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
Patients are randomized 1:1 ratio to blinded treatment with oral relugolix with E2/NETA 
(relugolix with add-back) or placebo. Stratification factors for randomization are as follows: 
• Baseline MBL volume in the Parent study (< 225 mL vs ≥ 225 mL) 
• Geographic region (North America vs Europe vs Latin America vs Rest of World) 
• Duration of exposure to relugolix (28 weeks vs 52 weeks). 
5.4. 
Directions for Administration 
The study drugs should be taken in the fasted state (water, tea, or coffee are allowed) 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 drugs should be taken as close as possible to the same time 
of morning each day. 
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 using adequate medical intervention should 
have their treatment interrupted until the toxicity improves to a grade 2 or lower severity. 
Patients may subsequently be restarted on study drug with the written approval of the sponsor (or 
designee). 


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5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20 – 25°C (68 – 770F) (with excursions permitted ± 5°C) to 15 - 30°C 
(59 - 860F) 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. 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, lot/batch number, expiry date, 
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. 
For randomized treatment, relugolix 40 mg will be supplied to the study site in blister cards. It 
will be co-packaged with the estradiol/norethindrone acetate. Open-label relugolix will be 
supplied in a bottle, and the open-label estradiol/norethindrone acetate will be supplied in a dial 
pack. 
5.7. 
Blinding 
During the double-blind Randomized Treatment and through the Safety Follow-up period, all 
patients, investigators, and sponsor staff or representatives involved in the conduct of the study 
will be blinded to treatment assignment, with the exception of an unblinded statistician(s) who is 
responsible for developing the randomization codes. 
Unblinding by the investigator for a given patient will occur only if the knowledge of treatment 
assignment will materially change the planned management of a medical emergency. 
Investigators will have direct access to a given patient’s individual study treatment and the 
decision to unblind a patient’s treatment assignment in an emergency situation resides with the 
investigator. However, the investigator should attempt to contact the medical monitor or 
appropriate study personnel to discuss options before unblinding the patient’s treatment 
assignment unless the urgency of the medical situation precludes this. If unblinding by the 
investigator occurs before sponsor personnel can be consulted or notified, the investigator must 
notify the sponsor as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded patient. Patients whose treatment assignment has been unblinded by 
the investigative site will be permanently discontinued from treatment. 


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The sponsor (or designee) may unblind the treatment assignment for any patient with a serious 
adverse event. 
For randomized patients whose menstrual blood volume returns to ≥ 80 mL during the 52-week 
randomized treatment period, therefore, will get retreatment with oral relugolix with E2/NETA, 
their randomized treatment assignment information is blinded during the 52-week randomized 
treatment period for all patients, investigators, and sponsor staff or representatives involved in 
the conduct of the study. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused and used study drugs 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. 
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 to the Safety 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 
 
Anti-convulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
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 intrauterine system 
 
Bone Agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
Anti-Coagulants/ 
Platelets/Fibrinolytics 
warfarin 
clopedigril 
tranexamic acid 
vitamin k preparations 
factor Xa inhibitors 
 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use (at screening) of 
systemic glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study is prohibited. 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/ritonavir 
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 
carvedilolg 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelor 
verapamil 
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. 
Abbreviation:  GnRH, gonadotropin-releasing hormone 
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. Metoprolol and atenolol are permitted 
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 
From the Week 52/Baseline visit to the Week 104/Early Termination visit, the use of analgesics 
for uterine fibroid-associated pain should be in accordance with the local standard of care and at 
the discretion of the investigator. 


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5.9.2.2. 
Iron Therapy 
Women who enter the Randomized Withdrawal study on iron therapy may continue iron 
treatment during the study. Women who develop new microcytic iron-deficiency anemia during 
the study, defined as a hemoglobin ≤ 10 g/dL, a mean corpuscular volume below the lower limit 
of normal, and low serum iron and ferritin, must also be started on iron therapy, either oral or 
parenteral. 
5.9.3. 
Prohibited Non-Drug Therapies 
Surgical and other interventional treatment of uterine fibroids is prohibited from the 
Week 52/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 
Table 1-1). Study procedures are briefly described in 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 Table 1-1). The study is divided into 2 periods:  Treatment period (Table 1-1) 
and Safety Follow-up period. Unscheduled visits may occur as needed to evaluate patients. 
6.2. 
Treatment Period (Week 52/Baseline to Week 104) 
As denoted in the Schedule of Activities (see Table 1-1), certain Week 52 visit procedures in the 
OLE study will serve as the Week 52/Baseline procedures for patients who are interested in 
participating in this Randomized Withdrawal study, and these Week 52 procedures will be 
performed under the informed consent for the OLE study. 
Patients will be required to sign an informed consent form for the Randomized Withdrawal study 
and will be eligible if they meet all the eligibility criteria. 
Once eligibility is determined, all additional Week 52/Baseline visit procedures described in the 
Schedule of Activities (see Table 1-1) that were not performed as part of the Week 52 visit of the 
OLE study will be completed. These include the following: 
• Informed consent; 
• Record concomitant medications; 
• Dispense study treatment; 
• Dispense feminine products; 
• Record adverse events, if any. 
Patients will record vaginal bleeding and feminine product use in a paper diary each day. Safety 
monitoring including physical examination, pregnancy tests, and adverse event assessment will 


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occur at each visit. Additional safety assessments will be performed as described in the Schedule 
of Activities (see Table 1-1). Bone densitometry will occur at the Week 52/Baseline, and 
Week 104/Early Termination visits. A transvaginal ultrasound (with or without a transabdominal 
ultrasound) will be performed at Week 52/Baseline visit. 
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 52/Baseline and Week 104/Early Termination visits and for 1 hour after administration of 
the study drug in the clinic. Laboratory requisitions must indicate whether the patient fasted for 
the chemistry and lipid testing. 
Patients will be randomized 1:1 to blinded treatment with oral relugolix with E2/NETA, once 
daily, or placebo beginning on the day following the Week 52/Baseline visit and continuing 
through the Week 104 visit. 
Patients will receive their last dose of study drug in the OLE study on the day of the 
Week 52/Baseline visit (as per the OLE study protocol), and the patient will be provided blinded 
study drug to begin dosing the following day. The first dose of study drug will be self-
administered the next morning following the Week 52/Baseline visit. After the 
Week 52/Baseline visit, a phone call will occur on Week 52 Day 1 (+ 2 days) to document the 
time of self-administration of the first dose of study drugs and record any reported adverse 
events. On-treatment study visits will occur every 4 weeks for a total of 104 Weeks. With the 
initiation of randomized treatment, patients will collect all stained/soiled feminine products and 
at the study visits return their feminine products for alkaline hematin testing. A venous blood 
sample (for hemoglobin) must be collected each time feminine products are returned and sent to 
the central laboratory conducting the alkaline hematin assessment. If the patient is having cyclic 
bleeding, the site must document the start and stop dates of the patient’s menses corresponding to 
the collected feminine products. The paper diary recording vaginal bleeding and feminine 
product use should be reviewed at each visit to assess compliance with feminine product 
collection. 
When the alkaline hematin analysis indicates MBL ≥ 80 mL, the patient will be asked to return 
with onset of the next menses, no later than cycle day #7 (where cycle day #1 is the first day of 
menstrual bleeding), to begin retreatment with open-label relugolix with E2/NETA. The timing 
of this visit may necessitate an unscheduled visit. The final dose of randomized treatment should 
be self-administered by the patient the day prior to presenting for retreatment. The first dose of 
retreatment with open-label relugolix with E2/NETA will be administered at the clinic visit. 
Feminine products do not need to be collected with the episode of menstrual bleeding associated 
with the initiation of retreatment, but once the episode is complete, all stained/soiled feminine 
products must be collected and returned at subsequent visits for alkaline hematin analysis until 
MBL < 80 mL is observed for two consecutive collections. 
6.3. 
Early Termination Visit and Safety 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; however, for 
patients whose last dose of study drug is during Week 56, bone densitometry does not need to be 


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performed. However, densitometry may be performed at the investigator’s discretion as an aid to 
adverse event follow-up. 
Patients who experience a return of heavy menstrual bleeding (or terminates early because they 
have a return of heavy menstrual bleeding) but decline retreatment with open-label study drug 
will complete an Early Termination visit and a 30-day Safety Follow-up visit. 
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 
uterine fibroids, whichever occurs first. However, the Safety Follow-up visit may be waived for 
patients who enroll directly into another relugolix clinical study upon completion of the 
Week 104 visit. 
The Safety 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 (Table 1-1) for individual study visit procedures during the Safety 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, to initiate retreatment, 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, etc., may be conducted as 
clinically indicated. See the Schedule of Activities (Table 1-1) for tests that may be performed, 
as indicated by the reason for a visit, 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 transvaginal ultrasound endometrial biopsy, or 
DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Bleeding Diary 
All women enrolled in the study will be provided with a paper bleeding diary along with 
instructions for its use. Patients will complete the diary daily including compliance with study 
drug, vaginal bleeding, and use of feminine products. 


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6.5.1.2. 
Menstrual Blood Loss as Assessed by the Alkaline Hematin Method 
The volume of menstrual blood loss is measured in milliliters using the alkaline hematin method 
[Hallberg, 1964]. The method involves pummeling used feminine products in a solution and 
measuring the resulting hematin absorbance against calibration curves. The method is validated 
in accordance with current FDA Guidance for Method Validations and is an accepted 
quantitative clinical endpoint for the assessment of heavy menstrual bleeding. The site staff will 
provide collection kits with standardized and validated feminine products to patients for the 
collection and assessment of those products to determine menstrual blood loss. 
The feminine products will be dispensed and all stained/soiled products will be collected at each 
visit starting with the initiation of randomized study drug treatment. Product collection will 
continue at each visit unless heavy menstrual bleeding (MBL ≥ 80 mL) is observed. Collection 
will resume following the initiation of retreatment with open-label relugolix with E2/NETA and 
continue until MBL is observed to be < 80 mL on two consecutive collections. If the patient is 
having cyclic bleeding, the site must document the start and stop dates of the patient’s menses. 
Each time the patient submits her feminine products from a menstrual cycle for analysis, a 
venous blood sample will be collected and sent to with the products to the  the laboratory for the 
alkaline hematin analysis. Details regarding materials, process, and requirements for the 
menstrual blood loss collection are provided in the Study Reference Manual. 
6.5.1.3. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal ultrasound will be performed for all subjects at the Week 52/Baseline visit as a part 
of the OLE study (MVT-601-3003). Once the transvaginal ultrasound is complete, a 
transabdominal ultrasound (with or without saline or gel contrast) may also be performed if the 
uterus cannot be adequately imaged on transvaginal ultrasound (e.g., due to enlarged size). 
Transvaginal ultrasound, with or without transabdominal ultrasound, is performed to determine 
uterine and myoma volumes. A single operator will be assigned to a patient and will perform 
each of the ultrasound scans using the same device, as far as possible, to avoid inter-observer and 
inter-device variations. This single operator should be the same person, if possible, as previously 
assigned to the patient during her participation in the Parent study. 
On the assumption that the uterus and myoma are spheroids, uterine and myoma volumes are 
calculated using the formula: 
Uterine or myoma volume = D1 × D2 × D3 × π / 6 
Where: 
o D1 = the longest diameter of the myoma or uterus (unit of length: cm) 
o D2 = the longest diameter of the myoma or uterus that is perpendicular to D1 
(unit of length: cm) 
o D3 = the diameter of the myoma or uterus that crosses the intersection of D1 and 
D2 (intersection “Z”) and is perpendicular to the D1/D2 plane (unit of 
length: cm). 
The D1, D2, and D3 locally-determined values for the uterus and myoma will be recorded 
centrally. The images will be submitted for central review to confirm myoma presence and size. 
Any ultrasounds performed after the Week 52/Baseline visit must be read locally. 


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6.5.1.4. 
Health Survey Standard (SF-36) 
The Health Survey Standard (SF-36) is a validated 36-item questionnaire which measures quality 
of life across eight health domains that can be combined into a physical and a mental summary 
component score. (see Appendix 1). The SF-36 has a 4-week recall period and will be completed 
on a paper questionnaire at the study site on a schedule described in the Schedule of Activities 
(see Table 1-1). With the exception of the Week 52/Baseline visit, patients will answer these 
questions before other types of study procedures are performed. 
6.5.1.5. 
Patient Global Assessment (PGA) for Function and Symptoms 
The PGAs for Function and Symptoms are completed by the patient; they are based on a 5-point 
Likert scales and have a 4-week recall period (see Appendix 2). The PGA for function and PGA 
for symptoms will be completed on a paper questionnaire at the study site on a schedule 
described in the Schedule of Activities (see Table 1-1). Except for the Week 52/Baseline visit, 
patients will answer these questions before other types of study procedures are performed. 
6.5.1.6. 
Work Productivity Activity Impairment-Uterine Fibroids (WPAI-UF) 
The Work Productivity Activity Impairment-Uterine Fibroids (WPAI-UF) is a validated 
instrument used to measure impairments in work and activities, which has been adapted for 
uterine fibroids (see Appendix 3). The WPAI-UF will be completed on a paper questionnaire at 
the study site on a schedule described in the Schedule of Activities (see Table 1-1). Except for 
the Week 52/Baseline visit, patients will answer these questions before other types of study 
procedures are performed. 
6.5.1.7. 
Uterine Fibroid Symptom and Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QoL) is a 
validated instrument used to evaluate the symptom severity and the quality of life of patients 
with uterine fibroids (see Appendix 4). The UFS-QoL will be completed on a paper 
questionnaire at the study site on a schedule described in the Schedule of Activities (see Table 
1-1). Except for the Week 52/Baseline visit, patients will answer these questions before other 
types of study procedures are performed. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight 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 and will include systolic and diastolic blood pressure and 
pulse rate. 


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6.5.2.3. 
Physical and Gynecologic Exams 
A complete physical examination will include examinations of head, ears, eyes, nose, mouth, 
thyroid, skin, heart and lung, 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 previous assessments. The gynecologic 
examination will include breast and pelvic exams. 
6.5.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities (see Table 1-1). Laboratory 
requisition forms must be completed, and samples must be clearly labeled with the Patient 
Identification Number, protocol number, site/center number, and visit date. Details for the 
preparation and shipment of samples will be provided. Reference ranges for all laboratory tests 
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 
Hemoglobin A1c 
Creatine Kinase 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Gamma-Glutamyl Transferase 
Alkaline phosphatase 
White Blood Cell (WBC) Count 
Protein 
WBC Differential 
Glucose 
Red Blood Cell Count 
Blood 
Hemoglobin 
Urobilinogen 
Hematocrit 
Bilirubin 
Mean Corpuscular Volume 
Color and Clarity 
Platelet Count 
pH 
Red Blood Cell (RBC) 
morphology 
Leucocyte Esterase 
 
 Ketones 
 
Nitrite 
 
Specific Gravity 
 
Urine Microscopy (reflex 
testing based on abnormal 
urine analysis) 
 
Lipids 
Pregnancy 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
Pregnancy test 
(human chorionic 
gonadotropin) 
Hormones 
 
 
Estradiol 
FSH 
 
 
 


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The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, 
serology, and plasma 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 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized. Abnormal and clinically significant 
results should be reported as adverse events. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 
To maintain blinding, concentrations of estradiol hormones will be reported to the investigator, 
other vendors, and sponsor personnel only after database lock and unblinding. Specimens for 
FSH will be collected and stored until the study is unblinded. The assay for FSH will be 
performed after unblinding on amenorrhoeic patients who were assigned to placebo. 
6.5.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at Week 52/Baseline visit in this study, as well as if needed to 
evaluate any signs or symptom that require an ECG to assess. ECGs will be measured using 
standardized equipment provided by 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. Any ECGs performed after the Week 52/Baseline 
visit will be read locally. 
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). 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 each patient. This should be the same as used for the patient 
during the OLE study. A central core imaging laboratory will collect and evaluate all DXA scans 
for acceptability and will have bone mineral density assessed as per the imaging charter. Data 
from the DXA scans will be managed and analyzed separately by the core laboratory and 
integrated into the study’s database at the end of the study. Bone mineral density changes for 
individual subjects will be monitored by a central radiology laboratory over the course of the 
study. 
Patients who experience a bone mineral density loss of ≥ 7% from the Parent study baseline at 
any of the anatomical sites assessed will be discontinued from the study and will undergo 
another bone densitometry scan as described below. Patients should be assessed for secondary 


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causes of bone loss and followed-up further if not improving on 6 months follow-up scan unless 
an alternative etiology has been identified.  
Patients with a bone mineral density loss of ≥ 7% at lumbar spine, total hip, or femoral neck at 
their Week 104/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 about medications and conditions (e.g., 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. 
6.5.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Safety Follow-up visit, the date of onset of the first menstruation is recorded in the electronic 
case report form (eCRF). Patients whose menses has not resumed as of the Safety Follow-up 
visit for whom there is no explanation for the lack of resumption (e.g., medical procedure or 
medications) will be contacted again by telephone 3 (± 0.5) months after the Safety 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, physical examinations, vital signs (and 
weight), 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 


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events (e.g., for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 
• An investigational abnormality (e.g., 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 (e.g., 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 (e.g., planned 
hospitalization for an elective procedure, with elective defined as known or planned at the 
time of signing of the informed consent); 
• Events of heavy menstrual bleeding, as heavy menstrual bleeding is quantified as an 
efficacy endpoint, unless meets seriousness criteria. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to 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. No 
toxicity-related dose reductions of study drug are permitted; however, study drug can be held for 
a period of up to 2 weeks for evaluation and treatment of an adverse event. The study drug may 
be restarted if deemed safe for the patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study 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 


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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 the 
Week 52/Baseline visit 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 (e.g., 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 that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria. Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local institutional review board (IRB) or institutional 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 answers to study questionnaires 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 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 Safety 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 uterine fibroids, whichever occurs first, as also specified in the study 
Schedule of Activities (Table 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 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 Safety Follow-up period 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 5. 
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 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 
Week 52/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 (i.e., 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 (e.g., 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 Report Form, all serious adverse events must be reported within 24 hours of the 
study site personnel’s knowledge of the event, regardless of the investigator assessment of the 
relationship of the event to study drug. 


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The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose is available on the serious adverse event report form and is as 
follows: 
Send completed Safety Report Forms to IQVIA RDS Inc: 
Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary reporting method) 
All study sites 
 
 
 
For questions on Serious Adverse Event/Adverse Event of Clinical Interest reporting, 
please call: 
• 
North/South America:  
 
• 
Europe, Asia, Pacific, and South Africa:  see region-specific phone numbers 
accompanying the Safety Report Form 
The initial report should include: 
• 
Study number (MVT-601-035); 
• 
Site address and number; 
• 
Investigator name; 
• 
Patient Identification Number, sex, and age; 
• 
Details of study drug administration; 
• 
The date of the report; 
• 
A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); 
• 
Causal relationship to the study drug. 
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. 
PPD
PPD
PPD


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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 (i.e., 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 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. 
Pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy report 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 
pregnancy report 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, weight, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions associated with relugolix in women include nonserious events of hot 
flush, headache, hyperhidrosis, arthralgia, and loss of bone mineral density. In this protocol, 
relugolix will be evaluated for its benefit on the heavy menstrual bleeding associated with uterine 


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fibroids. Hormonal add-back therapy with estradiol/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 interval [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’s 
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 
estradiol/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 52/Baseline 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 52/Baseline and 
Week 104/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzyme increases 
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 
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 
nonhormonal 
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 
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 malignancies, 
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 52/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 (e.g., 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 (e.g., removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets. Patient initials will not be collected or transmitted to the 
sponsor. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A Statistical Analysis Plan (SAP) will describe the detailed statistical methods and analyses for 
this study. The SAP will be prepared and finalized prior to unblinding of patient’s study 
treatment assignments. 


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All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%. 
Methodology to be used to maintain study-wide type I error rate of 5% testing across primary 
and key secondary endpoints will be described in the SAP. 
All efficacy and safety measures over the course of the study will be presented. Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients. Categorical data will be summarized by counts and percentages. 
The final analysis of efficacy and safety data will occur after approximately 360 patients 
(projected to be responders from the open-label extension study MVT-601-3003) who have been 
randomized and have had the opportunity to complete Week 104 visit or through the 30-day 
Safety Follow-up visit. 
9.1. 
Randomization Methods 
This is an international phase 3 Double-Blind, Placebo-controlled, Randomized Withdrawal 
study that will enroll eligible patients with uterine fibroids who have completed the 24-week 
treatment period in a Parent study (Study MVT-601-3001 or Study MVT-601-3002) and the 28-
week treatment period of the OLE study. Patients completing the OLE study and meeting the 
definition of responder will be randomized 1:1 into two different treatment groups: 
• Group A:  52 weeks of oral relugolix with E2/NETA, once daily;  
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo estradiol/norethindrone 
acetate. 
Randomization will be stratified by the following factors: 
• Geographic Region:  North America vs Europe vs Latin America vs Rest of World;  
• Mean screening menstrual blood loss using alkaline hematin method:  < 225 mL versus 
≥ 225 mL; and  
• Duration of relugolix exposure prior to randomization (28 weeks vs 52 weeks). 
The four stratification levels (North America vs Europe vs Latin America vs Rest of World) for 
geographic region considered for randomization take drug supply monitoring into consideration. 
For the purpose of stratified data analyses, the 4 regions will be pooled into two groups (North 
American vs Other) where Other includes Europe, Latin America and Rest of World. 
Statistical analyses for efficacy endpoints will incorporate these stratification factors unless 
otherwise specified. 
9.2. 
Analysis Populations 
The modified Intent-to-Treat (mITT) Population will consist of all patients randomized to 
treatment who have taken at least one dose of study treatment. The mITT Population will be the 
primary population used for the efficacy analysis. 
The Per-Protocol Population will consist of those members of the mITT Population who have no 
relevant major protocol violations, defined as a subset of all major protocol violations (details 
will be provided in the Statistical Analysis Plan). The Per-Protocol Population will not be 
analyzed if this population comprises more than 95% or less than 50% of the mITT Population. 


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This population will be used for confirmatory analysis of the primary efficacy endpoint. The Per-
Protocol Population will be identified prior to breaking the study blind. 
The primary population for safety analyses will be the Safety Population, which will consist of 
all patients who are randomized and took at least one dose of study treatment. 
9.3. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the mITT Population 
according to the randomized treatment assignment, and stratified analyses will be stratified by 
the randomization stratification factors. If the group of patients from any of the individual 
randomization stratification factors comprises less than 10% of the entire mITT population, this 
stratification factor will be ignored for stratified analyses. 
9.3.1. 
Primary Efficacy Endpoint 
The primary endpoint of the study is the proportion of women who maintain a menstrual blood 
loss volume of < 80 mL at Week 76 (24 weeks of the randomized treatment period) as measured 
by the alkaline hematin method. The primary endpoint of responder rate will be evaluated using 
the mITT Population. 
Week 52 of the OLE study will define as the baseline for this Randomized Withdrawal study and 
will be used as the reference point for all changes from baseline-related endpoints. Although 
responder status is based on Week 48 of the OLE study, the menstrual blood loss (MBL) volume 
at the Week 52 period of the OLE study will establish the patient’s baseline for evaluation of 
menstrual blood loss during the 52-week randomized treatment period of the study. 
9.3.1.1. 
Primary Analysis 
The primary hypothesis for the primary efficacy endpoint to be tested in this study is relugolix 
(Group A) is superior to placebo (Group B) with respect to the proportion of responders at Week 
76 (24 weeks after randomization) based on the MBL volume analyzed by alkaline hematin 
method: 
Null hypothesis H01:  πR ≤ πP    vs    Alternative hypothesis Ha1:  πR > πP 
where πR and πP are the responder rates for relugolix and placebo groups, respectively. 
The primary efficacy analysis is the treatment comparison between the relugolix Group A and 
the placebo Group B performed using a Cochran-Mantel-Haenszel (CMH) test statistic for 
proportions of responders stratified by baseline mean menstrual blood loss in the Parent study 
(< 225 mL vs ≥ 225 mL), geographic region (North America vs Other) and the duration of 
relugolix exposure prior to randomization (28 weeks vs 52 weeks). 
The study will be considered positive if the treatment effect for primary endpoint is statistically 
significant with 2-sided p-value < 0.05. The point estimate and 2-sided 95% confidence interval 
(CI) for treatment difference in responder rates for the primary efficacy endpoint will be 
calculated. 


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9.3.1.2. 
Subgroup Analyses 
Subgroup analyses of the primary efficacy endpoint comparing Group A versus Group B will be 
performed to determine whether treatment effect is consistent across clinically meaningful 
subgroups. The difference in responder rates and their 95% confidence intervals will be 
displayed in a forest plot. Subgroups will include but not be limited to the following: baseline 
MBL volume in the Parent study (< 225 mL vs ≥ 225 mL), geographic region (North America vs 
Other), duration of exposure to relugolix prior to randomization (28 weeks vs 52 weeks) as well 
as other baseline subgroups such as age, and race. Details are provided in the Statistical Analysis 
Plan. 
9.3.1.3. 
Sample Size Estimation 
Because this is an extension of the OLE study, the sample size of this study will be based on 
approximately the number of patients who have completed a Parent study (n = 780 patients in 
total), and who participated in the OLE study (n = 600 patients in total assuming about 20% 
dropout rate at 6 months from the Parent studies). Assuming the proportion of responders at 
Week 52 in the OLE study is 60%, it is estimated that approximately 360 patients will be 
randomized into this study. 
With 360 patients, the study will have at least 90% power to detect a difference of 20% or 
greater between relugolix Group A and placebo Group B for the primary endpoint. The 
following assumptions are used to determine the sample size for this study: 
• 2-sided type I error rate: 0.05 
• Randomization: 1:1 
• Responder rate for placebo Group B: 40% 
• Responder rate for Group A: 60% 
• Dropout rate: 20% 
9.3.2. 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed during the randomized treatment 
period or retreatment period: 
• Proportion of women who maintain a menstrual blood loss volume of < 80 mL at Week 104 
(52 weeks of the randomized treatment period) as measured by the alkaline hematin method; 
• Change from Week 52/Baseline to Week 76/Week 104 in menstrual blood volume (during 
the randomized treatment period); 
• Percentage change from Week 52/Baseline to Week 76 / Week 104 (during the randomized 
treatment period); 
• Proportion of patients who responded (menstrual blood loss volume of < 80 mL) to 
retreatment with relugolix 40 mg and E2/NETA during the retreatment period among placebo 
patients whose menstrual blood volume had returned to ≥ 80 mL during the 52-week 
randomized treatment period; 
 
The following secondary endpoints will be assessed at Week 76 and at Week 104 during the 
randomized treatment period: 


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• Proportion of women achieving or maintaining amenorrhea; 
• Proportion of women whose menses has resumed (among those who were amenorrhoeic at 
Week 52/Baseline); 
• Time to resumption of menses; 
• Proportion of women with menstrual blood volume ≥ 80 mL at any time point during the 
52-week randomized treatment period; 
• Time to resumption of menstrual blood volume ≥ 80 mL; 
• Change from Week 52/Baseline in hemoglobin; 
• Change from Week 52/Baseline in SF-36 domain and summary component scores; 
• Change from Week 52/Baseline in PGA for function and symptoms scores; 
• Change from Week 52/Baseline in the WPAI-UF scores; 
• Change from Week 52/Baseline in the UFS-QoL Symptom Severity scale and subscales as 
well as total scores. 
9.3.2.1. 
Secondary Efficacy Endpoint Analyses 
During Randomized Treatment Period 
For endpoints evaluating the change from Baseline, treatment comparisons will be performed 
using a mixed model repeated measures approach with treatment, randomization stratification 
factors, and treatment by visit interaction included as fixed effects and Week 52/Baseline value 
included as a covariate. The dependent variable (change from Baseline) for each patient at each 
visit will be calculated based on visit windows specified in the final Statistical Analysis Plan. In 
addition, descriptive statistics will be provided by treatment group and by visit. 
Change from baseline endpoints will be analyzed censoring the values at the time of retreatment 
with relugolix with E2/NETA. Details will be specified in the SAP. 
For endpoints evaluating proportions, treatment comparisons will be performed using a stratified 
Cochran-Mantel-Haenszel test as appropriate. 
Baseline menstrual blood loss is defined as total menstrual blood loss obtained from the Week 
52/Baseline visit prior to the date of the first dose of study drug in this Randomized Withdrawal 
study as assessed by the alkaline hematin method. The menstrual blood loss during the last on-
treatment cycle (Week 104) is the total menstrual blood loss during the last month (up to the last 
35 days) on-treatment as assessed by the alkaline hematin method. 
For time-to-event endpoints (time to achieving or maintaining a menstrual blood loss volume of 
< 80 mL 24 weeks after randomization, time to resuming menses, time to resumption of 
menstrual blood volume ≥ 80 mL), time-to-event will be defined as weeks from randomization 
of the Randomized Withdrawal study to first occurrence of the event. Patients without an event 
will be censored at last assessment date prior to the end of study. Kaplan-Meier methods will be 
used to describe the time to event distributions for each study treatment arm. 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by study treatment group. 


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During Retreatment Period 
For placebo patients whose menstrual blood volume had returned to ≥ 80 mL during the 52-week 
randomized treatment period and received retreatment: 
• the proportion of patients who responded to the retreatment (MBL < 80mL) will be 
estimated along with corresponding 95% CIs at the end of retreatment period 
• mean change and mean % change in menstrual blood volume from retreatment to end of 
retreatment period. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.4. 
Pharmacodynamic Analyses 
Pharmacodynamic estradiol concentration data will be listed and summarized by treatment arm 
and visit. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, 12-lead ECGs, and results of measurements of bone 
mineral density by DXA. 
The treatment-emergent period will be defined as the period of time from the first dose date of 
extension study drug through 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 uterine fibroids, 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’s CTCAE. All adverse events will be coded to preferred 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 
study Baseline versus post-baseline results. All data will be listed and summarized by visit. The 
change from study Baseline to each post-baseline study visit will be presented by 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 study Baseline to each post-baseline study visit will be presented by study 
treatment group for each parameter. 


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Clinical laboratory data consist of chemistry, hematology, and hormonal tests. Only data 
collected by the central laboratory will be used to do the analyses. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the 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. 
All BMD data will be listed and summarized by visit. The change, percent change from study 
Week 52/Baseline to Weeks 76 and 104 and associated 95% CIs will be presented by the study 
treatment group for each bone mineral density parameter. The number and percentage of patients 
meeting a bone mineral density decline of at least 3%, 4%, 5%, 6%, or 7% by body area (lumbar 
spine, total hip, or femoral neck) will be estimated with 95% CIs by the study treatment group. 
Additional analyses will be performed to exam 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. 
Interim Analyses 
There are no planned interim efficacy analyses. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant. For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR 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 


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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 
signed and dated by the patient. 
10.1.4. 
Confidentiality 
The investigator must assure that patient’s anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only patient number, date of birth, and an 
identification code (i.e., 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’s 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. 
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. 
10.1.6. 
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’s 
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, (e.g., history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., 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’s 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 


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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. 
10.1.7. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on Form FDA 1572 and/or other appropriate local health 
authority documents within a reasonable time period after data collection. This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
screening period if an eCRF was initiated). If a patient withdraws from the study, the reason 
must be noted on the eCRF. If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.8. 
Investigational Product Accountability 
The investigator or investigator’s designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), patient 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from the sponsor and quantities dispensed to patients, including lot number, 
date dispensed, Patient Identification Number, and the initials of the person dispensing the 
medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements. Drug may be returned or destroyed on an ongoing basis during the study if 
appropriate. At the end of the study, following final drug inventory reconciliation by the monitor, 
the study site will dispose of and/or destroy all unused study drug supplies, including empty 
containers, according to these procedures. If the site cannot meet the sponsor’s requirements for 
disposal, arrangements will be made between the site and the sponsor (or designee) for 
destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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10.1.9. 
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. 
10.1.10. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor. All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements. Approval must be obtained before changes can be 
implemented. The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required. In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken. The investigator must notify the sponsor (or designee) 
of any inadvertent protocol deviations upon their discovery and document the deviations 
appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies). The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of patients begins. Results will be posted as required. 


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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH 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: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 90 days before submission of 
the publication or presentation. The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 120 days in 
order to obtain patent protection if deemed necessary. 


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Fertility and Sterility 2000;74(3):534-539. Available at: 
http://www.fertstert.org/article/S0015-0282(00)00690-7/pdf. Accessed: 03 August 2017. 
Gliklich RE, Leavy MB, Velentgas P, Campion DM, Mohr P, Sabharwal R, Whicher D, Myers 
ER, Nicholson WK. Identification of Future Research Needs in the Comparative 
Management of Uterine Fibroid Disease. A Report on the Priority-Setting Process, 
Preliminary Data Analysis, and Research Plan. Effective Healthcare Research Report No. 
31. (Prepared by the Outcome DEcIDE Center, under Contract No. HHSA 290-2005-
0035-I, TO5). AHRQ Publication No. 11- EHC023-EF. Rockville, MD: Agency for 
Healthcare Research and Quality. March 2011. Available at: 
https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/uterine-fibroids-
2010_research.pdf. Accessed: 03 August 2017. 
Hallberg L, Nilsson L. Determination of menstrual blood loss. Scand J Clin Lab Invest. 
1964;16(2):244–248. 


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Hapangama DK, Bulmer Judith N. Pathophysiology of heavy menstrual bleeding. Women’s 
Health 2016;12(1):3-13. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstetrics & Gynecology 
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Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on hypoestrogenic 
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http://synapse.koreamed.org/Synapse/Data/PDFData/3021OGS/ogs-59-32.pdf. Accessed: 
03 August 2017. 
Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual 
bleeding. Cochrane Database of Systematic Reviews 2006;(2):CD003855. 
Marret H, Fritel X, Ouldamer L, Bendifallah S, Brun J.L, De Jesus I, Derrien J, Giraudet G, 
Kahn V, Koskas M, Legendre G, Lucot J.P, Niro J, Panel P, Pelage J.P, Fernandez H. 
Therapeutic management of uterine fibroid tumors: updated French guidelines. European 
Journal of Obstetrics and Gynecology 2012;165(2):156-164. 
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 
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Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reproductive Health: The Journal of the British 
Menopause Society. 2015;21(1):16-23. 
Stewart EA. Uterine Fibroids. Lancet. 2001 Jan 27;357(9252):293-8. 
Stewart EA. Clinical Practice. Uterine Fibroids. N Engl J Med. 2015;372(17):1646-55. 
Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a 
systematic review. BJOG. 2017 Sep;124(10):1501-1512. 
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. Archives of Gynecology and 
Obstetrics 2014;290(3):513-523. 
Wu JM, Wechter ME, Geller EJ, Nguyen TV, Visco AG. Hysterectomy rates in the United 
states, 2003. Obstet Gynecol 2007;110:1091-5. 
Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C, Sorrenti G. Add-back therapy 
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APPENDICES 
Appendix 1. 
Health Survey Standard (SF-36v2®) 
 
 
 


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Appendix 2. 
Patient Global Assessment (PGA) for Function and Symptoms 
 


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Appendix 3. 
Work Productivity Activity Impairment -Uterine Fibroids (WPAI-UF) 
 
 
 


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Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 


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Appendix 5. 
Assessment of Abnormal Liver Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with 
estradiol/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 (e.g., right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (e.g., 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 1; 
• 
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). 
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: 
An International Phase 3 Double-Blind, Placebo-controlled, 
Randomized Withdrawal Study of Relugolix Co-administered 
with Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-035 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
CH-4051 Basel 
Switzerland 
 
Regulatory Identifier(s): 
Eudra CT # 2018-001368-43 
IND # 131161 
Version and 
Effective Date: 
 
Original: 11-July-2018 
Amendment 1: 13-August-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-601-035 
Effective: 13-August-2018 
SPONSOR SIGNATURE PAGE 
An International Phase 3 Double-Blind, Placebo-controlled, Randomized Withdrawal Study of 
Relugolix Co-administered with Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number: MVT-601-035 
This protocol has been approved by Myovant Sciences GmbH. The following signatures 
document this approval. 
 
 
 
 
 
 
 
 
 
 
Myovant Sciences GmbH 
/3. -?J)f 
Date 
Date 
IJ  lolg" 
Date 
2 
CONFIDENTIAL 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Clinical Study Protocol:  MVT-601-035 
 
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INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol. 
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
 
Date 
 
Site 
 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR STATEMENT ............................................................................................................. 3 
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........................................................................................................................ 20 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding ..................................................................... 20 
2.2. 
Relugolix ................................................................................................................................... 21 
2.2.1. 
Indication .......................................................................................................................... 21 
2.2.2. 
Pharmacology ................................................................................................................... 21 
3. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 22 
4. 
INVESTIGATIONAL PLAN ..................................................................................................... 24 
4.1. 
Overall Study Design................................................................................................................. 24 
4.2. 
Discussion of Study Design, Including Dosing ......................................................................... 26 
4.3. 
Selection of Study Population ................................................................................................... 28 
4.3.1. 
Inclusion Criteria .............................................................................................................. 29 
4.3.2. 
Exclusion Criteria ............................................................................................................. 29 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number ............................. 30 
4.5. 
Removal of Patients from Therapy ............................................................................................ 31 
4.6. 
Contraception/Pregnancy Avoidance ........................................................................................ 32 
5. 
TREATMENTS ........................................................................................................................... 33 
5.1. 
Treatments Administered .......................................................................................................... 33 
5.2. 
Identity of Investigational Product ............................................................................................ 33 
5.2.1. 
Product Characteristics ..................................................................................................... 34 
5.3. 
Randomization and Stratification .............................................................................................. 34 
5.4. 
Directions for Administration .................................................................................................... 34 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 34 
5.6. 
Storage, Packaging, and Labeling ............................................................................................. 35 
5.7. 
Blinding ..................................................................................................................................... 35 
5.8. 
Study Drug Accountability and Treatment Compliance ........................................................... 36 


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5.9. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 36 
5.9.1. 
Prohibited Medications ..................................................................................................... 36 
5.9.2. 
Permitted Medications ...................................................................................................... 38 
5.9.3. 
Prohibited Non-Drug Therapies ........................................................................................ 39 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 39 
6.1. 
Schedule of Observations and Procedures ................................................................................. 39 
6.2. 
Treatment Period (Week 52/Baseline to Week 104) ................................................................. 39 
6.3. 
Early Termination Visit and Safety Follow-up Visit ................................................................. 40 
6.4. 
Unscheduled Visits .................................................................................................................... 41 
6.5. 
Study Procedures ....................................................................................................................... 41 
6.5.1. 
Efficacy-Related Procedures ............................................................................................. 41 
6.5.2. 
Safety-Related Procedures ................................................................................................ 43 
7. 
SAFETY CONSIDERATIONS .................................................................................................. 46 
7.1. 
Adverse Event Definitions......................................................................................................... 46 
7.1.1. 
Adverse Event ................................................................................................................... 46 
7.1.2. 
Serious Adverse Event ...................................................................................................... 47 
7.2. 
Adverse Event Reporting........................................................................................................... 48 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 49 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 49 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 49 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 50 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 50 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 51 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 51 
7.7. 
Study Drug Overdose Management .......................................................................................... 52 
7.8. 
Pregnancy Reporting ................................................................................................................. 53 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, Electrocardiograms, and Bone 
Mineral Density Measures ........................................................................................................ 53 
7.10. 
Benefit/Risk Assessment ........................................................................................................... 53 
8. 
DATA QUALITY ASSURANCE ............................................................................................... 56 
8.1. 
Clinical Procedures .................................................................................................................... 56 
8.2. 
Monitoring ................................................................................................................................. 56 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ........................................... 56 
9.1. 
Randomization Methods ............................................................................................................ 57 


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9.2. 
Analysis Populations ................................................................................................................. 57 
9.3. 
Efficacy Analyses ...................................................................................................................... 58 
9.3.1. 
Primary Efficacy Endpoint ............................................................................................... 58 
9.3.2. 
Secondary Efficacy Endpoints .......................................................................................... 59 
9.4. 
Pharmacodynamic Analyses ...................................................................................................... 61 
9.5. 
Safety Analyses ......................................................................................................................... 61 
9.6. 
Interim Analyses ........................................................................................................................ 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. 
Steering Committee .......................................................................................................... 64 
10.1.6. 
Study Files and Retention of Records ............................................................................... 64 
10.1.7. 
Electronic Case Report Forms .......................................................................................... 65 
10.1.8. 
Investigational Product Accountability ............................................................................. 65 
10.1.9. 
Inspections ........................................................................................................................ 66 
10.1.10. 
Protocol Compliance ......................................................................................................... 66 
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 ............................................................................... 67 
10.3.1. 
Access to Information Monitoring .................................................................................... 67 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 67 
10.3.3. 
Study Discontinuation ....................................................................................................... 67 
10.3.4. 
Publications ....................................................................................................................... 67 
REFERENCES .......................................................................................................................................... 68 
APPENDICES ........................................................................................................................................... 70 
Appendix 1. 
Health Survey Standard (SF-36v2®) ............................................................................. 70 
Appendix 2. 
Patient Global Assessment (PGA) for Function and Symptoms .................................. 76 
Appendix 3. 
Work Productivity Activity Impairment -Uterine Fibroids (WPAI-UF) ...................... 77 
Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire ...................................... 79 
Appendix 5. 
Assessment of Abnormal Liver Tests ........................................................................... 82 


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LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-035............................................................... 17 
Table 5-1 
Description of MVT-601-035 Study Drugs ...................................................................... 33 
Table 5-2 
Prohibited Medications ..................................................................................................... 36 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 44 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 50 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies ....................................................... 54 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury ...................... 82 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests .............................. 83 
 
LIST OF FIGURES 
Figure 4-1 
MVT-601 Uterine Fibroid Program Schematic ................................................................ 26 
 
 
 


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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMD 
Body Mass Data 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
E2/NETA 
estradiol 1.0 mg/norethindrone acetate 0.5 mg 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
HMB 
heavy menstrual bleeding 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MBL 
menstrual blood loss 
mITT 
modified Intent-to-Treat 
OLE 
Open-label extension; LIBERTY EXTENSION; MVT-601-3003 
PD 
pharmacodynamic 
PGA  
Patient Global Assessment 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT Interval Corrected by the Fridericia Correction Formula 
RBC 
red blood cell 
SF-36 
Short Form (36) 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
WPAI-UF 
Work Productivity Activity Impairment-Uterine Fibroids 
ULN 
Upper limit of normal 
US 
United States 
WBC 
white blood cells 
WPAI-UF 
Work Productivity Activity Impairment-Uterine Fibroids 
 


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1. 
PROTOCOL SYNOPSIS 
Study Title 
An International Phase 3 Double-Blind, Placebo-controlled, Randomized 
Withdrawal Study of Relugolix with Estradiol and Norethindrone Acetate in 
Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol 
Number 
MVT-601-035 
Location 
Multinational, including North and South America, Europe, and South Africa 
Study Centers 
Approximately 240 sites 
Study Phase 
Phase 3 
Target 
Population 
Women 18 to 51 years old diagnosed with uterine fibroids who complete the 
open-label extension study MVT-601-3003 (OLE study) and who meet the 
definition of responder. A responder is defined as a patient who demonstrates a 
menstrual blood loss of < 80 mL and at least a 50% reduction from Parent study 
baseline menstrual blood loss volume on the alkaline hematin analysis of the 
feminine products returned at Week 48 in the OLE study. 
Number of 
Patients 
Planned 
Approximately 360  
Study 
Objectives 
In women with uterine fibroids who complete the OLE study and are identified as 
responders, the efficacy objectives are as follows: 
 
Primary Efficacy Objective 
• 
To evaluate the long-term effect of relugolix 40 mg with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg (relugolix with E2/NETA) once daily, compared 
with placebo on menstrual blood loss at Week 76 (24 weeks after 
randomization). 
 
Secondary Efficacy Objectives 
• 
To evaluate the long-term effect of relugolix with E2/NETA once daily, 
compared with placebo on menstrual blood loss at 52-weeks after 
randomization. 
• 
To evaluate the effect of retreatment with relugolix with E2/NETA on 
menstrual blood loss in patients whose menstrual blood volume returned to 
≥ 80 mL during the 52-week randomized period. 
• 
To evaluate the long-term effect of relugolix with E2/NETA at 52 weeks after 
randomization on the following: 
• 
Achievement of amenorrhea 
• 
Resumption of menses 
• 
Resumption of heavy menstrual bleeding (HMB) 
• 
Hemoglobin 
• 
Health-related quality of life as measured by the Short Form (36) (SF-36)  
• 
Patient Global Assessment (PGA) for function and symptoms  
• 
Work and productivity impact as measured by the Work Productivity 
Activity Impairment-Uterine Fibroids (WPAI-UF)  


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• 
Disease-specific quality of life as measured by the Uterine Fibroid 
Symptom and Health-Related Quality of Life (UFS-QoL). 
 
Pharmacodynamic Objectives 
• To characterize the pharmacodynamic (PD) effect of withdrawal from relugolix 
with E2/NETA. 
Safety Objectives 
• 
To evaluate the safety and tolerability of relugolix with E2/NETA once daily for 
up to an additional 52 weeks, in patients who previously completed (responders 
and partial responders) the OLE study. 
• 
Adverse events 
• 
Changes in bone mineral density. 
Study Design 
Overall Study Design:  This is an international phase 3 double-blind, placebo-controlled, Randomized 
Withdrawal study that will enroll eligible patients with uterine fibroids who have completed the 
24-week treatment period in a Parent study (study MVT-601-3001 or study MVT-601-3002) and the 
28-week treatment period of the OLE (MVT-601-3003) study. When including treatment during the 
Parent study and the OLE study, patients completing this Randomized Withdrawal study will have 
received up to a total of 104 weeks of treatment. 
Study Population:  All patients who complete the OLE study with a response to treatment, provide 
informed consent, and met all eligibility criteria for study MVT-601-035 will be eligible to participate. 
Approximately 360 women (responders) with heavy menstrual bleeding associated with uterine fibroids 
will be enrolled. A responder is defined as a patient who demonstrates a menstrual blood loss of < 
80 mL and at least a 50% reduction from Parent study baseline menstrual blood loss volume on the 
alkaline hematin analysis of the feminine products returned at Week 48 in the OLE study. 
Objectives:  The objectives of the study are to evaluate long-term efficacy and safety of treatment with 
relugolix with E2/NETA for up to 104 weeks (total treatment duration includes the Parent study, OLE 
study, and Randomized Withdrawal study). 
Treatment Assignment 
Approximately 360 patients completing the OLE study and meeting the definition of responder and 
meeting all other eligibility criteria will be randomized 1:1 to blinded treatment with oral relugolix with 
E2/NETA or placebo, once daily, for up to 52 weeks. Stratification variables will include geographic 
region (North America vs Europe vs Latin America vs Rest of World), duration of relugolix exposure 
prior to randomization (28 weeks vs 52 weeks), and baseline menstrual blood loss volume in the Parent 
study (< 225 mL vs ≥ 225 mL). For patients whose menstrual bleeding returns to ≥ 80 mL (heavy 
menstrual bleeding), treatment with open-label relugolix with E2/NETA (latter also referred to as “add-
back” in context of hormonal “add-back”) will be restarted. A Schedule of Activities is provided in 
Table 1-1. 
Screening and Baseline Procedures:  The study consists of a screening period and a treatment period 
(randomized or open-label) of up to 52 weeks. Screening and baseline procedures will be done at the 
same visit for this Randomized Withdrawal study (referred to as the “Week 52/Baseline visit” in this 
study), which coincides with the Week 52 visit of the OLE study and will be defined as the date of 
completion of the last procedure in the OLE study (see Schedule of Activities; Table 1-1). The 
Week 52/Baseline visit will include vital signs, physical examination, laboratory assessments, a 12-lead 
electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, transvaginal 
ultrasound, and endometrial biopsy (only if required). When Week 52/Baseline procedures in the OLE 
study have been completed, the investigator will assess patient eligibility for participation in this study. 
The eligibility assessment will be based on data available at the Week 52/Baseline visit. No study 


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procedures will be performed until the consent form is signed. Patients will receive their last dose of 
study drug in the OLE study on the day of the Week 52/Baseline visit (as per the OLE study protocol). 
Following confirmation that the patient is eligible for this Randomized Withdrawal study and has 
provided informed consent to participate, the patient will be provided blinded study drug to begin 
dosing the following day. The first dose of study drug will be self-administered the next morning 
following the Week 52/Baseline visit. 
Post-baseline Procedures:  Study participants will be randomized to take either blinded study 
treatment (relugolix with E2/NETA or placebo) orally once daily or, when retreatment is indicated, 
open-label relugolix with E2/NETA for up to additional 52 weeks (beyond the 52 weeks of previous 
treatment during the Parent/OLE studies). All post-baseline procedures are provided in the Schedule of 
Activities (Table 1-1). Patients will be contacted on Week 52/Day 1 to confirm initiation of self-
administered dosing. 
Patients will be asked to provide feminine products for alkaline hematin analysis at each visit. If the 
analysis confirms return of heavy menstrual bleeding (defined as menstrual blood loss of ≥ 80 mL) the 
patient will be offered retreatment with open-label relugolix with E2/NETA with the onset of the next 
menses. They will resume collection of feminine products for alkaline hematin analysis until two 
consecutive analyses confirm resolution of heavy menstrual bleeding (menstrual blood loss of < 80 
mL). Patients will complete the bleeding diary daily including compliance with study drug, vaginal 
bleeding, and use of feminine products. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs and weight, 
physical examinations, clinical laboratory tests, and bone mineral density with dual-energy x-ray 
absorptiometry (DXA). Quality of life questionnaires will be completed according to the Schedule of 
Activities (Table 1-1). There is a Safety Follow-up visit (approximately 30 days after last dose of study 
drug) for all patients, and additional unscheduled follow-up visit(s) may be arranged at any time during 
the study for patients with study-related safety concerns, as needed. 
The PD effect of withdrawal from relugolix with E2/NETA will be characterized by measuring the pre-
dose concentration of estradiol at Week 56. 
Status of menstruation recovery will be documented at the Safety Follow-up visit (30 days after last 
dose of study drug). Patients whose menses have not resumed as of the Safety Follow-up visit and for 
whom there is no explanation for the lack of resumption (e.g., medical procedure or medications) will 
be contacted again by telephone 12 (± 2) weeks after the Safety Follow-up visit to determine if menses 
have resumed. These patients will be asked about factors that may affect resumption of menses. 
If a patient enrolls directly into another relugolix clinical study upon completion of the Week 104/Early 
Termination visit, then the Safety Follow-up visit, and the follow-up procedures performed under this 
protocol 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 are met at the time of the Week 52/Baseline visit: 
1. Completed the OLE study; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or 
study-specific procedures for MVT-601-035; 
Note:  Procedures conducted as part of the OLE study that also serve as baseline procedures for 
this study may be done under the informed consent for the OLE study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within 
the study period, including the Safety Follow-up period; 


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4. Is a responder:  Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from the 
Parent study baseline based on the results of the alkaline hematin testing performed on the feminine 
products returned at the Week 48 visit of the OLE study. Results from Week 44 may be used if 
Week 48 data is unavailable; 
5. Has a negative urine pregnancy test at the Week 52/Baseline visit; 
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the 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 24 weeks prior to the Week 52/Baseline 
visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at 
least 16 weeks prior to the Week 52/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 (e.g., 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:  None of the following criteria may be true for a patient to be eligible for 
enrollment into this study: 
1. Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or any 
other surgical procedure for fibroids, uterine artery embolization, magnetic resonance-guided 
focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding at any time 
during the Parent study or OLE study; 
2. 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 (e.g., bilateral hip 
replacement or spinal hardware in the lumbar spine); 
3. Anticipates use of any prohibited medications as detailed in Section 5.9.1; 
4. Has developed any contraindication to treatment with estradiol or norethindrone acetate including: 
a. Known or suspected breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism; 
d. 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. Porphyria; 
5. Has current active liver disease from any cause; 
6. Has a new diagnosis of a systemic autoimmune disease (e.g., systemic lupus erythematosus, 
Sjogren’s syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 


Clinical Study Protocol:  MVT-601-035 
 
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arthritis, vasculitic syndromes, etc.). Psoriasis not requiring or anticipated to require systemic 
therapy is permitted; 
7. Had any of the following clinical laboratory abnormalities at the OLE study Week 48 visit or any 
subsequent visit: 
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); 
c. Hemoglobin < 8 g/dL despite iron supplementation; 
8. Is currently pregnant or lactating, or intends to become pregnant during the study period or within 
4 weeks after the last dose of study drug, or plans to donate ova during the study period or within 
8 weeks after the last dose of study drug; 
9. 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; 
10. Met a withdrawal criterion in the OLE study. 
Dose and 
Route of 
Administration 
Test Product 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate. The hormonal add-back 
therapy will be over-encapsulated. 
 
Reference Product 
Placebo relugolix manufactured to match relugolix in size, shape, and color 
will be co-administered orally once daily with a placebo capsule designed to 
match the over-encapsulated active hormonal add-back therapy in size, 
shape, and color. 
 
Open-label Product 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate. 
 
Study treatment will be self-administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 52 weeks. 
Criteria for 
Evaluation 
Inferential efficacy assessments will be made on data observed from Week 52 to 
Week 104 between the following two study treatment groups: 
• 
Group A:  52 weeks of oral relugolix with E2/NETA, once daily; 
• 
Group B:  52 weeks of placebo relugolix plus capsule of placebo 
estradiol/norethindrone acetate. 
Week 52 of the OLE study will define the Baseline for this Randomized Withdrawal 
study and will be used as the reference point for all changes from baseline-related 
endpoints. The menstrual blood loss (MBL) volume at the Week 52 period of the 
OLE study will establish the patient’s baseline for evaluation of menstrual blood 
loss during the 52-week randomized treatment period of this Randomized 
Withdrawal study. 
 


Clinical Study Protocol:  MVT-601-035 
 
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Primary Efficacy Endpoint 
• 
Proportion of women who maintain a menstrual blood loss volume of < 80 mL 
at Week 76 (24 weeks of the randomized treatment period) as measured by the 
alkaline hematin method. 
 
Secondary Efficacy Endpoints 
• 
Proportion of women who maintain a menstrual blood loss volume of < 80 mL 
at Week 104 (Week 52 of the randomized treatment period) as measured by the 
alkaline hematin method; 
• 
Change from Week 52/Baseline to Week 76 and Week 104 in menstrual blood 
volume (during the randomized treatment period); 
• 
Percentage change from Week 52/Baseline to Week 76 and Week 104 in 
menstrual blood volume (during the randomized treatment period); 
• 
Proportion of patients who responded (menstrual blood loss volume of < 80 
mL) to retreatment with relugolix with E2/NETA during the retreatment 
period among placebo patients whose menstrual blood volume had returned to 
≥ 80 mL during the 52-week randomized treatment period. 
The following secondary endpoints will be assessed at Week 76 and at Week 104 
during the randomized treatment period: 
• 
Proportion of women achieving or maintaining amenorrhea; 
• 
Proportion of women whose menses has resumed (among those who were 
amenorrhoeic at Week 52/Baseline); 
• 
Time to resumption of menses; 
• 
Proportion of women with menstrual blood volume ≥ 80 mL at any timepoint 
during the 52-week randomized treatment period; 
• 
Time to resumption of menstrual blood volume ≥ 80 mL; 
• 
Change from Week 52/Baseline in hemoglobin; 
• 
Change from Week 52/Baseline in SF-36 domain and summary component 
scores; 
• 
Change from Week 52/Baseline in PGA for function and symptoms score; 
• 
Change from Week 52/Baseline in the WPAI-UF scores; 
• 
Change from Week 52/Baseline in the Uterine Fibroid Scale Quality of Life 
(UFS-QoL) Symptom Severity scale, and sub-scale scores and total scores. 
 
Pharmacodynamic Endpoint 
• 
Pre-dose concentration of estradiol at Week 56. 
Safety Endpoints 
• 
Incidence of adverse events, change in vital signs and clinical laboratory tests; 
• 
Percent change from Week 52/Baseline to Week 104 in bone mineral density at 
the lumbar spine (L1-L4), femoral neck, and total hip as assessed by DXA. 
Statistical Methods 
Efficacy 
The primary efficacy endpoint of the study is the proportion of women who maintain a menstrual blood 
loss volume of < 80 mL at Week 76 (24 weeks of the randomized treatment period) as measured by the 
alkaline hematin method. 
The primary efficacy analysis is the treatment comparison between the relugolix Group A and the 
placebo Group B performed using a Cochran-Mantel-Haenszel (CMH) test statistic for proportions of 


Clinical Study Protocol:  MVT-601-035 
 
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responders stratified by the Parent study baseline mean menstrual blood loss (< 225 mL vs ≥ 225 mL), 
geographic regions (North America vs Other) and the duration of relugolix exposure at 
Week 52/Baseline (28 weeks vs 52 weeks). 
The study will be considered positive if the treatment effect for the primary endpoint is statistically 
significant with 2-sided p-value < 0.05. The point estimate and 2-sided 95% confidence interval (CI) 
for treatment difference in responder rates for the primary efficacy endpoint will be calculated. 
Efficacy data will be summarized on the modified Intent-to-Treat Population (mITT) defined as all 
randomized patients who took at least one dose of randomized study drug. The analyses methods for 
efficacy endpoints are similar to those used for the Parent studies, unless otherwise specified in the 
Statistical Analysis Plan (SAP). 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, and bone mineral density determined by DXA. Safety data 
analyses will be performed on the Safety Population defined as all randomized patients who receive at 
least one dose of randomized or open-label study drug during the study. 
Drug exposure will be summarized by descriptive statistics. Severity of all treatment-emergent adverse 
events will be evaluated by the investigator based on the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE) and will be coded to preferred term, higher level 
term, and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The 
number and percentage of patients with adverse events will be presented by MedDRA system organ 
class and preferred term, relationship to study drug, and severity. Laboratory values also will be 
classified by toxicity grade based on the National Cancer Institute’s CTCAE. Laboratory shift tables of 
the study Week52/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 52/Baseline and Week 104/Early Termination visits. The absolute values, change, 
and percent change from the Parent study Baseline, and Z-scores will be summarized by visit and study 
treatment group. The mean percentage change from Week 52/Baseline to Week 104 in bone mineral 
density and corresponding 95% CI will be provided for each treatment group. 
Pharmacodynamics 
Pharmacodynamic estradiol concentration data (pre-dose concentration of estradiol at Week 56) will be 
listed and summarized by treatment arm and visit. 
Sample Size Estimation 
This Randomized Withdrawal study is an extension of the OLE study. The sample size of this study 
will be based on approximately the number of patients who have completed either Parent study (n = 
780 patients in total), and who have participated in the OLE study (approximately n = 600 patients in 
total assuming ~ 20% dropout rate at 6 months from the Parent studies). Assuming the proportion of 
responders at Week 52 in the OLE study is about 60%, it is estimated that approximately 360 patients 
will be responders. 
With 360 patients in the randomized cohort, the study will have at least 90% power to detect a 
difference of 20% or greater between relugolix Group A and placebo Group B for the primary 
endpoint. The following assumptions are used to determine the sample size for this study: 
• 
2-sided type I error rate: 0.05 
• 
Randomization: 1:1 
• 
Responder rate for placebo Group B: 40% 
• 
Responder rate for relugolix Group A: 60% 
• 
Dropout rate: 20%. 


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Stratification factors for Randomization 
• 
Baseline MBL volume in the Parent study (< 225 mL vs ≥ 225 mL) 
• 
Geographic region (North America vs Europe vs Latin America vs Rest of World) 
• 
Duration of exposure to relugolix (28 weeks vs 52 weeks). 
Stratification by the 4 geographic regions (North America vs Europe vs Latin America vs Rest of 
World) will be used for managing the supply of investigational product. For the purpose of stratified 
data analyses, the 4 regions will be pooled into 2 groups (North America vs Other) where Other 
includes Europe, Latin America and Rest of World. 


Clinical Study Protocol:  MVT-601-035 
 
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CONFIDENTIAL 
1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-035 
PERIOD 
TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/3002) 
Week 52/Baseline 
(Week 52 of OLE 
Study; Baseline of 
Study) 
Wk 
52, 
Day 1 
 
Wks 
56, 60 
Wk 
64 
Wks 
68, 72 
Wk 
76 
Wks 
80, 84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 104 
(or Early 
Termination 
of Study 
Drug) a  
Unsche
duled b 
Follow-up 
(~30 days 
after last 
dose of study 
drug) c 
Visit Window (days) 
OLE Study Day 
365 + 10 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
+ 10 
- 
- 3 to + 18 
Informed Consent 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications e 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
X 
Weight 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
X 
Complete Physical 
Exam 
X f 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Gynecologic Exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Signs and Symptoms-
Directed Physical 
Exam h 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X g 
X 
12-Lead ECG i 
X f 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
Clinical Laboratory 
Tests j 
X f 
 
 
X 
 
X 
 
 
 
 
 
X 
X g 
X 
Urinalysis 
X f 
 
 
 
 
X 
 
 
 
 
 
X 
X g 
 
Pregnancy Test 
(Urine) 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X 
Estradiol levels 
X 
 
X k 
 
 
 
 
 
 
 
 
 
 
 
FSHl 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 


Clinical Study Protocol:  MVT-601-035 
 
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PERIOD 
TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/3002) 
Week 52/Baseline 
(Week 52 of OLE 
Study; Baseline of 
Study) 
Wk 
52, 
Day 1 
 
Wks 
56, 60 
Wk 
64 
Wks 
68, 72 
Wk 
76 
Wks 
80, 84 
Wk 
88 
Wk 
92 
Wk 
96 
Wk 
100 
Wk 104 
(or Early 
Termination 
of Study 
Drug) a  
Unsche
duled b 
Follow-up 
(~30 days 
after last 
dose of study 
drug) c 
Visit Window (days) 
OLE Study Day 
365 + 10 
 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
+ 10 
- 
- 3 to + 18 
Transvaginal 
Ultrasound m 
X f 
 
 
 
 
 
 
 
 
 
 
 
X g 
 
Bone Densitometry n 
X f 
 
 
 
 
 
 
 
 
 
 
X o p 
X g 
 
Dispense Treatment q 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Take Study Drug Dose 
in Clinic r 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Daily Self-
Administration of 
Study Drugs 
 
X s 
X 
 
X g 
 
Daily Completion of 
Paper Bleeding Diary t 
X 
X g 
 
Dispense Feminine 
Products 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Feminine Product 
Collection and Venous 
Blood Sample u 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
Treatment Compliance 
X f 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
 
SF-36 Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PGA for function and 
symptoms 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
WPAI-UF 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
UFS-QoL 
Questionnaire 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
Adverse Event 
Collection 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


Clinical Study Protocol:  MVT-601-035 
 
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Abbreviations:  BP, blood pressure; ECG, electrocardiogram; HR, heart rate; PGA, Patient Global Assessment; SF-36, Short Form (36) Health Questionnaire; UFS-QoL, Uterine 
Fibroid Symptom and Health-Related Quality of Life; WPAI-UF, Work Productivity Activity Index-Uterine Fibroid 
a  
The Week 104 visit should occur on or after the 2-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 Safety 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 52/Baseline visit or during the Week 52/Baseline visit. Enrollment in MVT-601-035 is defined by administration of the first 
dose of MVT-601-035 study drug. 
e  
Record all prescription and nonprescription drug and supplements taken from the Week 52/Baseline visit through the Safety Follow-up period. 
f  
This is an MVT-601-3003 (OLE study) Week 52 procedure that serves as the Week 52/Baseline procedure for MVT-601-035 and is covered under the informed consent for 
the OLE study. 
g  
The indicated procedure may be performed at the unscheduled visit based on the purpose of the visit (e.g., follow-up for an adverse event or abnormal laboratory test). 
h  
The exam may include a gynecologic examination, if indicated based on signs and symptoms. 
i  
The 12-lead ECG will be submitted for central reading at the Week 52/Baseline visit. Any subsequent ECGs performed at investigator discretion will be read locally. 
j  
Clinical laboratory tests required include clinical chemistries and a complete blood count. At the Week 52/Baseline visit and Week 104 visit, additional tests include: fasting 
(at least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
k  
Pre-dose specimen drawn at Week 56 only. 
l  
Specimen for FSH will be collected on patients who have been amenorrhoeic (i.e., those who have not required the use of any feminine products) since randomization. 
m  
Transvaginal ultrasound, with or without transabdominal ultrasound, and with or without saline or gel contrast, is performed to determine uterine and myoma volumes and to 
exclude any other uterine or pelvic pathology. To avoid inter-observer and inter-device variations, a single operator will be assigned to a patient and will perform each of the 
ultrasound scans using the same device as far as possible. Once the transvaginal ultrasound is done, a transabdominal ultrasound may also be done if the uterus cannot be 
adequately imaged on transvaginal ultrasound; for example, due to enlarged size. Results must be submitted to a central reader. 
n  
Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
o  
This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 60 or earlier. However, the procedure may be 
done if it will aid in the evaluation of an ongoing adverse event. 
p  
Patients with a bone mineral density loss of > 7% at their Week 104/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 (estradiol, 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. 
q  
Patients will be dispensed randomized treatment at the Week 52/Baseline visit, for self-administration beginning the following day, Week 52, Day 1. Randomized treatment 
will be dispensed at subsequent visits until HMB (MBL ≥ 80 mL) is documented by alkaline hematin testing. When HMB has been documented, the patient will be invited for 
a visit to begin retreatment with open-label study drug. The timing of that visit should be within 7 days of the onset of the patient’s next menses (Cycle day 1-7 where Cycle 
day 1 is the first day of menstrual bleeding). 
r  
Patients will take the first dose of study drugs for this study once daily starting at Week 52, Day 1 (self-administered with phone follow-up). The last dose of study drug will 
be taken in the clinic during the Week 104/Early Termination visit. 
s  
Site to call patient and confirm first dose of study drug was taken that day. 
t  
Patients enter diary information on menstruation status and feminine product use. 
u  
Patients will collect and return all stained and soiled feminine products to the site with the initiation of randomized study drug treatment until return of heavy menstrual 
bleeding (MBL ≥ 80 mL) is observed. Collection will resume following the initiation of retreatment with open-label relugolix with add back and continue until MBL is 
observed to be < 80 mL on two consecutive collections. When the feminine products are returned, a venous blood sample (for hemoglobin) is to be collected and sent with the 
products to the central laboratory conducting the alkaline hematin assessment. 
 
                                                 


Clinical Study Protocol:  MVT-601-035 
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2. 
INTRODUCTION 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding 
Uterine leiomyomas (often referred to as fibroids or myomas) are common benign, estrogen-
dependent tumors that grow in the muscular wall of the uterus and occur in approximately 75% 
of women by the onset of menopause. While the majority of uterine fibroids are asymptomatic, 
approximately 25% of women with fibroids develop symptoms requiring treatment 
[Stewart, 2001; Stewart, 2017]. The most problematic symptom for women with uterine fibroids 
is heavy menstrual bleeding, with menstrual periods of increased duration and volume. In 
women with uterine fibroids, menstrual periods can last as long as 10 to 14 days rather than the 
usual 5 to 7 days, and blood loss can be as high as 300 to 500 mL, with anything more than 
80 mL during a given cycle considered abnormal. The heavy menstrual bleeding associated with 
uterine fibroids is likely caused by the increase in surface area of the uterine cavity, poor uterine 
contraction due to the myoma, and increased circulation, congestion, or impaired hemostasis due 
to hypertrophy of the endometrium near the myoma [Hapangama, 2016]. Persistent heavy 
menstrual bleeding can induce iron-deficiency anemia and associated fatigue and loss of energy. 
Heavy menstrual bleeding is a primary reason for the deterioration in the health-related quality of 
life assessed in patients with uterine fibroids and is a major cause of elective hysterectomy. Other 
symptoms include bulk symptoms, such as pain or pressure in the abdomen and pelvis due to 
large myoma(s), low back pain, urinary frequency or urinary tract obstruction, constipation, and 
pregnancy loss. 
The incidence of uterine fibroids increases as women grow older, and risk factors include 
nulliparity, obesity, family history, black race, and hypertension. Fibroids typically arise during 
the reproductive years, tend to enlarge during pregnancy, and regress after menopause as these 
tumors are dependent upon estrogen and progesterone for their growth. Transvaginal ultrasound 
is used most commonly to diagnose these benign tumors, and magnetic resonance imaging, 
sonohysterography, and hysteroscopy are used to evaluate their size and position. The type of 
treatment recommended for uterine fibroids typically depends upon their size, location, the 
patient’s age, reproductive plans, and obstetrical history. Few medical options are available for 
women with heavy menstrual bleeding associated with uterine fibroids, and approximately 60% 
of women who received medical therapy in one study underwent a surgical procedure within 
2 years [Marjoribanks, 2006], suggesting many women are inadequately treated with the 
currently available medical therapies. 
Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide acetate (also known as 
leuprorelin) are effective in lowering estrogen and progesterone levels, decreasing menstrual 
bleeding, and decreasing fibroid size. However, they cannot be used for more than 6 months due 
to bone mineral density loss from the resulting hypoestrogenic state. The GnRH agonists, which 
are administered by injection at 1- or 3-month intervals, first stimulate secretion of luteinizing 
hormone (LH) and follicle-stimulating hormone (FSH), which, in turn, increase estradiol and 
progesterone levels resulting in a flare of clinical symptoms. This initial rise in hormonal levels 
is followed by a gradual decline in levels over 4 weeks as the pituitary becomes desensitized to 
the chronic stimulation of the GnRH agonist and LH and FSH levels fall. Other medical 
treatments are used but have limited clinical effectiveness, including tranexamic acid, aromatase 
inhibitors, nonsteroidal anti-inflammatory medications, and danazol. 


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The current mainstay of treatment for women with heavy menstrual bleeding associated with 
uterine fibroids is surgery. Several surgical procedures are frequently performed including 
myomectomy by various techniques, endometrial ablation, endometrial uterine artery 
embolization, and magnetic resonance-guided focused-ultrasound surgery. Each of these 
procedures has complications. For example, abdominal myomectomy results in complications 
requiring hysterectomy in up to 3 to 4% of cases, along with the frequent development of 
intraoperative adhesions [Gliklich, 2011]. Furthermore, recurrence of heavy menstrual bleeding 
after myomectomy is common, with at least 25% of women requiring additional treatment 
[Stewart, 2015; Marret, 2012; ACOG Practice Bulletin No. 96, 2008]. Hysterectomy is the 
definitive procedure with more than 200,000 hysterectomies performed annually in the United 
States (US) for uterine fibroids [Farquhar, 2002; Wu, 2007]. Major complications have been 
reported to occur in up to 25% of women undergoing hysterectomy, including infection, severe 
bleeding, and injuries to the urethra, bowel, or bladder. One study showed that among women 
with Medicaid insurance who underwent abdominal hysterectomy, there was a 10% risk of 
transfusion and up to a 28% risk of medical or surgical complications including major blood loss, 
wound infection, and febrile episodes [Gliklich, 2011]. 
Approximately 3 million women in the US suffer from symptomatic uterine fibroids that are 
inadequately treated with medical therapy, and related US health care costs for uterine fibroids 
exceeds $34 billion [Stewart, 2015; Cardozo, 2012; Gliklich, 2011]. There is a great need for a 
safe and efficacious medicine that can decrease the symptoms of uterine fibroids so women have 
an alternative to myomectomy and hysterectomy. 
2.2. 
Relugolix 
The current relugolix Investigator’s Brochure summarizes the nonclinical toxicology and 
previous human experience with relugolix. The previous human experience with relugolix 
includes results of phase 1 and phase 2 studies evaluating relugolix monotherapy in women with 
uterine fibroids or endometriosis and in men with prostate cancer, and phase 3 studies in women 
with uterine fibroids. The Investigator’s Brochure also provides a full discussion of the safety 
profile of relugolix. 
2.2.1. 
Indication 
Relugolix 40 mg with estradiol 1.0 mg/norethindrone acetate 0.5 mg (relugolix with E2/NETA) 
is being developed as a once-daily oral medication for the treatment of heavy menstrual bleeding 
associated with uterine fibroids. 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. 
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. 


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Relugolix antagonizes human GnRH receptors present on 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 LH 
and FSH 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 when 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 
The objectives of this Randomized Withdrawal study are to evaluate the long-term efficacy and 
safety of relugolix with E2/NETA, once daily, for up to 104 weeks in patients with uterine 
fibroids who have completed a total of 52 weeks of treatment including 24-week treatment 
period in a Parent study (study MVT-601-3001 or study MVT-601-3002) and 28-week treatment 
period of the OLE study and who meet the definition of responder. A responder is defined as a 
patient who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from 
Parent study baseline menstrual blood loss volume on the alkaline hematin analysis of the 
feminine products returned at Week 48 in the OLE study. 
Primary and secondary assessment of efficacy and safety assessments will be made in the 
following two study treatment groups: 
• Group A:  52 weeks of relugolix with E2/NETA, once daily; 
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo 
estradiol/norethindrone acetate. 
Week 52 of the OLE study will define the baseline for this Randomized Withdrawal study and 
will be used as the reference point for all changes from baseline-related endpoints. The Week 48 
blood loss volume establishes responder status. Menstrual blood loss volume in this study will be 
compared to the threshold of 80 mL. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA, once daily, compared with 
placebo on menstrual blood loss at Week 76 
(24 weeks after randomization). 
• 
Proportion of women who maintain a 
menstrual blood loss volume of < 80 mL at 
Week 76 (24 weeks of the Randomized 
treatment period) as measured by the alkaline 
hematin method. 


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Objective(s) 
Endpoint(s) 
Secondary Efficacy 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA, once daily compared with 
placebo on menstrual blood loss at 52 weeks 
after randomization. 
• 
Proportion of women who maintain a 
menstrual blood loss volume of < 80 mL at 
Week 104 (52 weeks of the randomized 
treatment period) as measured by the alkaline 
hematin method; 
• 
Change from Week 52/Baseline to Week 76 
and Week 104 in menstrual blood volume 
(during the randomized treatment period); 
• 
Percentage change from Week 52/Baseline to 
Week 76 and Week 104 in menstrual blood 
volume (during the randomized treatment 
period). 
• 
To evaluate the effect of retreatment with 
relugolix with E2/NETA on menstrual blood 
loss in patients whose menstrual blood 
volume returned to ≥ 80 mL during the 52-
week randomized period. 
• 
Proportion of patients who responded 
(menstrual blood loss volume of < 80 mL) to 
retreatment during the retreatment period 
among placebo patients whose menstrual 
blood volume returns to ≥ 80 mL during the 
52-week randomized treatment period. 
• 
To evaluate the long-term effect of relugolix 
with E2/NETA at 52 weeks after 
randomization on the following: 
• 
Achievement of amenorrhea 
• 
Resumption of menses 
• 
Resumption of heavy menstrual bleeding 
(HMB) 
• 
Hemoglobin 
• 
Health-related Quality of Life as 
measured by the Short Form (36) Health 
(SF-36) questionnaire 
• 
Patient Global Assessment (PGA) for 
function and symptoms  
• 
Work and Productivity impact as 
measured by the Work Productivity 
Activity Impairment-Uterine Fibroids 
(WPAI-UF) questionnaire 
• 
Disease-specific quality of life as assessed 
by the Uterine Fibroid Symptom and 
Health-Related Quality of Life (UFS-
QoL) questionnaire 
The following secondary endpoints will be 
assessed at Week 76 and Week 104 during the 
randomized treatment period: 
• 
Proportion of women achieving or 
maintaining amenorrhea; 
• 
Proportion of women whose menses has 
resumed (among those who were 
amenorrhoeic at Week 52/Baseline); 
• 
Time to resumption of menses; 
• 
Proportion of women with menstrual blood 
volume ≥ 80 mL at any timepoint during the 
52-week randomized treatment period; 
• 
Time to resumption of menstrual blood 
volume ≥ 80 mL; 
• 
Change from Week 52/Baseline in 
hemoglobin; 
• 
Change from Week 52/Baseline in SF-36 
domain and summary component scores; 
• 
Change from Week 52/Baseline in PGA for 
function and symptoms score; 
• 
Change from Week 52/Baseline in the WPAI-
UF scores; 
• 
Change from Week 52/Baseline in the UFS-
QoL scale and sub-scale scores as well as the 
total score. 


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Objective(s) 
Endpoint(s) 
Pharmacodynamic 
• To characterize the pharmacodynamic (PD) 
effect of withdrawal from relugolix with 
E2/NETA 
• Pre-dose concentration of estradiol at 
Week 56 
Safety 
• 
To evaluate the safety and tolerability of 
relugolix with E2/NETA, once daily, for up to 
an additional 52 weeks, in patients who 
previously completed (responders and partial 
responders) the OLE study 
• 
Adverse events 
• 
Changes in bone mineral density 
• 
Incidence of adverse events, change in vital 
signs and clinical laboratory tests; 
• 
Percent change from Week 52/Baseline to 
Week 104 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by DXA. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This Randomized Withdrawal study (MVT-601-035) is an international phase 3 double-blind, 
placebo-controlled study that will enroll eligible patients with uterine fibroids who have 
completed the 24-week treatment period in a Parent study (study MVT-601-3001 or study 
MVT-601-3002) and the 28-week treatment period of the OLE study. When including treatment 
during the Parent study and the OLE study, patients completing this Randomized Withdrawal 
study will have received up to a total of 104 weeks of treatment with relugolix. 
Study Population:  All patients completing the OLE study with a response to treatment and 
consenting will be eligible to participate. Approximately 360 women with heavy menstrual 
bleeding associated with uterine fibroids will be enrolled. A responder is defined as a patient 
who demonstrates a menstrual blood loss of < 80 mL and at least a 50% reduction from Parent 
study baseline menstrual blood loss volume on the alkaline hematin analysis of the feminine 
products returned at Week 48 in the OLE study. 
Objectives:  The objectives of the study are to evaluate long-term efficacy and safety of 
treatment with relugolix with E2/NETA for up to 104 weeks (total treatment duration includes 
the Parent study, OLE study, and Randomized Withdrawal study). 
Approximately 360 patients completing the OLE study and meeting the definition of responder 
and all other eligibility criteria will be randomized 1:1 to blinded treatment with oral relugolix 
with E2/NETA, once daily or placebo for up to 52 weeks. For patients whose menstrual bleeding 
returns to ≥ 80 mL (heavy menstrual bleeding), treatment with open-label relugolix with 
E2/NETA will be restarted. A Schedule of Activities is provided in Table 1-1. 
Screening and Baseline Procedures:  Screening procedures will be done on the same day as the 
Week 52 visit for OLE. This visit will be referred to as the “Week 52/Baseline visit”. The Week 
52/Baseline visit will include vital signs, physical examination, laboratory assessments, a 12-lead 
electrocardiogram (ECG), bone densitometry, patient-reported outcome assessments, 


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transvaginal ultrasound, and endometrial biopsy (only if required). When Week 52/Baseline 
procedures in the OLE study have been completed, the investigator will assess patient eligibility 
for participation in this study. The eligibility assessment will be based on data available at the 
Week 52/Baseline visit. No study procedures will be performed until the consent form is signed. 
Patients will receive the last dose of study drug in the OLE study on the day of the 
Week 52/Baseline visit (per the OLE protocol) and will be dispensed study drug for this 
Randomized Withdrawal study in the clinic after the patient is determined to be eligible for this 
study and has provided informed consent to participate. The first dose of study drug for the 
Randomized Withdrawal study will be self-administered the next morning following the 
Week 52/Baseline visit. Dosing will be confirmed by telephone. 
Post-baseline Procedures:  All post-baseline procedures are provided in the Schedule of 
Activities (Table 1-1). 
Patients will be asked to provide feminine products for alkaline hematin analysis at each visit 
until the analysis confirms the return of heavy menstrual bleeding (defined as menstrual blood 
loss of ≥ 80 mL). The patients will then be offered retreatment with open-label relugolix with 
E2/NETA (latter also referred to as “add-back” in context of hormonal “add-back”) with the 
onset of the next menses. They will resume collection of feminine products for alkaline hematin 
analysis until two consecutive analyses confirm resolution of heavy menstrual bleeding 
(menstrual blood loss of < 80 mL). Patients who experience a return of heavy menstrual bleeding 
(or terminate early because they have a return of heavy menstrual bleeding) but decline 
retreatment with open-label study drug will complete an Early Termination visit and a 30-day 
Safety Follow-up visit. 
At the Week 104/Early Termination visit, all other patients will have an assessment of bone 
mineral density via dual-energy x-ray absorptiometry (DXA). Patients will complete the bleeding 
diary daily including compliance with study drug, vaginal bleeding, and use of feminine 
products. 
The pharmacodynamic effect of withdrawal from relugolix with E2/NETA will be characterized 
by measuring the pre-dose concentration of estradiol at Week 56. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, and bone mineral density with DXA. 
Quality of life questionnaires will be completed according to the Schedule of Activities (Table 
1-1). 
Status of menstruation recovery will be documented at the Safety Follow-up visit (30 days after 
last dose of study drug). Patients whose menses have not resumed as of the Safety Follow-up 
visit and for whom there is no explanation for the lack of resumption (e.g., medical procedure or 
medications) will be contacted again by telephone 12 (± 2) weeks after the Safety Follow-up 
visit to determine if menses have resumed. These patients will be asked about factors that may 
affect the resumption of menses. 
If a patient enrolls directly into another relugolix clinical study upon completion of the 
Week 104/Early Termination visit, then the Safety Follow-up visit and the follow-up procedures 
performed under this protocol may be waived. 
A schematic of the MVT-601 Uterine Fibroid Program including the MVT-601-035 Study is 
provided in Figure 4-1. 


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Figure 4-1 
MVT-601 Uterine Fibroid Program Schematic  
 
 
4.2. 
Discussion of Study Design, Including Dosing 
This Randomized Withdrawal study (MVT-601-035) is an extension of the 2 replicate, 24-week 
phase 3 Parent studies (MVT-601-3001 and MVT-601-3002) and subsequent 28-week open-
label extension study (MVT-601-3003). The Parent studies and open-label extension study were 
designed to establish the efficacy and safety of relugolix with E2/NETA, once daily, for up to 52 
weeks. This subsequent 52-week Randomized Withdrawal study provides additional efficacy and 
safety data for up to 104 weeks of treatment. The primary objective is to assess the long-term 
efficacy of relugolix with E2/NETA, once daily, for up to 104 weeks on reduction of heavy 
menstrual bleeding, the most common and burdensome symptom of uterine fibroids. Because 
heavy menstrual bleeding due to uterine fibroids is a chronic condition in premenopausal 
women, this investigation is clinically relevant since patients are anticipated to require ongoing 
therapy. 
In this design, the long-term efficacy of relugolix with E2/NETA will be assessed by comparing 
the maintenance of response in patients receiving continuous treatment to that in patients who are 
withdrawn from therapy. Patients who responded to open-label relugolix with E2/NETA in the 
OLE will be randomly assigned to continued active treatment or placebo in this study. Upon 
relapse, i.e., the return of heavy menstrual bleeding (MBL ≥ 80 mL), retreatment with open-label 
relugolix with E2/NETA, once daily, will be permitted. This design allows for placebo-
controlled assessment of maintenance of efficacy while minimizing the duration of time in which 
symptomatic patients are without treatment. The effect of active treatment will be demonstrated 
by observing the difference in response between continued active treatment and placebo groups. 
This design also affords the opportunity to assess the effectiveness of retreatment. This is 
important because, in clinical practice, interruption of treatment for variable lengths of time may 
occur due to circumstances such as poor compliance, desire to conceive, reimbursement issues, 
or intercurrent illness or surgery. Patients in this Randomized Withdrawal study who are given 
retreatment will be assessed to evaluate whether improvement in heavy menstrual bleeding can 
be recaptured. 
The dose of relugolix for this Randomized Withdrawal study 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 


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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 demonstrated the 40 mg dose provided the greatest reduction in menstrual blood loss and 
was the optimal dose to move forward into phase 3 development. 
The 40 mg dose has been used in two phase 3 studies in Japan. One study demonstrated that 
relugolix 40 mg administered once daily to women experiencing heavy menstrual bleeding due 
to uterine fibroids reduced menstrual blood loss similar to leuprolide. The second study 
compared 40 mg relugolix to placebo in women having pain symptoms associated with uterine 
fibroids. The study included women with a Numerical Rating Scale (NRS) of score of ≥ 4 in the 
menstrual cycle prior to randomization. The proportion of subjects without pain symptoms 
(NRS = 0) during the 28 days before the final dose of study drug was higher in the relugolix 
40 mg group (48.5%) than in the placebo group (3.1%). 
However, data on bone mineral density from DXA scanning in both the phase 2 and phase 3 
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 limits dosing of relugolix 
to short term use only. To mitigate this known adverse consequence of estrogen suppression, 
relugolix is given with E2/NETA in phase 3 clinical studies, including this study. Estradiol 1.0 
mg with norethindrone acetate 0.5 mg 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 led to less bone mineral density loss, these doses did not 
provide adequate relief from heavy menstrual bleeding in a high enough percentage of women to 
move forward into phase 3 clinical development.  Additionally, based on the DXA data from the 
phase 2 study, these lower doses 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 with 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 heavy menstrual blood loss. It 
is well known that bone is exquisitely sensitive to estrogen and low-doses of supplemental 
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, 2017]. 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, 2015; Lee, 2016; Franke, 2000]. The estradiol/norethindrone 
acetate combination proposed for evaluation in combination with relugolix in this Randomized 
Withdrawal phase 3 study is currently approved in the US as long-term hormone replacement 


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therapy to prevent bone loss and alleviate vasomotor symptoms in postmenopausal women 
[Activella US Prescribing Information, 2017]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix with E2/NETA demonstrated that this dose of add-back therapy maintains 
serum estradiol in the 25 to 50 pg/mL range, a 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 hormonal 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, 2017]) 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 Randomized Withdrawal study 
(1.0 mg and 0.5 mg, respectively) are also used in the Parent studies (MVT-601-3001 and MVT-
601-3002) and the OLE study (MVT-3003). This 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 marked decrease in the heavy 
menstrual bleeding associated with uterine fibroids in a majority of women in well-designed 
phase 2 and phase 3 studies. However, its administration was associated with a degree of bone 
mineral density loss unacceptable for long-term treatment. This phase 3 double-blind, placebo-
controlled Randomized Withdrawal study will assess long-term efficacy and safety of relugolix 
with E2/NETA, once daily, for the reduction of heavy menstrual bleeding associated with uterine 
fibroids, and for mitigation of bone mineral density loss and other side effects associated with a 
hypoestrogenic state such as hot flushes. 
This Randomized Withdrawal study will provide information on long-term efficacy and safety 
data for an additional 52 weeks of treatment, providing approximately 2 years of efficacy and 
safety data from the women with uterine fibroids treated with relugolix in the Parent studies 
(MVT-601-3001 and MVT 601-3002) and the OLE (MVT 601-3003) study. 
4.3. 
Selection of Study Population 
The study population will include approximately 360 responders who have completed the 
24-week treatment period in a Parent study (Study MVT-601-3001 or Study MVT-601-3002) 
and the 28-week treatment period of the OLE study with a response to treatment and meet all 
eligibility criteria for this study. 
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. 


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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 Criteria 
A woman will be eligible for enrollment in this study only if all of the following inclusion 
criteria are met at the time of the Week 52/Baseline visit: 
1. Completed the OLE study (MVT-601-3003); 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures for MVT-601-035; 
Note:  Procedures conducted as part of the OLE study that also serve as baseline procedures 
for this study may be done under the informed consent for the OLE study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids 
within the study period, including the Safety Follow-up period; 
4. Is a responder:  Has a menstrual blood loss of < 80 mL AND at least a 50% reduction from 
the Parent study baseline based on the results of the alkaline hematin testing performed on 
the feminine products returned at the Week 48 visit of the OLE. Results from Week 44 may 
be used if Week 48 data is unavailable; 
5. Has a negative urine pregnancy test at the Week 52/Baseline visit; 
6. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the 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 24 weeks prior to the 
Week 52/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 16 weeks prior to the Week 52/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 (e.g., 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. 
4.3.2. 
Exclusion Criteria 
None of the following criteria may be true for a patient to be eligible for enrollment into this 
study: 
1. Has undergone myomectomy, ultrasound-guided laparoscopic radiofrequency ablation, or 
any other surgical procedure for fibroids, uterine artery embolization, magnetic resonance-


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guided focused ultrasound for fibroids, or endometrial ablation for abnormal uterine bleeding 
at any time during the Parent study or OLE study; 
2. 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 (e.g., 
bilateral hip replacement or spinal hardware in the lumbar spine); 
3. Anticipates use of any prohibited medications as detailed in Section 5.9.1; 
4. Has developed any contraindication to treatment with estradiol or norethindrone acetate, 
including: 
a. Known or suspected breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism; 
d. 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. Porphyria; 
5. Has current active liver disease from any cause; 
6. Has a new diagnosis of a systemic autoimmune disease (e.g., 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; 
7. Had any of the following clinical laboratory abnormalities at the OLE study Week 48 visit or 
any subsequent visit: 
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); 
c. Hemoglobin < 8 g/dL despite iron supplementation; 
8. Is currently pregnant or lactating, or intends to become pregnant during the study period or 
within 4 weeks after the last dose of study drug, or plans to donate ova during the study 
period or within 8 weeks after the last dose of study drug; 
9. 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. 
10. Met a withdrawal criterion in the OLE study. 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number 
Eligible patients who sign consent will be identified with the same Patient Identification Number 
assigned to the patient during the OLE study. All patients completing the OLE study with a 


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response to treatment and consenting will be eligible to screen. Once eligibility is confirmed, 
they will be randomized 1:1 to blinded treatment with oral relugolix with E2/NETA, once daily 
or placebo for up to 52 weeks. 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 104 visit with appropriate safety follow-up 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; Table 1-1) and will have a follow-up 
visit to assess safety approximately 30 days after the end of study drug treatment (i.e., after the 
patient’s last dose of study drugs). 
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 an 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%); 
• If an iron deficiency anemia related to heavy menstrual bleeding develops with a 
hemoglobin < 8g/dL and is unresponsive to iron supplementation; 
• 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 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 OLE 
study Week 52 DXA assessment of bone mineral density; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements. This may include < 75% compliance with 
the study drug for at least 2 months; not returning any feminine products despite having 
menstrual bleeding for > 2 consecutive cycles; or missing multiple study visits; 
• 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 make at least 3 documented attempts to contact the 
subject by telephone, or if necessary by certified letter 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. 
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 52/Baseline visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™) at least 4 months prior to the Week 52/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 (e.g., 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 whom none of the above methods 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 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). 


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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Approximately 360 patients completing the OLE study and meeting the definition of responder 
and meeting all other eligibility criteria will be randomized 1:1 to blinded treatment with oral 
relugolix with E2/NETA (relugolix with add-back) or placebo for up to 52 weeks. 
• Group A:  52 weeks of oral relugolix with E2/NETA, once daily; 
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo 
estradiol/norethindrone acetate. 
The placebo relugolix tablet is manufactured to match the relugolix tablet in size, shape, and 
color. The placebo capsule is designed to match the over-encapsulated estradiol/norethindrone 
acetate active product in size, shape, color, and odor. 
After randomization, if the alkaline hematin analysis confirms the return of heavy menstrual 
bleeding (defined as menstrual blood loss of ≥ 80 mL) the patient will be offered retreatment at 
their next visit with open-label relugolix with add-back for the remainder of the treatment period. 
Descriptions of all study drugs are provided in Table 5-1. 
Table 5-1 
Description of MVT-601-035 Study Drugs 
Name of 
Investigational 
Product 
Blinded and 
Open-Label 
Relugolix 
Relugolix 
Placebo 
Blinded 
Estradiol / 
Norethindrone 
Acetate 
Estradiol / 
Norethindrone 
Acetate Placebo 
Open-Label 
Estradiol / 
Norethindrone 
Acetate 
Formulation 
Description 
Round film-
coated pink 
tablet 
Round film-
coated pink 
tablet 
A Swedish 
orange, over-
encapsulated 
round film-
coated white 
tablet with 
back-fill 
material 
A Swedish 
orange capsule 
with placebo 
back-fill 
material 
Round, white, 
biconvex, film-
coated tablet 
Dosage Form 
Tablet 
Tablet 
Capsule 
Capsule 
Tablet 
Unit Dose 
Strength 
40 mg 
0 mg 
Estradiol 1.0 mg 
/ Norethindrone 
acetate 0.5 mg 
0 mg 
Estradiol 1.0 mg 
/ Norethindrone 
acetate 0.5 mg 
Route of 
Administration/ 
Duration 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
Oral once daily 
for up to 52 
weeks 
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)/norethindrone acetate (0.5 mg) is a fixed-dose combination product. 


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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/norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
Patients are randomized 1:1 ratio to blinded treatment with oral relugolix with E2/NETA 
(relugolix with add-back) or placebo. Stratification factors for randomization are as follows: 
• Baseline MBL volume in the Parent study (< 225 mL vs ≥ 225 mL) 
• Geographic region (North America vs Europe vs Latin America vs Rest of World) 
• Duration of exposure to relugolix (28 weeks vs 52 weeks). 
5.4. 
Directions for Administration 
The study drugs should be taken in the fasted state (water, tea, or coffee are allowed) 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 drugs should be taken as close as possible to the same time 
of morning each day. 
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 using adequate medical intervention should 
have their treatment interrupted until the toxicity improves to a grade 2 or lower severity. 
Patients may subsequently be restarted on study drug with the written approval of the sponsor (or 
designee). 


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5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20 – 25°C (68 – 770F) (with excursions permitted ± 5°C) to 15 - 30°C 
(59 - 860F) 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. 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, lot/batch number, expiry date, 
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. 
For randomized treatment, relugolix 40 mg will be supplied to the study site in blister cards. It 
will be co-packaged with the estradiol/norethindrone acetate. Open-label relugolix will be 
supplied in a bottle, and the open-label estradiol/norethindrone acetate will be supplied in a dial 
pack. 
5.7. 
Blinding 
During the double-blind Randomized Treatment and through the Safety Follow-up period, all 
patients, investigators, and sponsor staff or representatives involved in the conduct of the study 
will be blinded to treatment assignment, with the exception of an unblinded statistician(s) who is 
responsible for developing the randomization codes.  The blind will be maintained during 
assessment of pharmacodynamic testing.  Estradiol and FSH concentrations will be reported to 
the sponsor only after database lock and unblinding, or provisions will be made to provide data 
only to personnel approved for unblinding. 
Unblinding by the investigator for a given patient will occur only if the knowledge of treatment 
assignment will materially change the planned management of a medical emergency. 
Investigators will have direct access to a given patient’s individual study treatment and the 
decision to unblind a patient’s treatment assignment in an emergency situation resides with the 
investigator. However, the investigator should attempt to contact the medical monitor or 
appropriate study personnel to discuss options before unblinding the patient’s treatment 
assignment unless the urgency of the medical situation precludes this. If unblinding by the 
investigator occurs before sponsor personnel can be consulted or notified, the investigator must 


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notify the sponsor as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded patient. Patients whose treatment assignment has been unblinded by 
the investigative site will be permanently discontinued from treatment. 
The sponsor (or designee) may unblind the treatment assignment for any patient with a serious 
adverse event. 
For randomized patients whose menstrual blood volume returns to ≥ 80 mL during the 52-week 
randomized treatment period, therefore, will get retreatment with oral relugolix with E2/NETA, 
their randomized treatment assignment information is blinded during the 52-week randomized 
treatment period for all patients, investigators, and sponsor staff or representatives involved in 
the conduct of the study. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused and used study drugs 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. 
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 to the Safety 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 
 
Anti-convulsant drugs 
(specified) 
phenobarbital 
carbamazepine 
phenytoin 
valproic acid 
primidone 
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 intrauterine system 
 
Bone Agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
Anti-Coagulants/ 
Platelets/Fibrinolytics 
warfarin 
clopedigril 
tranexamic acid 
vitamin k preparations 
factor Xa inhibitors 
 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
Anticipated use (at screening) of 
systemic glucocorticoids at an oral 
prednisone-equivalent dose of more 
than 5 mg every other day during 
the study is prohibited. 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/ritonavir 
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 
carvedilolg 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelor 
verapamil 
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. 
Abbreviation:  GnRH, gonadotropin-releasing hormone 
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. Metoprolol and atenolol are permitted 
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 
From the Week 52/Baseline visit to the Week 104/Early Termination visit, the use of analgesics 
for uterine fibroid-associated pain should be in accordance with the local standard of care and at 
the discretion of the investigator. 


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5.9.2.2. 
Iron Therapy 
Women who enter the Randomized Withdrawal study on iron therapy may continue iron 
treatment during the study. Women who develop new microcytic iron-deficiency anemia during 
the study, defined as a hemoglobin ≤ 10 g/dL, a mean corpuscular volume below the lower limit 
of normal, and low serum iron and ferritin, must also be started on iron therapy, either oral or 
parenteral. 
5.9.3. 
Prohibited Non-Drug Therapies 
Surgical and other interventional treatment of uterine fibroids is prohibited from the 
Week 52/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 
Table 1-1). Study procedures are briefly described in 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 Table 1-1). The study is divided into 2 periods:  Treatment period (Table 1-1) 
and Safety Follow-up period. Unscheduled visits may occur as needed to evaluate patients. 
6.2. 
Treatment Period (Week 52/Baseline to Week 104) 
As denoted in the Schedule of Activities (see Table 1-1), certain Week 52 visit procedures in the 
OLE study will serve as the Week 52/Baseline procedures for patients who are interested in 
participating in this Randomized Withdrawal study, and these Week 52 procedures will be 
performed under the informed consent for the OLE study. 
Patients will be required to sign an informed consent form for the Randomized Withdrawal study 
and will be eligible if they meet all the eligibility criteria. 
Once eligibility is determined, all additional Week 52/Baseline visit procedures described in the 
Schedule of Activities (see Table 1-1) that were not performed as part of the Week 52 visit of the 
OLE study will be completed. These include the following: 
• Informed consent; 
• Record concomitant medications; 
• Dispense study treatment; 
• Dispense feminine products; 
• Record adverse events, if any. 
Patients will record vaginal bleeding and feminine product use in a paper diary each day. Safety 
monitoring including physical examination, pregnancy tests, and adverse event assessment will 


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occur at each visit. Additional safety assessments will be performed as described in the Schedule 
of Activities (see Table 1-1). Bone densitometry will occur at the Week 52/Baseline, and 
Week 104/Early Termination visits. A transvaginal ultrasound (with or without a transabdominal 
ultrasound) will be performed at Week 52/Baseline visit. 
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 52/Baseline and Week 104/Early Termination visits and for 1 hour after administration of 
the study drug in the clinic. Laboratory requisitions must indicate whether the patient fasted for 
the chemistry and lipid testing. 
Patients will be randomized 1:1 to blinded treatment with oral relugolix with E2/NETA, once 
daily, or placebo beginning on the day following the Week 52/Baseline visit and continuing 
through the Week 104 visit. 
Patients will receive their last dose of study drug in the OLE study on the day of the 
Week 52/Baseline visit (as per the OLE study protocol), and the patient will be provided blinded 
study drug to begin dosing the following day. The first dose of study drug will be self-
administered the next morning following the Week 52/Baseline visit. After the 
Week 52/Baseline visit, a phone call will occur on Week 52 Day 1 (+ 2 days) to document the 
time of self-administration of the first dose of study drugs and record any reported adverse 
events. On-treatment study visits will occur every 4 weeks for a total of 104 Weeks. With the 
initiation of randomized treatment, patients will collect all stained/soiled feminine products and 
at the study visits return their feminine products for alkaline hematin testing. A venous blood 
sample (for hemoglobin) must be collected each time feminine products are returned and sent to 
the central laboratory conducting the alkaline hematin assessment. If the patient is having cyclic 
bleeding, the site must document the start and stop dates of the patient’s menses corresponding to 
the collected feminine products. The paper diary recording vaginal bleeding and feminine 
product use should be reviewed at each visit to assess compliance with feminine product 
collection. 
When the alkaline hematin analysis indicates MBL ≥ 80 mL, the patient will be asked to return 
with onset of the next menses, no later than cycle day #7 (where cycle day #1 is the first day of 
menstrual bleeding), to begin retreatment with open-label relugolix with E2/NETA. The timing 
of this visit may necessitate an unscheduled visit. The final dose of randomized treatment should 
be self-administered by the patient the day prior to presenting for retreatment. The first dose of 
retreatment with open-label relugolix with E2/NETA will be administered at the clinic visit. 
Feminine products do not need to be collected with the episode of menstrual bleeding associated 
with the initiation of retreatment, but once the episode is complete, all stained/soiled feminine 
products must be collected and returned at subsequent visits for alkaline hematin analysis until 
MBL < 80 mL is observed for two consecutive collections. 
6.3. 
Early Termination Visit and Safety 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; however, for 
patients whose last dose of study drug is during Week 56, bone densitometry does not need to be 


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performed. However, densitometry may be performed at the investigator’s discretion as an aid to 
adverse event follow-up. 
Patients who experience a return of heavy menstrual bleeding (or terminates early because they 
have a return of heavy menstrual bleeding) but decline retreatment with open-label study drug 
will complete an Early Termination visit and a 30-day Safety Follow-up visit. 
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 
uterine fibroids, whichever occurs first. However, the Safety Follow-up visit may be waived for 
patients who enroll directly into another relugolix clinical study upon completion of the 
Week 104 visit. 
The Safety 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 (Table 1-1) for individual study visit procedures during the Safety 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, to initiate retreatment, 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, etc., may be conducted as 
clinically indicated. See the Schedule of Activities (Table 1-1) for tests that may be performed, 
as indicated by the reason for a visit, 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 transvaginal ultrasound endometrial biopsy, or 
DXA, unless urgently indicated. 
6.5. 
Study Procedures 
6.5.1. 
Efficacy-Related Procedures 
6.5.1.1. 
Bleeding Diary 
All women enrolled in the study will be provided with a paper bleeding diary along with 
instructions for its use. Patients will complete the diary daily including compliance with study 
drug, vaginal bleeding, and use of feminine products. 


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6.5.1.2. 
Menstrual Blood Loss as Assessed by the Alkaline Hematin Method 
The volume of menstrual blood loss is measured in milliliters using the alkaline hematin method 
[Hallberg, 1964]. The method involves pummeling used feminine products in a solution and 
measuring the resulting hematin absorbance against calibration curves. The method is validated 
in accordance with current FDA Guidance for Method Validations and is an accepted 
quantitative clinical endpoint for the assessment of heavy menstrual bleeding. The site staff will 
provide collection kits with standardized and validated feminine products to patients for the 
collection and assessment of those products to determine menstrual blood loss. 
The feminine products will be dispensed and all stained/soiled products will be collected at each 
visit starting with the initiation of randomized study drug treatment. Product collection will 
continue at each visit unless heavy menstrual bleeding (MBL ≥ 80 mL) is observed. Collection 
will resume following the initiation of retreatment with open-label relugolix with E2/NETA and 
continue until MBL is observed to be < 80 mL on two consecutive collections. If the patient is 
having cyclic bleeding, the site must document the start and stop dates of the patient’s menses. 
Each time the patient submits her feminine products from a menstrual cycle for analysis, a 
venous blood sample will be collected and sent to with the products to the  the laboratory for the 
alkaline hematin analysis. Details regarding materials, process, and requirements for the 
menstrual blood loss collection are provided in the Study Reference Manual. 
6.5.1.3. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal ultrasound will be performed for all subjects at the Week 52/Baseline visit as a part 
of the OLE study (MVT-601-3003). Once the transvaginal ultrasound is complete, a 
transabdominal ultrasound (with or without saline or gel contrast) may also be performed if the 
uterus cannot be adequately imaged on transvaginal ultrasound (e.g., due to enlarged size). 
Transvaginal ultrasound, with or without transabdominal ultrasound, is performed to determine 
uterine and myoma volumes. A single operator will be assigned to a patient and will perform 
each of the ultrasound scans using the same device, as far as possible, to avoid inter-observer and 
inter-device variations. This single operator should be the same person, if possible, as previously 
assigned to the patient during her participation in the Parent study. 
On the assumption that the uterus and myoma are spheroids, uterine and myoma volumes are 
calculated using the formula: 
Uterine or myoma volume = D1 × D2 × D3 × π / 6 
Where: 
o D1 = the longest diameter of the myoma or uterus (unit of length: cm) 
o D2 = the longest diameter of the myoma or uterus that is perpendicular to D1 
(unit of length: cm) 
o D3 = the diameter of the myoma or uterus that crosses the intersection of D1 and 
D2 (intersection “Z”) and is perpendicular to the D1/D2 plane (unit of 
length: cm). 
The D1, D2, and D3 locally-determined values for the uterus and myoma will be recorded 
centrally. The images will be submitted for central review to confirm myoma presence and size. 
Any ultrasounds performed after the Week 52/Baseline visit must be read locally. 


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6.5.1.4. 
Health Survey Standard (SF-36) 
The Health Survey Standard (SF-36) is a validated 36-item questionnaire which measures quality 
of life across eight health domains that can be combined into a physical and a mental summary 
component score. (see Appendix 1). The SF-36 has a 4-week recall period and will be completed 
on a paper questionnaire at the study site on a schedule described in the Schedule of Activities 
(see Table 1-1). With the exception of the Week 52/Baseline visit, patients will answer these 
questions before other types of study procedures are performed. 
6.5.1.5. 
Patient Global Assessment (PGA) for Function and Symptoms 
The PGAs for Function and Symptoms are completed by the patient; they are based on a 5-point 
Likert scales and have a 4-week recall period (see Appendix 2). The PGA for function and PGA 
for symptoms will be completed on a paper questionnaire at the study site on a schedule 
described in the Schedule of Activities (see Table 1-1). Except for the Week 52/Baseline visit, 
patients will answer these questions before other types of study procedures are performed. 
6.5.1.6. 
Work Productivity Activity Impairment-Uterine Fibroids (WPAI-UF) 
The Work Productivity Activity Impairment-Uterine Fibroids (WPAI-UF) is a validated 
instrument used to measure impairments in work and activities, which has been adapted for 
uterine fibroids (see Appendix 3). The WPAI-UF will be completed on a paper questionnaire at 
the study site on a schedule described in the Schedule of Activities (see Table 1-1). Except for 
the Week 52/Baseline visit, patients will answer these questions before other types of study 
procedures are performed. 
6.5.1.7. 
Uterine Fibroid Symptom and Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life Questionnaire (UFS-QoL) is a 
validated instrument used to evaluate the symptom severity and the quality of life of patients 
with uterine fibroids (see Appendix 4). The UFS-QoL will be completed on a paper 
questionnaire at the study site on a schedule described in the Schedule of Activities (see Table 
1-1). Except for the Week 52/Baseline visit, patients will answer these questions before other 
types of study procedures are performed. 
6.5.2. 
Safety-Related Procedures 
6.5.2.1. 
Weight 
Patients should have weight 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 and will include systolic and diastolic blood pressure and 
pulse rate. 


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6.5.2.3. 
Physical and Gynecologic Exams 
A complete physical examination will include examinations of head, ears, eyes, nose, mouth, 
thyroid, skin, heart and lung, 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 previous assessments. The gynecologic 
examination will include breast and pelvic exams. 
6.5.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities (see Table 1-1). Laboratory 
requisition forms must be completed, and samples must be clearly labeled with the Patient 
Identification Number, protocol number, site/center number, and visit date. Details for the 
preparation and shipment of samples will be provided. Reference ranges for all laboratory tests 
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 
Hemoglobin A1c 
Creatine Kinase 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Gamma-Glutamyl Transferase 
Alkaline phosphatase 
White Blood Cell (WBC) Count 
Protein 
WBC Differential 
Glucose 
Red Blood Cell Count 
Blood 
Hemoglobin 
Urobilinogen 
Hematocrit 
Bilirubin 
Mean Corpuscular Volume 
Color and Clarity 
Platelet Count 
pH 
Red Blood Cell (RBC) 
morphology 
Leucocyte Esterase 
 
 Ketones 
 
Nitrite 
 
Specific Gravity 
 
Urine Microscopy (reflex 
testing based on abnormal 
urine analysis) 
 
Lipids 
Pregnancy 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
Pregnancy test 
(human chorionic 
gonadotropin) 
Hormones 
 
 
Estradiol 
FSH 
 
 
 


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The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, 
serology, and plasma 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 28 days after the last dose of study drug should be repeated 
until the values return to normal, baseline, or have stabilized. Abnormal and clinically significant 
results should be reported as adverse events. 
The investigator will maintain a copy of the reference ranges (with the record of the reference 
ranges) for the laboratory or laboratories used. 
To maintain blinding, concentrations of hormones will be reported to the investigator, other 
vendors, and sponsor personnel only after database lock and unblinding.  
6.5.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at Week 52/Baseline visit in this study, as well as if needed to 
evaluate any signs or symptom that require an ECG to assess. ECGs will be measured using 
standardized equipment provided by 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. Any ECGs performed after the Week 52/Baseline 
visit will be read locally. 
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). 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 each patient. This should be the same as used for the patient 
during the OLE study. A central core imaging laboratory will collect and evaluate all DXA scans 
for acceptability and will have bone mineral density assessed as per the imaging charter. Data 
from the DXA scans will be managed and analyzed separately by the core laboratory and 
integrated into the study’s database at the end of the study. Bone mineral density changes for 
individual subjects will be monitored by a central radiology laboratory over the course of the 
study. 
Patients who experience a bone mineral density loss of ≥ 7% from the Parent study baseline at 
any of the anatomical sites assessed will be discontinued from the study and will undergo 
another bone densitometry scan as described below. Patients should be assessed for secondary 
causes of bone loss and followed-up further if not improving on 6 months follow-up scan unless 
an alternative etiology has been identified.  


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Patients with a bone mineral density loss of ≥ 7% at lumbar spine, total hip, or femoral neck at 
their Week 104/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 about medications and conditions (e.g., 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. 
6.5.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Safety Follow-up visit, the date of onset of the first menstruation is recorded in the electronic 
case report form (eCRF). Patients whose menses has not resumed as of the Safety Follow-up 
visit for whom there is no explanation for the lack of resumption (e.g., medical procedure or 
medications) will be contacted again by telephone 3 (± 0.5) months after the Safety 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, physical examinations, vital signs (and 
weight), 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 (e.g., for a fall secondary to dizziness, both “dizziness” and “fall” should be 
recorded separately); and 


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• An investigational abnormality (e.g., 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 (e.g., 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 (e.g., planned 
hospitalization for an elective procedure, with elective defined as known or planned at the 
time of signing of the informed consent); 
• Events of heavy menstrual bleeding, as heavy menstrual bleeding is quantified as an 
efficacy endpoint, unless meets seriousness criteria. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to 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. No 
toxicity-related dose reductions of study drug are permitted; however, study drug can be held for 
a period of up to 2 weeks for evaluation and treatment of an adverse event. The study drug may 
be restarted if deemed safe for the patient by the investigator. 
7.1.2. 
Serious Adverse Event 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death; 
b. Is life-threatening; 
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the study 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 


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for elective treatment of a pre-existing condition that did not worsen from the 
Week 52/Baseline visit 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 (e.g., 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 that jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria. Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local institutional review board (IRB) or institutional 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 answers to study questionnaires 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 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 


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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 Safety 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 uterine fibroids, whichever occurs first, as also specified in the study 
Schedule of Activities (Table 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 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 


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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 Safety Follow-up period 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 5. 
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 


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• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or INR > 1.5; or 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
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 
Week 52/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 (i.e., 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 (e.g., 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 Report Form, all serious adverse events must be reported within 24 hours of the 
study site personnel’s knowledge of the event, regardless of the investigator assessment of the 
relationship of the event to study drug. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose is available on the serious adverse event report form and is as 
follows: 


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Send completed Safety Report Forms to IQVIA RDS Inc: 
Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary reporting method) 
All study sites 
 
 
 
For questions on Serious Adverse Event/Adverse Event of Clinical Interest reporting, 
please call: 
• 
North/South America:  
 
• 
Europe, Asia, Pacific, and South Africa:  see region-specific phone numbers 
accompanying the Safety Report Form 
The initial report should include: 
• 
Study number (MVT-601-035); 
• 
Site address and number; 
• 
Investigator name; 
• 
Patient Identification Number, sex, and age; 
• 
Details of study drug administration; 
• 
The date of the report; 
• 
A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity); 
• 
Causal relationship to the study drug. 
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 (i.e., 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: 
PPD
PPD
PPD


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• 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 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. 
Pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy report 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 
pregnancy report 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, weight, physical examinations, clinical laboratory tests, ECGs, and bone mineral density. 
7.10. 
Benefit/Risk Assessment 
Adverse drug reactions associated with relugolix in women include nonserious events of hot 
flush, headache, hyperhidrosis, arthralgia, and loss of bone mineral density. In this protocol, 
relugolix will be evaluated for its benefit on the heavy menstrual bleeding associated with uterine 
fibroids. Hormonal add-back therapy with estradiol/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 interval [QTc] prolongation), hepatic enzyme increases, phospholipidosis (PLD), 


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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’s 
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 
estradiol/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 52/Baseline 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 52/Baseline and 
Week 104/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzyme increases 
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 
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 
nonhormonal 
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 
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 malignancies, 
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 52/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 (e.g., 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 (e.g., removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets. Patient initials will not be collected or transmitted to the 
sponsor. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A Statistical Analysis Plan (SAP) will describe the detailed statistical methods and analyses for 
this study. The SAP will be prepared and finalized prior to unblinding of patient’s study 
treatment assignments. 


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All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%. 
Methodology to be used to maintain study-wide type I error rate of 5% testing across primary 
and key secondary endpoints will be described in the SAP. 
All efficacy and safety measures over the course of the study will be presented. Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients. Categorical data will be summarized by counts and percentages. 
The final analysis of efficacy and safety data will occur after approximately 360 patients 
(projected to be responders from the open-label extension study MVT-601-3003) who have been 
randomized and have had the opportunity to complete Week 104 visit or through the 30-day 
Safety Follow-up visit. 
9.1. 
Randomization Methods 
This is an international phase 3 Double-Blind, Placebo-controlled, Randomized Withdrawal 
study that will enroll eligible patients with uterine fibroids who have completed the 24-week 
treatment period in a Parent study (Study MVT-601-3001 or Study MVT-601-3002) and the 28-
week treatment period of the OLE study. Patients completing the OLE study and meeting the 
definition of responder will be randomized 1:1 into two different treatment groups: 
• Group A:  52 weeks of oral relugolix with E2/NETA, once daily;  
• Group B:  52 weeks of placebo relugolix plus a capsule of placebo estradiol/norethindrone 
acetate. 
Randomization will be stratified by the following factors: 
• Geographic Region:  North America vs Europe vs Latin America vs Rest of World;  
• Mean screening menstrual blood loss using alkaline hematin method:  < 225 mL versus 
≥ 225 mL; and  
• Duration of relugolix exposure prior to randomization (28 weeks vs 52 weeks). 
The four stratification levels (North America vs Europe vs Latin America vs Rest of World) for 
geographic region considered for randomization take drug supply monitoring into consideration. 
For the purpose of stratified data analyses, the 4 regions will be pooled into two groups (North 
American vs Other) where Other includes Europe, Latin America and Rest of World. 
Statistical analyses for efficacy endpoints will incorporate these stratification factors unless 
otherwise specified. 
9.2. 
Analysis Populations 
The modified Intent-to-Treat (mITT) Population will consist of all patients randomized to 
treatment who have taken at least one dose of study treatment. The mITT Population will be the 
primary population used for the efficacy analysis. 
The Per-Protocol Population will consist of those members of the mITT Population who have no 
relevant major protocol violations, defined as a subset of all major protocol violations (details 
will be provided in the Statistical Analysis Plan). The Per-Protocol Population will not be 
analyzed if this population comprises more than 95% or less than 50% of the mITT Population. 


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This population will be used for confirmatory analysis of the primary efficacy endpoint. The Per-
Protocol Population will be identified prior to breaking the study blind. 
The primary population for safety analyses will be the Safety Population, which will consist of 
all patients who are randomized and took at least one dose of study treatment. 
9.3. 
Efficacy Analyses 
Unless otherwise specified, efficacy analyses will be conducted using the mITT Population 
according to the randomized treatment assignment, and stratified analyses will be stratified by 
the randomization stratification factors. If the group of patients from any of the individual 
randomization stratification factors comprises less than 10% of the entire mITT population, this 
stratification factor will be ignored for stratified analyses. 
9.3.1. 
Primary Efficacy Endpoint 
The primary endpoint of the study is the proportion of women who maintain a menstrual blood 
loss volume of < 80 mL at Week 76 (24 weeks of the randomized treatment period) as measured 
by the alkaline hematin method. The primary endpoint of responder rate will be evaluated using 
the mITT Population. 
Week 52 of the OLE study will define as the baseline for this Randomized Withdrawal study and 
will be used as the reference point for all changes from baseline-related endpoints. Although 
responder status is based on Week 48 of the OLE study, the menstrual blood loss (MBL) volume 
at the Week 52 period of the OLE study will establish the patient’s baseline for evaluation of 
menstrual blood loss during the 52-week randomized treatment period of the study. 
9.3.1.1. 
Primary Analysis 
The primary hypothesis for the primary efficacy endpoint to be tested in this study is relugolix 
(Group A) is superior to placebo (Group B) with respect to the proportion of responders at Week 
76 (24 weeks after randomization) based on the MBL volume analyzed by alkaline hematin 
method: 
Null hypothesis H01:  πR ≤ πP    vs    Alternative hypothesis Ha1:  πR > πP 
where πR and πP are the responder rates for relugolix and placebo groups, respectively. 
The primary efficacy analysis is the treatment comparison between the relugolix Group A and 
the placebo Group B performed using a Cochran-Mantel-Haenszel (CMH) test statistic for 
proportions of responders stratified by baseline mean menstrual blood loss in the Parent study 
(< 225 mL vs ≥ 225 mL), geographic region (North America vs Other) and the duration of 
relugolix exposure prior to randomization (28 weeks vs 52 weeks). 
The study will be considered positive if the treatment effect for primary endpoint is statistically 
significant with 2-sided p-value < 0.05. The point estimate and 2-sided 95% confidence interval 
(CI) for treatment difference in responder rates for the primary efficacy endpoint will be 
calculated. 


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9.3.1.2. 
Subgroup Analyses 
Subgroup analyses of the primary efficacy endpoint comparing Group A versus Group B will be 
performed to determine whether treatment effect is consistent across clinically meaningful 
subgroups. The difference in responder rates and their 95% confidence intervals will be 
displayed in a forest plot. Subgroups will include but not be limited to the following: baseline 
MBL volume in the Parent study (< 225 mL vs ≥ 225 mL), geographic region (North America vs 
Other), duration of exposure to relugolix prior to randomization (28 weeks vs 52 weeks) as well 
as other baseline subgroups such as age, and race. Details are provided in the Statistical Analysis 
Plan. 
9.3.1.3. 
Sample Size Estimation 
Because this is an extension of the OLE study, the sample size of this study will be based on 
approximately the number of patients who have completed a Parent study (n = 780 patients in 
total), and who participated in the OLE study (n = 600 patients in total assuming about 20% 
dropout rate at 6 months from the Parent studies). Assuming the proportion of responders at 
Week 52 in the OLE study is 60%, it is estimated that approximately 360 patients will be 
randomized into this study. 
With 360 patients, the study will have at least 90% power to detect a difference of 20% or 
greater between relugolix Group A and placebo Group B for the primary endpoint. The 
following assumptions are used to determine the sample size for this study: 
• 2-sided type I error rate: 0.05 
• Randomization: 1:1 
• Responder rate for placebo Group B: 40% 
• Responder rate for Group A: 60% 
• Dropout rate: 20% 
9.3.2. 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed during the randomized treatment 
period or retreatment period: 
• Proportion of women who maintain a menstrual blood loss volume of < 80 mL at Week 104 
(52 weeks of the randomized treatment period) as measured by the alkaline hematin method; 
• Change from Week 52/Baseline to Week 76/Week 104 in menstrual blood volume (during 
the randomized treatment period); 
• Percentage change from Week 52/Baseline to Week 76 / Week 104 (during the randomized 
treatment period); 
• Proportion of patients who responded (menstrual blood loss volume of < 80 mL) to 
retreatment with relugolix 40 mg and E2/NETA during the retreatment period among placebo 
patients whose menstrual blood volume had returned to ≥ 80 mL during the 52-week 
randomized treatment period; 
 
The following secondary endpoints will be assessed at Week 76 and at Week 104 during the 
randomized treatment period: 


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• Proportion of women achieving or maintaining amenorrhea; 
• Proportion of women whose menses has resumed (among those who were amenorrhoeic at 
Week 52/Baseline); 
• Time to resumption of menses; 
• Proportion of women with menstrual blood volume ≥ 80 mL at any time point during the 
52-week randomized treatment period; 
• Time to resumption of menstrual blood volume ≥ 80 mL; 
• Change from Week 52/Baseline in hemoglobin; 
• Change from Week 52/Baseline in SF-36 domain and summary component scores; 
• Change from Week 52/Baseline in PGA for function and symptoms scores; 
• Change from Week 52/Baseline in the WPAI-UF scores; 
• Change from Week 52/Baseline in the UFS-QoL Symptom Severity scale and subscales as 
well as total scores. 
9.3.2.1. 
Secondary Efficacy Endpoint Analyses 
During Randomized Treatment Period 
For endpoints evaluating the change from Baseline, treatment comparisons will be performed 
using a mixed model repeated measures approach with treatment, randomization stratification 
factors, and treatment by visit interaction included as fixed effects and Week 52/Baseline value 
included as a covariate. The dependent variable (change from Baseline) for each patient at each 
visit will be calculated based on visit windows specified in the final Statistical Analysis Plan. In 
addition, descriptive statistics will be provided by treatment group and by visit. 
Change from baseline endpoints will be analyzed censoring the values at the time of retreatment 
with relugolix with E2/NETA. Details will be specified in the SAP. 
For endpoints evaluating proportions, treatment comparisons will be performed using a stratified 
Cochran-Mantel-Haenszel test as appropriate. 
Baseline menstrual blood loss is defined as total menstrual blood loss obtained from the Week 
52/Baseline visit prior to the date of the first dose of study drug in this Randomized Withdrawal 
study as assessed by the alkaline hematin method. The menstrual blood loss during the last on-
treatment cycle (Week 104) is the total menstrual blood loss during the last month (up to the last 
35 days) on-treatment as assessed by the alkaline hematin method. 
For time-to-event endpoints (time to achieving or maintaining a menstrual blood loss volume of 
< 80 mL 24 weeks after randomization, time to resuming menses, time to resumption of 
menstrual blood volume ≥ 80 mL), time-to-event will be defined as weeks from randomization 
of the Randomized Withdrawal study to first occurrence of the event. Patients without an event 
will be censored at last assessment date prior to the end of study. Kaplan-Meier methods will be 
used to describe the time to event distributions for each study treatment arm. 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by study treatment group. 


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During Retreatment Period 
For placebo patients whose menstrual blood volume had returned to ≥ 80 mL during the 52-week 
randomized treatment period and received retreatment: 
• the proportion of patients who responded to the retreatment (MBL < 80mL) will be 
estimated along with corresponding 95% CIs at the end of retreatment period 
• mean change and mean % change in menstrual blood volume from retreatment to end of 
retreatment period. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.4. 
Pharmacodynamic Analyses 
Pharmacodynamic estradiol concentration data will be listed and summarized by treatment arm 
and visit. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, 12-lead ECGs, and results of measurements of bone 
mineral density by DXA. 
The treatment-emergent period will be defined as the period of time from the first dose date of 
extension study drug through 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 uterine fibroids, 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’s CTCAE. All adverse events will be coded to preferred 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 
study Baseline versus post-baseline results. All data will be listed and summarized by visit. The 
change from study Baseline to each post-baseline study visit will be presented by 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 study Baseline to each post-baseline study visit will be presented by study 
treatment group for each parameter. 


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Clinical laboratory data consist of chemistry, hematology, and hormonal tests. Only data 
collected by the central laboratory will be used to do the analyses. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the 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. 
All BMD data will be listed and summarized by visit. The change, percent change from study 
Week 52/Baseline to Weeks 76 and 104 and associated 95% CIs will be presented by the study 
treatment group for each bone mineral density parameter. The number and percentage of patients 
meeting a bone mineral density decline of at least 3%, 4%, 5%, 6%, or 7% by body area (lumbar 
spine, total hip, or femoral neck) will be estimated with 95% CIs by the study treatment group. 
Additional analyses will be performed to exam 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. 
Interim Analyses 
There are no planned interim efficacy analyses. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant. For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR 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 


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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 
signed and dated by the patient. 
10.1.4. 
Confidentiality 
The investigator must assure that patient’s anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only patient number, date of birth, and an 
identification code (i.e., 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’s 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. 
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. 
10.1.6. 
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’s 
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, (e.g., history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (i.e., 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’s 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 


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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. 
10.1.7. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the investigator or 
sub-investigator (as appropriate) listed on Form FDA 1572 and/or other appropriate local health 
authority documents within a reasonable time period after data collection. This also applies to 
records for those patients who fail to complete the study (even during a pre-randomization 
screening period if an eCRF was initiated). If a patient withdraws from the study, the reason 
must be noted on the eCRF. If a patient is withdrawn from the study because of a treatment-
limiting adverse event, thorough efforts should be made to clearly document the outcome. 
10.1.8. 
Investigational Product Accountability 
The investigator or investigator’s designee (i.e., pharmacist) is responsible for ensuring adequate 
accountability (including dates and lot numbers) of all used and unused study drug. This includes 
acknowledgment of receipt of each shipment of study product (quantity and condition), patient 
dispensing records, and returned or destroyed study product. Dispensing records will document 
quantities received from the sponsor and quantities dispensed to patients, including lot number, 
date dispensed, Patient Identification Number, and the initials of the person dispensing the 
medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements. Drug may be returned or destroyed on an ongoing basis during the study if 
appropriate. At the end of the study, following final drug inventory reconciliation by the monitor, 
the study site will dispose of and/or destroy all unused study drug supplies, including empty 
containers, according to these procedures. If the site cannot meet the sponsor’s requirements for 
disposal, arrangements will be made between the site and the sponsor (or designee) for 
destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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10.1.9. 
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. 
10.1.10. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor. All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements. Approval must be obtained before changes can be 
implemented. The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required. In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken. The investigator must notify the sponsor (or designee) 
of any inadvertent protocol deviations upon their discovery and document the deviations 
appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies). The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of patients begins. Results will be posted as required. 


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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH 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: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 90 days before submission of 
the publication or presentation. The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 120 days in 
order to obtain patent protection if deemed necessary. 


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REFERENCES 
ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of 
Leiomyomas. Obstetrics & Gynecology 2008;112(2 Part 1):387-400. 
Activella US Prescribing Information. Revised 11/2017. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020907s019lbl.pdf. 
Accessed: 15 June 2018. 
Archer DF, Chwalisz K, Feldman R, Stewart EA, Lukes AS, North J, Gao J, Williams LA, Jain 
R. Elagolix for the management of heavy menstrual bleeding (HMB) associated with 
uterine fibroids (UF): Results from a phase 2A proof-of-concept study. American Society 
for Reproductive Medicine (Oct 17-21). October 20, 2015. Abstract O-181, available at: 
http://www.fertstert.org/article/S0015-0282(15)00717-7/pdf. Accessed: 03 August 2017. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. American 
Journal of Obstetrics and Gynecology 1992;166(2):740-5. 
Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual 
cost of uterine leiomyomata in the United States. American Journal of Obstetrics and 
Gynecology 2012;206(3): 211.e1-211.e9. 
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. Reproductive Sciences 2012;19(6):563-71. 
Farquhar CM, Stinert CA.  Hysterectomy rates in the United States 1990-1997. Obstet Gynecol 
2002;99:229-34. 
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, van der Mooren MJ. Gonadotropin-releasing 
hormone agonist plus add-back’ hormone replacement therapy for treatment of 
endometriosis: a prospective, randomized, Placebo-controlled, Double-Blind trial. 
Fertility and Sterility 2000;74(3):534-539. Available at: 
http://www.fertstert.org/article/S0015-0282(00)00690-7/pdf. Accessed: 03 August 2017. 
Gliklich RE, Leavy MB, Velentgas P, Campion DM, Mohr P, Sabharwal R, Whicher D, Myers 
ER, Nicholson WK. Identification of Future Research Needs in the Comparative 
Management of Uterine Fibroid Disease. A Report on the Priority-Setting Process, 
Preliminary Data Analysis, and Research Plan. Effective Healthcare Research Report No. 
31. (Prepared by the Outcome DEcIDE Center, under Contract No. HHSA 290-2005-
0035-I, TO5). AHRQ Publication No. 11- EHC023-EF. Rockville, MD: Agency for 
Healthcare Research and Quality. March 2011. Available at: 
https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/uterine-fibroids-
2010_research.pdf. Accessed: 03 August 2017. 
Hallberg L, Nilsson L. Determination of menstrual blood loss. Scand J Clin Lab Invest. 
1964;16(2):244–248. 


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Hapangama DK, Bulmer Judith N. Pathophysiology of heavy menstrual bleeding. Women’s 
Health 2016;12(1):3-13. 
Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide Acetate Depot and Hormonal 
Add-Back in Endometriosis: A 12-Month Study. Obstetrics & Gynecology 
1998;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. Obstetrics & gynecology science 2016;59(1):32-8. Available at:  
http://synapse.koreamed.org/Synapse/Data/PDFData/3021OGS/ogs-59-32.pdf. Accessed: 
03 August 2017. 
Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual 
bleeding. Cochrane Database of Systematic Reviews 2006;(2):CD003855. 
Marret H, Fritel X, Ouldamer L, Bendifallah S, Brun J.L, De Jesus I, Derrien J, Giraudet G, 
Kahn V, Koskas M, Legendre G, Lucot J.P, Niro J, Panel P, Pelage J.P, Fernandez H. 
Therapeutic management of uterine fibroid tumors: updated French guidelines. European 
Journal of Obstetrics and Gynecology 2012;165(2):156-164. 
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. Fertility and Sterility 2008;89(2):421-428. 
Simpson PD, McLaren JS, Rymer J, Morris EP. Minimising menopausal side effects whilst 
treating endometriosis and fibroids. Post Reproductive Health: The Journal of the British 
Menopause Society. 2015;21(1):16-23. 
Stewart EA. Uterine Fibroids. Lancet. 2001 Jan 27;357(9252):293-8. 
Stewart EA. Clinical Practice. Uterine Fibroids. N Engl J Med. 2015;372(17):1646-55. 
Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a 
systematic review. BJOG. 2017 Sep;124(10):1501-1512. 
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. Archives of Gynecology and 
Obstetrics 2014;290(3):513-523. 
Wu JM, Wechter ME, Geller EJ, Nguyen TV, Visco AG. Hysterectomy rates in the United 
states, 2003. Obstet Gynecol 2007;110:1091-5. 
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. Fertility and Sterility 2004;82(5):1303-
1308. 


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APPENDICES 
Appendix 1. 
Health Survey Standard (SF-36v2®) 
 
 
 


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Appendix 2. 
Patient Global Assessment (PGA) for Function and Symptoms 
 


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Appendix 3. 
Work Productivity Activity Impairment -Uterine Fibroids (WPAI-UF) 
 
 
 


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Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 


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Appendix 5. 
Assessment of Abnormal Liver Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with 
estradiol/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 (e.g., right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (e.g., 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 1; 
• 
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). 
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 1:  SUMMARY OF CHANGES 
The MVT-601-035 protocol has been amended as described in the table below.  The primary purpose of the 
amendment is to provide clarification on the maintenance of blinding during pharmacodynamic testing and reporting 
of estradiol and FSH concentrations to the sponsor. 
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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Section 
Item 
Original 
Amendment 1 
Rationale 
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnote l 
Specimen for FSH will be collected and stored 
until the study is unblinded. The assay for FSH 
will be performed after unblinding on 
amenorrhoeic patients who were assigned to 
placebo.. 
Specimen for FSH will be collected on patients 
who have been amenorrhoeic (i.e., those who 
have not required the use of any feminine 
products) since randomization. 
Clarification on FSH sample 
collection. 
Section 5.7 
Blinding 
During the double-blind Randomized Treatment 
and through the Safety Follow-up period, all 
patients, investigators, and sponsor staff or 
representatives involved in the conduct of the 
study will be blinded to treatment assignment, 
with the exception of an unblinded statistician(s) 
who is responsible for developing the 
randomization codes. 
During the double-blind Randomized Treatment 
and through the Safety Follow-up period, all 
patients, investigators, and sponsor staff or 
representatives involved in the conduct of the 
study will be blinded to treatment assignment, 
with the exception of an unblinded statistician(s) 
who is responsible for developing the 
randomization codes.  The blind will be 
maintained during assessment of 
pharmacodynamic testing.  Estradiol and FSH 
concentrations will be reported to the sponsor 
only after database lock and unblinding, or 
provisions will be made to provide data only 
to personnel approved for unblinding. 
Language updated to clarify 
that blinding will be maintained 
during pharmacodynamic 
testing. 
Section 6.5.2.4 
Clinical Laboratory 
Samples 
To maintain blinding, concentrations of estradiol 
hormones will be reported to the investigator, 
other vendors, and sponsor personnel only after 
database lock and unblinding.  Specimens for 
FSH will be collected and stored until the study 
is unblinded.  The assay for FSH will be 
performed after unblinding on amenorrhoeic 
patients who were assigned to placebo. 
To maintain blinding, concentrations of 
hormones will be reported to the investigator, 
other vendors, and sponsor personnel only after 
database lock and unblinding. 
Language updated to clarify 
that blinding will be maintained 
during pharmacodynamic 
testing. 
 

SAP_001.pdf: 
MVT-601-035 
Clinical Study Report Appendices 
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16.1.9 
Documentation of Statistical Methods 
Statistical Analysis Plan, v1.0 


Statistical Analysis Plan  
 
MVT-601-035 
 
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STATISTICAL ANALYSIS PLAN  
 
Study Titles: 
An International Phase 3 Double-Blind, Placebo-controlled, 
Randomized Withdrawal Study of Relugolix Co-administered with 
Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids 
Investigational 
Product: 
 
Relugolix 
Protocol Number: 
MVT-601-035 
 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
CH-4051 Basel 
Switzerland 
 
Regulatory 
Identifier(s): 
Eudra CT # 2018-001368-43 
IND # 131161 
 
Version/Effective Date: 
15 Mar 2021 
 
 
 
 
 
 
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. 


Statistical Analysis Plan  
 
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STATISTICAL ANALYSIS PLAN APPROVAL SHEET  
An International Phase 3 Double-Blind, Placebo-controlled, Randomized Withdrawal Study of 
Relugolix Co-administered with Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids 
This statistical analysis plan has been approved by Myovant Sciences GmbH.  The following 
signatures document this approval. 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
Date 
 
 
 
 
 
 
Date 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan  
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL SHEET ............................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................8 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Study Objectives and Endpoints .................................................................................11 
2. 
STUDY DESIGN .......................................................................................................15 
2.1. 
Summary of Study Design ..........................................................................................15 
2.2. 
Sample Size Considerations .......................................................................................16 
3. 
PLANNED ANALYSES ............................................................................................17 
3.1. 
Interim Analyses .........................................................................................................17 
3.2. 
Final Analyses ............................................................................................................17 
3.3. 
Safety Follow-Up Analyses ........................................................................................17 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA ............................................................................18 
4.1. 
Data Presentation Conventions ...................................................................................18 
4.2. 
Analysis Populations ..................................................................................................19 
4.2.1. 
Modified Intent-to-Treat Population ...........................................................................19 
4.2.2. 
Per-Protocol Population ..............................................................................................19 
4.2.3. 
Safety Population ........................................................................................................19 
4.2.4. 
Retreatment Population ..............................................................................................19 
4.3. 
Definitions, Computation, and Convention ................................................................20 
4.3.1. 
Definition of Date of First Dose and Date of Last Dose of Study Drug 
During the Randomized Treatment Period .................................................................20 
4.3.2. 
Definition of Date of First Dose and Date of Last Dose of Retreatment Drug ..........20 
4.3.3. 
Study Day ...................................................................................................................20 
4.3.4. 
Definition of Treatment Duration During the Randomized Treatment Period ...........20 
4.3.5. 
Definition of Treatment Duration During the Retreatment Period .............................21 
4.3.6. 
Definition of Baseline Value and Post-Baseline Value ..............................................21 
4.3.7. 
Visit Windows ............................................................................................................21 
4.4. 
General Rules for Missing Data .................................................................................24 


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4.4.1. 
By-Visit Endpoints .....................................................................................................24 
4.4.2. 
Adverse Events and Concomitant Medications ..........................................................25 
5. 
STUDY POPULATION .............................................................................................26 
5.1. 
Subject Disposition .....................................................................................................26 
5.2. 
Protocol Deviations ....................................................................................................26 
5.3. 
Demographic and Baseline Characteristics ................................................................27 
5.4. 
Medical History ..........................................................................................................28 
5.5. 
Prior Medications and Concomitant Medications ......................................................28 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................30 
7. 
EFFICACY ANALYSES ...........................................................................................31 
7.1. 
General Considerations ...............................................................................................31 
7.1.1. 
Analyses for Categorical Data ....................................................................................31 
7.1.2. 
Analyses for Continuous Data ....................................................................................31 
7.1.3. 
Analyses for Time to Event Data ................................................................................32 
7.2. 
Multiplicity Adjustment..............................................................................................32 
7.3. 
Primary Efficacy Endpoint .........................................................................................32 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................33 
7.3.1.1. 
Kaplan-Meier Analysis ...............................................................................................33 
7.3.1.2. 
Censoring Rules ..........................................................................................................34 
7.3.2. 
Definitions Related to Menstrual Blood Loss for Each Feminine Product 
Collection Interval ......................................................................................................36 
7.3.2.1. 
Menstrual Blood Loss Volume ...................................................................................37 
7.3.2.2. 
Week 52/Baseline Menstrual Blood Loss Volume .....................................................37 
7.3.2.3. 
Feminine Product Collection Interval .........................................................................37 
7.3.2.4. 
Menstrual Blood Loss Volume for Each Feminine Product Collection 
Interval ........................................................................................................................38 
7.3.2.5. 
Feminine Product Return Rate by Visit ......................................................................38 
7.3.3. 
Identifying Responder Status and Incomplete Feminine Product Collection at 
Each Visit ....................................................................................................................39 
7.3.4. 
Sensitivity Analyses ....................................................................................................39 
7.3.4.1. 
Sensitivity Analysis 1 .................................................................................................39 
7.3.4.2. 
Sensitivity Analysis 2 .................................................................................................40 
7.3.4.3. 
Sensitivity Analysis 3 .................................................................................................40 


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7.3.5. 
Subgroup Analyses .....................................................................................................40 
7.4. 
Secondary Efficacy Endpoints ....................................................................................41 
7.4.1. 
Key Secondary Endpoints ...........................................................................................41 
7.4.1.1. 
Time to Relapse (Menstrual Blood Loss Volume ≥ 80 mL) ......................................42 
7.4.1.2. 
Proportion of Patients Who Maintained a Menstrual Blood Loss Volume of 
< 80 mL at Week 104 .................................................................................................42 
7.4.1.3. 
Proportion of Patients Achieving or Maintaining Amenorrhea ..................................43 
7.4.2. 
Other Secondary Endpoints ........................................................................................44 
7.4.2.1. 
Proportion of Patients Who Responded to Retreatment During the 
Retreatment Period .....................................................................................................44 
7.4.2.2. 
Change and Percent Change from Week 52/Baseline in Menstrual Blood 
Loss Volume During the Randomized Treatment Period ...........................................45 
7.4.2.3. 
Proportion of Patients Whose Menses Has Resumed .................................................45 
7.4.2.4. 
Time to Resumption of Menses ..................................................................................46 
7.4.2.5. 
Proportion of Patients with Menstrual Blood Volume ≥ 80 mL at Any 
Timepoint During the 52-week Randomized Treatment Period .................................47 
7.4.2.6. 
Change and Percent Change from Week 52/Baseline in Hemoglobin .......................47 
7.4.2.7. 
Proportion of Patients with Anemia or Below Lower Limit of Normal .....................47 
7.4.2.8. 
Change from Week 52/Baseline in SF-36v2 Scores...................................................47 
7.4.2.9. 
Change from Week 52/Baseline in PGA Score ..........................................................48 
7.4.2.10. 
Change from Week 52/Baseline in the WPAI-UF Scores ..........................................48 
7.4.2.11. 
Change from Week 52/Baseline in the UFS-QoL Score ............................................49 
8. 
PHARMACODYNAMIC ANALYSES .....................................................................53 
9. 
SAFETY ANALYSES ...............................................................................................54 
9.1. 
Adverse Events ...........................................................................................................54 
9.1.1. 
Relationship to Study Drug ........................................................................................56 
9.1.2. 
Severity of Adverse Event ..........................................................................................56 
9.1.3. 
Serious Adverse Event ................................................................................................57 
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug ...............................................57 
9.1.5. 
Adverse Events Leading to Dose Interruption ............................................................57 
9.1.6. 
Adverse Events Resulting to Fatal Outcome ..............................................................57 
9.1.7. 
Other Safety Parameters of Interest ............................................................................57 
9.1.8. 
Adverse Events of Clinical Interest ............................................................................58 
9.2. 
Laboratory Data ..........................................................................................................58 


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9.3. 
Other Safety Analyses ................................................................................................59 
9.3.1. 
Electrocardiograms .....................................................................................................59 
9.3.2. 
Vital Signs and Body Weight .....................................................................................60 
9.3.3. 
Bone Mineral Density .................................................................................................61 
9.3.3.1. 
Analysis Using Week 52/Baseline Bone Mineral Density as Baseline ......................61 
9.3.3.2. 
Analysis Using the Pivotal Study Baseline Bone Mineral Density as Baseline .........62 
9.3.3.3. 
Analysis Using Pivotal Week 12 BMD as Baseline ...................................................63 
9.3.4. 
Endometrial Biopsy and Transvaginal Ultrasound .....................................................65 
10. 
REFERENCES ...........................................................................................................66 
APPENDIX 1:  PRE-DEFINED CATEGORIES FOR LAB SHIFT TABLE ..............................67 
APPENDIX 2:  LIST OF PRE-DEFINED THRESHOLDS IN SELECTED 
CHEMISTRY AND HEMATOLOGY TEST RESULTS .........................................68 
 


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LIST OF TABLES  
Table 1: 
Study Objectives and Endpoints .................................................................................12 
Table 2: 
Visit Windows for Monthly Assessments ..................................................................22 
Table 3: 
Visit Windows for Bone Mineral Density Assessments.............................................23 
Table 4: 
Visit Windows for UFS-QoL Assessments ................................................................23 
Table 5: 
Visit Windows for Clinical Laboratory Tests and Vital Signs ...................................23 
Table 6: 
Time Window for Feminine Product Collection ........................................................24 
Table 7: 
Categories for Demographic and Baseline Characteristics ........................................27 
Table 8: 
Censoring Rules for Kaplan-Meier Analysis During Randomized Treatment 
Period ..........................................................................................................................36 
Table 9: 
Identifying Incomplete Feminine Product Collection and Derivation of 
Responder Status at Each Visit During Randomized Treatment Period ....................39 
Table 10: Planned Subgroup Analyses .......................................................................................41 
Table 11: Rules for Determining Reported Amenorrhea by Visit ..............................................44 
Table 12 
Rules for Determining Resumption of Menses by Visit .............................................46 
Table 13: Patient Global Assessment Numerical Scores ............................................................48 
Table 14: Formulas for Scoring and Transforming UFS-QoL Scale Scores and UFS-
QoL Total Score .........................................................................................................51 
Table 15: Other Safety Parameters of Interest ............................................................................58 
Table 16:  Categories of Liver Test Elevations ...........................................................................59 
Table 17: Categories of Potentially Clinically Significant Abnormalities in Vital Signs ..........60 
Table 18: Categories of Potentially Clinically Significant Abnormalities in Weight ................61 
Table 19: Planned Subgroup Analyses for Bone Mineral Density .............................................62 
Table 20: Combined Analysis Groups for Bone Mineral Density ..............................................64 
 
 


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LIST OF FIGURES  
Figure 1: 
Fixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints ....................................................................................................................42 


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LIST OF ABBREVIATIONS  
 
Term 
Definition/Explanation 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMD 
bone mineral density 
BMI 
body mass index 
BPD 
bleeding and pelvic discomfort 
bpm 
beats per minute 
CI 
confidence interval 
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 
EOT 
end of treatment 
FP 
feminine product 
FPRR 
feminine product return rate 
ICH 
International Council on Harmonisation 
LLN  
lower limit of normal 
LOCF 
last observation carried forward 
LS 
least squares 
MBL 
menstrual blood loss 
MCS 
mental component summary 
mITT 
modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
msec 
millisecond 
NETA 
norethindrone acetate 
NRS 
numerical rating scale 
LTE 
long-term extension 
PCS 
physical component summary 
PGA 
Patient Global Assessment 
PT 
Preferred Term 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF-36v2  
Short Form (36) version 2 
SMQ 
standard MedDRA query 
SOC 
System Organ Class 


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Term 
Definition/Explanation 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
VAS 
visual analogue score 
WHO 
World Health Organization 
WPAI-UF  
Work Productivity Activity Impairment-Uterine Fibroids 


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1. 
INTRODUCTION  
The purpose of this statistical analysis plan (SAP) is to describe the efficacy and safety analyses 
planned for phase 3 study MVT-601-035, entitled “An International Phase 3 Double-Blind, 
Placebo-controlled, Randomized Withdrawal Study of Relugolix Co-Administered with Estradiol 
and Norethindrone Acetate in Women with Heavy Menstrual Bleeding Associated with Uterine 
Fibroids.”  Patients who completed the 24-week treatment period in a pivotal study (study 
MVT-601-3001 or study MVT-601-3002) and the 28-week treatment period of the long-term 
extension (LTE) (MVT-601-3003) study and met all eligibility criteria for study MVT-601-035 
(including met the definition of responder) are enrolled in MVT-601-035.  Enrolled patients are 
randomized to one of two treatment groups: once daily oral relugolix 40 mg with 
estradiol/norethindrone acetate (E2/NETA) 1 mg/0.5 mg for 52 weeks (referred to as the relugolix + 
E2/NETA group) or placebo for 52 weeks (referred to as the placebo group).  
This SAP was developed in accordance with the International Council on Harmonisation (ICH) 
E9 guidelines.  All decisions regarding statistical analysis of the study, as defined in this SAP, 
will be made prior to unblinding of the study data.   
This SAP is based on: 
• Protocol MVT-601-035, Amendment 1, dated 13 Aug 2018; 
• ICH guidelines E3 (Clinical Study Reports) and E9 (Statistical Principles for Clinical 
Trials). 
The methods used for analysis of the MVT-601-035 study are consistent with those used for the 
phase 3 studies (MVT-601-3001, MVT-601-3002 and MVT-601-3003).  The SAP will be 
finalized, approved by the sponsor, and placed on file before the database is locked.  Changes to 
the final approved plan will be noted in the clinical study report (CSR).   
1.1. 
Study Objectives and Endpoints  
The objectives of Study MVT-601-035 are to evaluate the long-term efficacy and safety of relugolix 
+E2/NETA, once daily, for up to 104 weeks in patients with uterine fibroids who have completed a 
total of 52 weeks of treatment including 24-week treatment period in a pivotal study (study MVT-601-
3001 or study MVT-601-3002) and 28-week treatment period of the LTE study (study MVT-601-
3003) and who meet the definition of responder.  A responder is defined as a patient who demonstrates 
a menstrual blood loss of < 80 mL and at least a 50% reduction from pivotal study baseline menstrual 
blood loss volume on the alkaline hematin analysis of the feminine products (FPs) returned at Week 
48 in the LTE study.  The study objectives and endpoints are listed in Table 1.  The endpoints in italics 
are not listed in the protocol, but they have been identified as important for the assessment of 
treatment effect based on emerging data and clinical relevance to the study objectives and therefore are 
prespecified in the SAP.  The endpoints listed in Table 1 will also be analyzed in general using data 
collected during the combination treatment period (ie, while patients are on randomized treatment or 
re-treatment), unless otherwise specified (see details in Section 7, Section 8, and Section 9). 
Primary and secondary assessment of efficacy and safety assessments will be made in the 
following two study treatment groups: 
• 52 weeks of a relugolix tablet and an over-encapsulated tablet of E2/NETA, once daily; 
• 52 weeks of a placebo relugolix tablet and a capsule of placebo E2/NETA acetate, once daily. 


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Week 52 of the LTE study will define the baseline for this randomized withdrawal study and will 
be used as the reference point for all changes from baseline-related endpoints unless otherwise 
specified.  The Week 48 menstrual blood loss volume in the LTE study will establish responder 
status (results from Week 44 may be used if Week 48 data are unavailable at the time eligibility 
was being assessed).  
Table 1: 
Study Objectives and Endpoints  
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To evaluate the long-term effect of relugolix + 
E2/NETA, once daily, compared with placebo 
on menstrual blood loss at Week 76 (24 
weeks after randomization). 
• 
Proportion of women who maintained a 
menstrual blood loss volume of < 80 mL at 
Week 76 (24 weeks of the Randomized 
treatment period) as measured by the alkaline 
hematin method (referred to as sustained 
responder rate at Week 76), defined as the 
cumulative probability of MBL volume 
< 80 mL while on randomized treatment 
through Week 76. 
Key Secondary Efficacy 
• 
To evaluate the long-term effect of relugolix + 
E2/NETA compared with placebo on the 
following 
The following key secondary endpoints will be 
assessed at Week 76, at Week 104 and by visit (as 
appropriate) during the randomized treatment 
period: 
• 
Resumption of heavy menstrual bleeding 
(HMB) 
• 
Time to menstrual blood loss volume 
≥ 80 mL; 
• 
Menstrual blood loss 
• 
Proportion of women who maintained a 
menstrual blood loss volume of < 80 mL at 
Week 104 (52 weeks of the randomized 
treatment period) as measured by the alkaline 
hematin method (named as sustained 
responder rate at Week 104), defined as the 
cumulative probability of MBL volume 
< 80 mL while on randomized treatment 
through Week 104; 
• 
Achievement of amenorrhea 
• 
Proportion of women achieving or 
maintaining amenorrhea at Week 76/EOT; 


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Objective(s) 
Endpoint(s) 
Other Secondary Efficacy 
• 
To evaluate the long-term effect of relugolix + 
E2/NETA, once daily compared with placebo 
on menstrual blood loss at Week 104 (52 
weeks after randomization). 
• 
Change from Week 52/Baseline to Week 76 
and Week 104 in menstrual blood loss volume 
(during the randomized treatment period); 
• 
Percentage change from Week 52/Baseline to 
Week 76 and Week 104 in menstrual blood 
loss volume (during the randomized treatment 
period); 
• 
Proportion of women achieving or 
maintaining amenorrhea at Week 104/EOT. 
• 
To evaluate the effect of retreatment with 
relugolix + E2/NETA on menstrual blood loss 
in patients whose menstrual blood volume 
returned to ≥ 80 mL during the 52-week 
randomized period. 
• 
Proportion of patients who responded 
(menstrual blood loss volume of < 80 mL) to 
retreatment during the retreatment period 
among placebo patients whose menstrual 
blood loss volume returns to ≥ 80 mL during 
the 52-week randomized treatment period. 
• 
To evaluate the long-term effect of relugolix + 
E2/NETA at 52 weeks after randomization on 
the following: 
The following secondary endpoints will be 
assessed at Week 76, at Week 104 and by visit (as 
appropriate) during the randomized treatment 
period: 
• 
Resumption of menses 
• 
Proportion of women whose menses has 
resumed (among those who were amenorrheic 
at Week 52/Baseline); 
• 
Time to resumption of menses (among those 
who were amenorrheic at Week 52/Baseline). 
• 
Resumption of heavy menstrual bleeding 
(HMB) 
• 
Proportion of women with menstrual blood 
loss volume ≥ 80 mL at any timepoint during 
the 52-week randomized treatment period; 
• 
Hemoglobin 
• 
Change and percent change from Week 
52/Baseline in hemoglobin; 
• 
Proportion of patients who had hemoglobin 
level <=10.5g/dL over time 
• 
Proportion of patients who had hemoglobin 
level < 11.6g/dL over time 
• 
Health-related Quality of Life as 
measured by the Short Form (36) Health 
(SF-36) questionnaire 
• 
Change from Week 52/Baseline in SF-36 
domain and summary component scores; 
• 
Patient Global Assessment (PGA) for 
function and symptoms  
• 
Change from Week 52/Baseline in PGA for 
function and symptoms score; 
• 
Work and Productivity impact as 
measured by the Work Productivity 
Activity Impairment-Uterine Fibroids 
(WPAI-UF) questionnaire 
• 
Change from Week 52/Baseline in the WPAI-
UF scores; 


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Objective(s) 
Endpoint(s) 
• 
Disease-specific quality of life as assessed 
by the Uterine Fibroid Symptom and 
Health-Related Quality of Life (UFS-
QoL) questionnaire 
• 
Change from Week 52/Baseline in the UFS-
QoL scale and sub-scale scores as well as the 
total score. 
Pharmacodynamic 
• 
To characterize the pharmacodynamic (PD) 
effect of withdrawal from relugolix + 
E2/NETA 
• 
Pre-dose concentration of estradiol at 
Week 56 
Safety 
• 
To evaluate the safety and tolerability of 
relugolix + E2/NETA, once daily, for up to an 
additional 52 weeks 
The following safety endpoints will be assessed: 
• 
Adverse events 
• 
Incidence of adverse events; 
• 
Change in vital signs; 
• 
Clinical laboratory tests. 
• 
Changes in bone mineral density 
• 
Percent change from Week 52/Baseline to 
Week 104 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by DXA. 
• 
Change from Week 52/Baseline to Week 104 
in bone mineral density Z-score at the lumbar 
spine (L1-L4), femoral neck, and total hip as 
assessed by DXA. 
• 
Percent change from pivotal study Baseline to 
Week 104 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by DXA. 
Abbreviations:  DXA = dual-energy x-ray absorptiometry; E2 = estradiol; EOT = End of Treatment; HMB = heavy 
menstrual bleeding; MBL = menstrual blood loss; NETA = norethindrone acetate; PGA = Patient Global 
Assessment; UFS-QoL = Uterine Fibroid Symptom and Health-Related Quality of Life; WPAI-UF = Work 
Productivity Activity Impairment-Uterine Fibroids. 


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2. 
STUDY DESIGN  
2.1. 
Summary of Study Design  
This randomized withdrawal study (MVT-601-035) is an international phase 3 double-blind, 
placebo-controlled study that enrolled eligible patients with uterine fibroids who have completed 
the 24-week treatment period in a pivotal study (study MVT-601-3001 or study MVT 601-3002) 
and the 28-week treatment period of the LTE study, MVT-601-3003.  When including treatment 
during a pivotal study and the extension study, patients completing this randomized withdrawal 
study will have received up to a total of 104 weeks of treatment with relugolix. 
All consenting patients completing MVT-601-3003 with a response to treatment were eligible to 
participate.  A responder was defined as a patient who demonstrated a menstrual blood loss of < 
80 mL and at least a 50% reduction from a pivotal study baseline menstrual blood loss volume 
on the alkaline hematin analysis of the FPs returned at Week 48 in MVT-601-3003.  The 
objectives of the current study are to evaluate long-term efficacy and safety of treatment with 
relugolix + E2/NETA for up to 104 weeks (total treatment duration includes the pivotal study, 
the extension study, and the randomized withdrawal study).  Approximately 360 patients 
completing the extension study and meeting the definition of a responder as well as all other 
eligibility criteria were expected to be randomized 1:1 to blinded treatment with oral relugolix + 
E2/NETA or placebo, once daily, for up to 52 weeks.  For patients whose menstrual bleeding 
returned to ≥ 80 mL (heavy menstrual bleeding), treatment with open-label relugolix + E2/NETA 
was to be restarted. 
Screening procedures were to be done on the same day as the Week 52 visit for MVT-601-3003.  
This visit will be referred to as the “Week 52/Baseline visit”.   
Patients were to receive the last dose of study drug in the study MVT-601-3003 on the day of the 
Week 52/Baseline visit (per the LTE study protocol) and to be dispensed study drug for this 
randomized withdrawal study in the clinic after being determined eligible for this study and 
providing informed consent to participate.  The first dose of study drug for the randomized 
withdrawal study was to be self-administered the next morning following the Week 52/Baseline 
visit.  Dosing was to be confirmed by telephone.   
Patients were to be asked to collect FPs for alkaline hematin analysis and to return them at each 
visit until the analysis confirmed the return of heavy menstrual bleeding (defined as menstrual 
blood loss volume of ≥ 80 mL).  The patients were then to be offered re-treatment with open-
label relugolix +E2/NETA with the onset of the next menses.  They were to continue collection 
of FPs for alkaline hematin analysis until two consecutive analyses confirmed resolution of 
heavy menstrual bleeding (menstrual blood loss of < 80 mL).  Patients who experienced a return 
of heavy menstrual bleeding (or terminate early because they have a return of heavy menstrual 
bleeding) but who decline retreatment with open-label study drug were to complete an Early 
Termination visit and a 30-day Safety Follow-Up visit. 
At the Week 104/Early Termination visit, all other patients were to have an assessment of bone 
mineral density (BMD) via dual-energy x-ray absorptiometry (DXA).  Patients were to complete 
the bleeding diary daily, including compliance with study drug, vaginal bleeding, and use of FPs. 


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If a patient enrolls directly into another relugolix clinical study upon completion of the Week 
104/Early Termination visit, then the Safety Follow-Up visit and the follow-up procedures 
performed under this protocol may be waived. 
2.2. 
Sample Size Considerations  
Because this is an extension of study MVT-601-3003, the sample size of this study was based on 
approximately the number of patients who completed a pivotal study (n = 780 patients in total), 
and who participated in the LTE study (n = 600 patients in total assuming about 20% dropout 
rate at 6 months from the pivotal studies).  Assuming the proportion of responders at Week 52 in 
MVT-601-3003 LTE study is 60%, it was estimated that approximately 360 patients were to be 
randomized into this study. 
With 360 patients, the study would have at least 90% power to detect a difference of 20% or 
greater between relugolix+ E2/NETA group and placebo group for the primary endpoint.  The 
following assumptions were used to determine the sample size for this study: 
• 2-sided type I error rate: 0.05 
• Randomization: 1:1 
• Responder rate for placebo group: 40% 
• Responder rate for relugolix + E2/NETA group: 60% 
• Dropout rate: 20% 


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3. 
PLANNED ANALYSES  
3.1. 
Interim Analyses  
There are no planned interim efficacy analyses. 
3.2. 
Final Analyses  
The final analysis of efficacy and safety data will occur after approximately 360 patients 
(projected to be responders from MVT-601-3003) who have been randomized and have had the 
opportunity to complete the study through either the Week 104 visit or the 30-day Safety Follow-
up visit. 
3.3. 
Safety Follow-Up Analyses  
Patients who experience a BMD loss of ≥ 7% from the pivotal study baseline at any of the 
anatomical sites assessed will be discontinued from the study and will undergo another bone 
densitometry scan as described below.  Patients with a BMD loss of ≥ 7% at lumbar spine, total 
hip, or femoral neck at their Week 104/Early Termination visit relative to pivotal study baseline 
measurement will undergo another bone densitometry scan at 6 (± 1) months after the last dose 
of study drug and will be contacted to obtain information about medications and conditions (eg, 
pregnancy) that might affect BMD through the time of the follow-up bone densitometry scan.  
Patients should be assessed for secondary causes of bone loss and followed-up further if the 6-
month follow-up scan does not show improvement, unless an alternative etiology has been 
identified.  The follow-up bone densitometry scan will be submitted for central reading. 
Patients whose menses have not resumed as of the safety follow-up visit and for whom there is 
no explanation for the lack of resumption (eg, medical procedure or medications) will be 
contacted again by telephone 12 (± 2) weeks after the Safety Follow-up visit to determine if 
menses have resumed. 
Complete data collected during the additional safety follow-up period will be summarized and 
reported in an addendum to the CSR. 


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4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA  
4.1. 
Data Presentation Conventions  
All statistical analyses will be conducted using SAS® Version 9.2 or higher. 
All confidence intervals (CIs) will be reported as two-sided unless otherwise stated. 
Where appropriate, variables will be summarized descriptively by study visit.  For the 
categorical variables, the count and proportions of each possible value will be tabulated by 
treatment group.  For continuous variables, the number of patients with non-missing values, 
mean, median, standard deviation (SD), minimum, and maximum values will be tabulated. 
Unless otherwise specified, the following conventions will be applied to all analyses: 
• Mean and median values will be formatted to one more decimal place than the measured 
value.  Standard deviation values will be formatted to two more decimal places than the 
measured value.  Minimum and maximum values will be presented to the same number 
of decimal places as the measured value.  If the measured value is large (eg, > 100), 
fewer decimal places may be displayed. 
• Percentages will be rounded to one decimal place; 
• p-values will be rounded to four decimal places.  p-values < 0.0001 will be presented as 
“< 0.0001” and p-values > 0.9999 will be presented as “> 0.9999”; 
• 1 month = 30.4375 days.  Month is calculated as (days/30.4375) rounded to one decimal 
place; 
• 1 year = 365.25 days.  Year is calculated as (days/365.25) rounded to one decimal place; 
• Age will be calculated using the date of randomization.  If only year of birth is collected, 
1 July of the year of birth will be used to calculate age. 
• 1 pound = 0.454 kg; 
• 1 inch = 2.54 cm; 
• Missing efficacy or safety data will not be imputed, unless otherwise specified; 
• For laboratory results above or below sensitivity limits displayed as “<” or “>,” a 
quantification threshold, 0.0000000001, will be subtracted or added, respectively, to the 
threshold to derive a numeric result for analyses; 
• For MBL volume reported as below the limit of quantification (eg, MBL below 
Quantification Level < 5.0 mL or < 2.5 mL), 0.0000000001 will be subtracted from the 
reported quantification threshold for the visit to derive a numeric result for analyses; 
• For safety analyses, calculation of percentages will be calculated on the basis of the 
number of patients in the analysis population in each treatment group;  
• For by-visit observed data analyses, calculation of percentages will be calculated on the 
basis of the number of patients with non-missing data as the denominator, unless 
otherwise specified; 


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• For other continuous endpoints, the summary statistics will include mean, SD, median, 
and range (minimum and maximum); 
• For time-to-event endpoints, the summary statistics will include median time to event-
free survival, 25th and 75th percentiles and number of patients at risk at specified time 
points; 
• For categorical endpoints, the summary statistics will include counts and percentages; 
• Confidence intervals, when presented, will generally be constructed at the 95% level.  For 
binomial variables, exact methods will be employed, unless otherwise specified. 
4.2. 
Analysis Populations  
Four analysis populations are defined below.  Number and percent of patients meeting the 
definition of each analysis population will be summarized by treatment group. 
4.2.1. 
Modified Intent-to-Treat Population  
Efficacy analyses will be performed using the modified Intent-to-Treat (mITT) population, 
unless otherwise specified.  The mITT population consists of all patients randomized to 
treatment who have taken at least one dose of study treatment (relugolix/placebo or 
E2/NETA/placebo).  Efficacy analyses will be performed by treatment group as randomized. 
4.2.2. 
Per-Protocol Population  
The Per-Protocol population consists of those patients in the mITT population who have no 
relevant major protocol deviations, defined as a subset of all major protocol deviations (see 
Section 5.2).  
The Per-Protocol population will not be analyzed if this population comprises > 95% or < 50% 
of the mITT Population.  This population will be used for supportive analysis of the primary 
efficacy endpoint.  The Per-Protocol population will be identified prior to breaking the study 
blind. 
4.2.3. 
Safety Population  
The Safety population consists of all patients who were randomized and took at least one dose of 
study treatment.  All safety analyses will be performed using the safety population, unless 
otherwise specified.  Safety data will be analyzed by treatment group according to the actual 
treatment received (not the randomized treatment).  Any patient who received at least one dose 
of relugolix during the randomized treatment period will be considered as a relugolix patient.   
4.2.4. 
Retreatment Population  
The Retreatment population consists of those patients in the mITT Population who started the 
retreatment.  Selected efficacy and safety data will be analyzed using the retreatment population. 


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4.3. 
Definitions, Computation, and Convention  
4.3.1. 
Definition of Date of First Dose and Date of Last Dose of Study Drug During the 
Randomized Treatment Period  
The randomized treatment period is the period when a patient was on one of the randomized 
study drugs (relugolix + E2/NETA or placebo).  The date of first dose of study drug is defined as 
the date when a patient receives the first dose of study drug for the randomized withdrawal study 
following randomization.  The first dose of study drug for the randomized withdrawal study was 
to be self-administered the next morning following the Week 52/Baseline visit. 
The date of the last dose of randomized study drug is defined as the date a patient receives the 
last dose of randomized study drug in this randomized withdrawal study, prior to re-treatment or 
on the Week 104 visit date.  If the complete date of last dose of study drug is unknown, the last 
date the study drug was known to have been taken will be used. 
4.3.2. 
Definition of Date of First Dose and Date of Last Dose of Retreatment Drug  
The date of first dose of retreatment drug is defined as the date when a patient receives the first 
dose of retreatment drug (open-label relugolix + E2/NETA).  When the return of heavy 
menstrual bleeding (defined as menstrual blood loss of ≥ 80 mL) was confirmed for a patient 
during the randomized treatment period, the patient was to be offered retreatment with open-
label relugolix + E2/NETA with the onset of the next menses.  
The date of the last dose of retreatment drug is defined as the date a patient receives the last dose 
of retreatment drug in this randomized withdrawal study, prior to or on the Week 104 visit date.  
If the complete date of last dose of retreatment drug is unknown, the last date the retreatment 
drug was known to have been taken will be used. 
4.3.3. 
Study Day  
Study day will be calculated with respect to the date of the first dose of randomized withdrawal 
study drug in this study (Study Day 1).  For assessments conducted on or after the date of the 
first dose of randomized withdrawal study drug, study day will be calculated as: 
(Assessment date – date of first dose of randomized withdrawal study drug) + 1 
For assessments conducted before the date (and time) of the first dose of randomized withdrawal 
study drug, study day will be calculated as: 
(Assessment date – date of first dose of randomized withdrawal study drug) 
For patients who do not receive any amount of randomized withdrawal study drug, study day 
will be calculated as above with respect to the date of randomization. 
4.3.4. 
Definition of Treatment Duration During the Randomized Treatment Period  
Treatment duration during the randomized treatment period is defined as the duration of time 
from the date of the first dose of study drug to the date of the last dose of study drug as follows:  
(Date of last dose of study drug – Date of first dose of study drug) + 1 


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For patients without complete date of last dose of study drug, the last date study drug was known 
to have been taken will be used to calculate treatment duration.  For patients who did not return 
for the Early Termination visits during the randomized treatment period, the time after their last 
visit will not be included in calculations of treatment duration.   
4.3.5. 
Definition of Treatment Duration During the Retreatment Period  
The retreatment period is the period when a patient was on the open-label retreatment drug.  
Treatment duration of retreatment drug is defined as the duration of time from the date of the 
first dose of retreatment drug to the date of the last dose of retreatment drug as follows:  
(Date of last dose of retreatment drug – Date of first dose of retreatment drug) + 1 
For patients without complete date of last dose of retreatment drug, the last date retreatment drug 
was known to have been taken will be used to calculate treatment duration.  For patients who did 
not return for the Early Termination visits during the retreatment period, the time after their last 
visit will not be included in calculations of treatment duration.   
The cumulative treatment period includes both the randomized treatment period and the 
retreatment period. 
4.3.6. 
Definition of Baseline Value and Post-Baseline Value  
Unless otherwise specified, Baseline values are defined as the last available measurement before 
the first administration (date and time) of study drug in the randomized withdrawal study.  This 
is for randomized treatment period and for cumulative treatment period, which includes the 
randomized treatment and retreatment periods.  A post-Baseline value is defined as a 
measurement taken after the first dose of study drug.  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.  For patients who receive no study medication, the date of 
randomization will be used in place of the date of first dose in determining Baseline and post-
Baseline values. 
Baseline for the retreatment period is defined as the last available measurement before the first 
dose of retreatment drug unless otherwise specified.  A post-retreatment-baseline value is 
defined as a measurement taken after the first administration of retreatment drug.  Change from 
retreatment baseline is defined as (post-retreatment-baseline value – retreatment baseline value).   
The BMD measurement taken at Week 52 of the extension study will be used as the Week 
52/Baseline in the randomized withdrawal study, as long as it was within 30 days of the first 
dose date of the randomized withdrawal study drug.  If there are multiple BMD measurements at 
Week 52 in the extension study, the one closest to the first dose date of the randomized 
withdrawal study drug will be used as Week 52/Baseline in the randomized withdrawal study.   
For menstrual blood loss volume, the baseline definition will be specified in Section 7.3.2.   
4.3.7. 
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 


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Table 2 (for monthly assessment, SF-36v2, PGA, WPAI-UF), Table 3 (for BMD), Table 4 (for 
UFS-QoL), and Table 5 (for clinical laboratory tests and vital signs), respectively.  For both 
efficacy and safety assessments, the study day will be used to determine the associated visit 
window.   
The data collected in the paper diary related to bleeding and use of FPs will be assigned to visit 
windows as specified in Table 6 and will be used to calculate the feminine product return rate 
(FPRR) as specified in Section 7.3.2.5. 
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 except for FP collection, which 
is specified in Section 7.3.2.4.  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 2: 
Visit Windows for Monthly Assessments  
Visit (Long label) 
Visit (Short label) 
Start Day 
Target Day 
End Day 
Week 56 (4 weeks 
after randomization) a  
Week 56  
1 
29 
43 
Week 60 (8 weeks 
after randomization) 
Week 60  
44 
57 
71 
Week 64 (12 weeks 
after randomization) 
Week 64 
72 
85 
99 
Week 68 (16 weeks 
after randomization) 
Week 68 
100 
113 
127 
Week 72 (20 weeks 
after randomization) 
Week 72 
128 
141 
155 
Week 76 (24 weeks 
after randomization) 
Week 76 
156 
169 
183 
Week 80 (28 weeks 
after randomization) 
Week 80  
184 
197 
211 
Week 84 (32 weeks 
after randomization) 
Week 84  
212 
225 
239 
Week 88 (36 weeks 
after randomization) 
Week 88 
240 
253 
267 
Week 92 (40 weeks 
after randomization) 
Week 92 
268 
281 
295 
Week 96 (44 weeks 
after randomization) 
Week 96  
296 
309 
323 
Week 100 (48 weeks 
after randomization) 
Week 100  
324 
337 
351 
Week 104 (52 weeks 
after randomization) 
Week 104 
352 
365 
Date of last dose + 
14 days b 
a 
Start day of Week 56 for study day 1 includes only post-Baseline assessments that occurred after the first dose. 
b 
For SF-36v2, PGA, WPAI-UF, 14 days after date of last dose is used as the end day of Week 104.   


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Table 3: 
Visit Windows for Bone Mineral Density Assessments  
Visit (Long label)  
Visit (Short label) 
Start Day 
Target Day 
End Day 
Week 104 (52 weeks 
after randomization) 
Week 104 
281 
365 
449 
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 uterine 
fibroids.  Assessments after date of last dose of study drug + 60 days will also be excluded from analysis. 
 
Table 4: 
Visit Windows for UFS-QoL Assessments  
Visit (Long label)  
Visit (Short label) 
Start Day 
Target Day 
End Day 
Week 64 (12 weeks 
after randomization) 
Week 64 
64 
85 
106 
Week 76 (24 weeks 
after randomization) 
Week 76 
148 
169 
196 
Week 88 (36 weeks 
after randomization) 
Week 88 
197 
253 
308 
Week 100 (48 weeks 
after randomization) 
Week 100  
309 
337 
351 
Week 104 (52 weeks 
after randomization) 
Week 104 
352 
365 
421 
Abbreviations:  UFS-QoL = Uterine Fibroid Symptom and Health-Related Quality of Life.   
 
Table 5: 
Visit Windows for Clinical Laboratory Tests and Vital Signs 
Visit (Long label)  
Visit (Short label) 
Start Day 
Target Day 
End Day 
Week 64 (12 weeks 
after randomization) a  
Week 64 
64 
85 
106 
Week 76 (24 weeks 
after randomization) 
Week 76 
148 
169 
196 
Week 104 (52 weeks 
after randomization) 
Week 104 
309 
365 
Date of last dose + 
6 days  
Safety Follow-Up b 
Safety Follow-Up Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a This visit is only for clinical laboratory tests.  
b The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids. 
 
 


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Table 6: 
Time Window for Feminine Product Collection  
Visit (Long label) 
Visit (Short label) 
Feminine Product 
Collection Visit Datea,b  
Time Windowa 
Week 56 (4 weeks after 
randomization) a  
Week 56 
X1 
(Date of Study Day 1) – < X1 
Week 60 (8 weeks after 
randomization) 
Week 60 
X2 
(X1 +1) – ≤ X2 
Week 64 (12 weeks after 
randomization) 
Week 64 
X3 
(X2 +1) – ≤ X3 
Week 68 (16 weeks after 
randomization) 
Week 68 
X4 
(X3 +1) – ≤ X4 
Week 72 (20 weeks after 
randomization) 
Week 72 
X5 
(X4 +1) – ≤ X5 
Week 76 (24 weeks after 
randomization) 
Week 76 
X6 
(X5 +1) – ≤ X6 
Week 80 (28 weeks after 
randomization) 
Week 80 
X7 
(X6 +1) – ≤ X7 
Week 84 (32 weeks after 
randomization) 
Week 84 
X8 
(X7 +1) – ≤ X8 
Week 88 (36 weeks after 
randomization) 
Week 88 
X9 
(X8 +1) – ≤ X9 
Week 92 (40 weeks after 
randomization) 
Week 92 
X10 
(X9 +1) – ≤ X10 
Week 96 (44 weeks after 
randomization) 
Week 96 
X11 
(X10 +1) – ≤ X11 
Week 100 (48 weeks after 
randomization) 
Week 100 
X12 
(X11 +1) – ≤ X12 
Week 104 (52 weeks after 
randomization) /EOT 
Week 104/EOT 
XLastc 
(Previous Feminine Product 
Returned Visit +1) – ≤ XLast 
a If feminine products are collected at more than 1 visit within a given visit window (Table 2), the last feminine 
product collection date will be used to define the time window.  If the patient missed the previous visit, a planned 
study visit date will be used to calculate the window. 
b In the absence of feminine product collection due to amenorrhea the visit date when amenorrhea was reported will 
be used. 
c   Date of last non-missing feminine product collection within the interval from (previous visit end date + 1) to (last 
dose date + 7 days) (see Section 7.3.2).  
 
4.4. 
General Rules for Missing Data  
Handling of missing data for the primary efficacy analysis is described in Section 7.3.3.  
4.4.1. 
By-Visit Endpoints  
By-visit endpoints will be analyzed using observed data, unless otherwise specified.  For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included. 


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4.4.2. 
Adverse Events and Concomitant Medications  
The following imputation rules for the safety analyses will be used to address the issues with 
partial dates.  The imputed dates will be used to determine the treatment-emergent period.  For 
adverse events with a partial date, available date parts (year, month, and day) of the partial date 
will be compared with the corresponding date components of the start date and end dates of the 
treatment-emergent period to determine if the event is treatment emergent.  When in doubt, the 
adverse event will be considered treatment emergent by default.  If the adverse events were 
recorded in pivotal or LTE studies, the rules used to impute the partial dates in corresponding 
study will be used.   
The following rules will be applied to impute partial dates for adverse events when they were 
newly recorded in the randomized withdrawal study: 
• If start date of an adverse event is partially missing, impute as follows: 
− If both Month and Day are missing and Year = Year of treatment start date, then set to 
treatment start date, as long as adverse event end date is not prior to treatment start date; 
− If both Month and Day are missing and Year ≠ Year of treatment start date, then set 
to January 1; 
− If Day is missing and Month and Year = Month and Year of treatment start date, then set 
to treatment start date, as long as adverse event end date is not prior to treatment start date; 
− If Day is missing and Month and Year ≠ Month and Year of treatment start date, then 
set to first of the month; 
− If start date is completely missing, set to treatment start date, as long as adverse event 
end date is not prior to treatment start date. 
• If end date of an adverse event is partially missing, impute as follows: 
− If both Month and Day are missing, then set to December 31; 
− If only Day is missing, then set to last day of the month; 
− If end date is completely missing, do not impute. 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant (or both).   
The following rules will be applied to impute partial dates for medications: 
• If start date of a medication is partially missing, impute as follows: 
− If both Month and Day are missing, then set to January 1; 
− If only Day is missing, then set to the first of the month. 
• If end date of a medication is partially missing, impute as follows: 
− If both Month and Day are missing, then set to December 31; 
− If only Day is missing, then set to last day of the month. 
• If start date or end date of a medication is completely missing, do not impute. 


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5. 
STUDY POPULATION  
5.1. 
Subject Disposition  
The number of patients for each of the following categories will be summarized by treatment 
group: 
• All randomized patients; 
• Patients included in the Safety population;  
• Patients who completed 76-week treatment; 
• Patients who completed 104-week treatment; 
• Patients who discontinued early from the study and reasons for discontinuation; 
Patient disposition will be summarized for all randomized patients.  Summaries will include the 
number and percentage of patients in the mITT and Safety populations.  The number and 
percentage of patients who prematurely discontinue study drug and the reasons for 
discontinuation will be summarized by treatment group.   
5.2. 
Protocol Deviations  
Protocol deviations that occurred during the randomized withdrawal study will be categorized as 
important or minor per the protocol deviation plan.  Important protocol deviations will include, 
but will not be limited to, the following categories: 
• Randomized patient who did not satisfy key entry criteria; 
• Randomized patient who met withdrawal criteria during the study but was not withdrawn; 
• Randomized patient who received the wrong treatment; 
• Randomized patient who received a prohibited concomitant medication that met criteria 
for an important protocol deviation; 
• Unintentional unblinding of treatment assignment. 
Important protocol deviations will be summarized by deviation category for all patients in the 
mITT population.  A patient listing of all important protocol deviations will be provided. 
A selected subset of the major protocol deviations that are likely to affect analysis of efficacy 
will be identified to define the Per-Protocol population prior to the database lock.  This subset 
will include but will not be limited to the following important protocol deviations:  
• Did not satisfy key entry criteria (restricted to patients who did not meet inclusion 
criterion 4 of MVT-601-035, ie, patients who were not responders at the time eligibility 
was being assessed );  
• Drug compliance during the randomized treatment period < 75%; 
• Patient received prohibited concomitant medications that met criteria for important 
protocol deviation: restricted to patients who received prohibited concomitant 
medications that may cause significant drug-drug interaction; 


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• Unintentional unblinding of treatment assignment. 
5.3. 
Demographic and Baseline Characteristics  
Demographic and Baseline characteristics at pivotal study baseline (Pivotal Baseline) and at this 
randomized withdrawal study baseline (Week 52/Baseline) will be summarized by treatment 
group for the mITT population.  Categorical data will be summarized using frequencies and 
percentages, by treatment group and overall (see Table 7 below) for each baseline.  Summaries 
of continuous data will display the mean, SD, median, minimum, and maximum.  The numbers 
of missing values will also be summarized. 
Table 7: 
Categories for Demographic and Baseline Characteristics  
Variable 
Category 
For both Pivotal Baseline and Week 52/Baseline  
Age (years) 
< 40, ≥ 40  
BMI (kg/m2)  
< 18.5, 18.5 to <25, 25 to <30, 30 to < 35,  
35 to < 40, ≥ 40 
 
< 30, ≥ 30 
UFS-QoL 
       Bleeding and Pelvic Discomfort Scale 
 
0 to < 25, 25 to <50, 50 to <75, 75 to 100 
Patient Global Assessment 
     Function 
No limitation at all, Mild limitation, Moderate 
limitation, Quite a bit of limitation, Extreme limitation 
     Symptoms 
Not severe, Mildly severe, Moderately severe, Very 
severe, Extremely severe 
Hemoglobin (g/dL) 
Min to < 8, ≥ 8 to <10.5, ≥ 10.5 to <12, ≥ 12 
For Week 52/Baseline Only  
Geographic region 
North America, Other 
 
North America, Europe, Latin America, Rest of World 
Duration of relugolix exposure prior to 
randomization (weeks) 
28, 52  
For Pivotal Baseline Only  
Race 
Black or African American, White, American Indian 
or Alaska Native, Asian, Native Hawaiian or Other 
Pacific Islander, Other  
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino, or Not 
reported 
Menstrual blood loss volume at baseline (mL) 
< 225, ≥ 225 
Menstrual blood loss volume at baseline (mL) 
< 160, ≥ 160 


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Variable 
Category 
History of prior pregnancy  
Yes, No  
Disease duration of uterine fibroid (years) 
Min to <1, ≥ 1 to < 3, ≥3 to <5, ≥5 to <10, ≥ 10 
Type of uterine fibroids  
     Subserous fibroid 
Yes, No  
     Intramural fibroid 
Yes, No 
     Submucosal fibroid 
Yes, No 
     Other 
Yes, No 
Any surgery for uterine fibroids 
Yes, No 
Volume of myoma at Pivotal Baseline (cm3) 
< 25, ≥ 25 
Volume of uterus at Pivotal Baseline (cm3) 
< 300, ≥ 300 
Maximum NRS score for uterine fibroid-
associated pain at Pivotal Baseline 
< 4, ≥ 4 
Alcohol use 
None, Moderate (2 - 6 drinks per week),  
Heavy (≥ 7 drinks per week) 
Smoking history 
Current smoker, Past smoker, Never 
Abbreviations:  BMI = body mass index; NRS = Numerical Rating Scale; UFS-QoL = Uterine Fibroid Symptom 
and Health-Related Quality of Life. 
 
5.4. 
Medical History  
Medical history collected at the time of entry into the pivotal studies 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 Safety population.  Additionally, summaries 
of uterine fibroid–specific medical and surgical treatment history collected at the time of entry 
into the pivotal study will be provided.  A patient with multiple occurrences of medical history 
within a PT will be counted only once in that PT.  Medical history is not collected in the eCRF of 
randomized withdrawal study.  Adverse events that were collected in the pivotal studies or 
extension study and ended prior to the start of the randomized withdrawal study will be listed 
and summarized.   
5.5. 
Prior Medications and Concomitant Medications  
Prior medications and concomitant medications taken during this Randomized Withdrawal Study 
treatment period will be summarized for all patients in the Safety population by randomized 
treatment group.  In addition, concomitant medications taken during the retreatment period will 
also be summarized for Safety Population by their randomized treatment group.  Medications are 
considered concomitant for randomized treatment period if exposure occurs during the 
randomized treatment period.  Medications are considered concomitant for retreatment period if 
exposure occurs during the retreatment period.  Medications are considered prior if exposure 
started prior to the date of first dose of randomized withdrawal study drug.   


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The number and percentage of patients who took at least one dose of a prior or concomitant 
medication will be summarized by randomized treatment group and overall using the World 
Health Organization (WHO) Drug Dictionary and summarized according to the Anatomical 
Therapeutic Chemical (ATC) Classification System and generic medication name.  A patient 
who has been administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name.   


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6. 
STUDY DRUG EXPOSURE AND COMPLIANCE  
All analyses of extent of exposure to study drug and compliance will be summarized by actual 
treatment received in this randomized withdrawal study.  Extent of exposure to and compliance 
with relugolix (or relugolix placebo) and E2/NETA (or placebo) during this randomized 
treatment period and the retreatment period will be summarized for patients in the Safety 
population.  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 dosages of relugolix and E2/NETA taken 
in milligrams, the total number of tablets (or capsules) taken, and treatment duration.  Total 
dosages of relugolix and E2/NETA taken during the randomized treatment period and the 
retreatment period will be summarized by randomized treatment group.  Treatment duration 
during the randomized treatment period and during the retreatment period with any study drug 
(relugolix, E2/NETA, or placebo) will be summarized by randomized treatment group.   
Study drug compliance will be summarized for the randomized 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 
randomized treatment period of the study.  Tablets that were dispensed and not returned will be 
assumed to have been taken.  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 post-Week 52/Baseline visits and did not 
return dispensed study drug, study drug compliance will not be calculated and will be 
categorized as “not able to calculate” in summaries of 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%). 
The study drug compliance during the retreatment period will be calculated similarly and will be 
summarized for retreatment period by the randomized treatment group. 
 
 


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7. 
EFFICACY ANALYSES  
7.1. 
General Considerations  
Unless otherwise specified, efficacy analyses will be conducted using the mITT population 
according to the randomized treatment assignment.  Stratified analyses will be stratified by the 
randomization stratification factors, which include pivotal study baseline menstrual blood loss 
(MBL) volume (< 225 vs. ≥225 mL), geographic region (North America vs. Other, where 
Europe, Latin America, and Rest of World will be pooled together as Other), and duration of 
relugolix exposure prior to randomization (28 weeks vs. 52 weeks).  If the group of patients at 
any factor level from a randomization stratification factor (eg, patients with pivotal study 
Baseline MBL volume ≥ 225 mL) comprises < 10% of the entire mITT population, this 
stratification factor (eg, pivotal study Baseline MBL volume) will not be used for stratified 
analyses.  In addition, based on the pooled baseline data, there are < 10 patients in 1 of the 8 
strata (derived from the 3 stratification factors each with 2 levels, < 5 patients within a 
randomized treatment group), geographic region will not be used for stratified analysis.  
Stratification factors of pivotal study Baseline MBL volume (< 225 vs. ≥225 mL) and duration of 
relugolix exposure prior to randomization (28 weeks vs. 52 weeks) will be used in the stratified 
analysis for more robust strata-adjusted estimation of treatment effect.  The stratification 
category used at the time of randomization (in the Interactive Web Recognition Service [IWRS] 
system) will be used for all analyses rather than data recorded on the electronic case report form 
(eCRF) unless otherwise specified.  A sensitivity analysis of the primary endpoint will be 
performed if the data in the IWRS and eCRF for stratification factors differ by > 5%.   
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 treatment group and visit as appropriate. 
7.1.2. 
Analyses for Continuous Data  
This section describes analysis for continuous endpoints in general, not including MBL volume 
related continuous endpoints.  Analyses of change and percent change in MBL volume are 
described in Section 7.4.2. 
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 treatment group.  
Additionally, the mean of observed results will also be calculated at each visit, including only the 
patients who are in the analysis population and who have data at that visit by treatment group. 
For endpoints evaluating the change (absolute or percent change) from baseline, mean change as 
well as least squares (LS) mean change and 95% CI will be summarized.  LS means and 95% CI 
will be derived using a mixed-effects model repeated measures approach with treatment, 


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randomization stratification factors, visit, and treatment by visit interaction included as fixed 
effects.  The Baseline value will be included as a covariate, and an unstructured variance-
covariance matrix will be assumed.  If the mixed-effects model fails to converge, a first-order 
autoregressive variance-covariance matrix will be used.  Calculation of the dependent variable 
(change from baseline) for each patient at each visit will be calculated based on the visit 
windows specified in Section 4.3.7.  In addition, summary statistics (LS mean change or LS 
mean % change) will be graphically presented as appropriate.  Note, the mixed-effects models 
will not be applied to the data analysis during the randomized treatment period due to 
informative censoring patient’s data at the time of retreatment for patients who had MBL volume 
≥ 80 mL during the randomized period.  They will be applied to data analysis during the 
cumulative treatment period. 
7.1.3. 
Analyses for Time to Event Data  
Time-to-event endpoints will be summarized using the Kaplan-Meier method.  The median, 
quartiles, and probabilities of an event at particular time points will be estimated by the 
Kaplan-Meier method. 
Confidence interval for the Kaplan-Meier estimation is calculated using the exponential 
Greenwood formula via log-log transformation of the survival function. 
A stratified log-rank test will be used to compare relugolix+E2/NETA group to placebo group.  
Randomization stratification factors (pivotal study baseline MBL volume (<225 mL vs. 225 mL) 
and duration of exposure to relugolix (28 week vs. 52 weeks)) will be used for the stratified log-
rank test.. 
7.2. 
Multiplicity Adjustment  
The primary and the three key secondary efficacy analyses will be performed at an overall two-
sided type I error of 0.05.  A test will be deemed statistically significant if the two-sided p-value 
rounded to 4 decimal places is < 0.05.  If the result of the primary endpoint analysis meets the 
respective evaluation criterion of the primary endpoint, the key secondary endpoints will then be 
tested with a fixed-sequence testing procedure to maintain the overall familywise error rate of 
0.05 for the testing of primary and key secondary endpoints.  The key secondary endpoints with 
alpha-protection for potential labelling purposes are described in Section 7.4.1.  All p-values (if 
provided) aside from the endpoints listed in the testing order are not adjusted in multiplicity, thus 
are at a nominal level of 0.05. 
7.3. 
Primary Efficacy Endpoint  
The primary efficacy endpoint of the study is the proportion of patients who maintained a 
menstrual blood loss volume of < 80 mL at Week 76 (24 weeks/EOT of the randomized 
treatment period) as measured by the alkaline hematin method.  The primary endpoint will be 
referred to as sustained responder rate at Week 76 and defined as the cumulative probability of 
MBL volume < 80 mL measured while on randomized treatment through Week 76.  For the 
primary analysis, primary endpoint will incorporate the censoring rules described in 
Section 7.3.1.  The primary endpoint of sustained responder rate will be evaluated using the 
mITT Population.   


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7.3.1. 
Primary Efficacy Analysis  
The primary hypothesis for the primary efficacy endpoint to be tested in this study is relugolix+ 
E2/NETA group is superior to placebo group with respect to the sustained responder rate at 
Week 76 based on the MBL volume analyzed by alkaline hematin method: 
Null hypothesis H01:  πR ≤ πP    vs.    Alternative hypothesis Ha1:  πR > πP 
where πR and πP are the sustained responder rates for relugolix and placebo groups, respectively. 
The primary efficacy analysis is the treatment comparison between the relugolix+E2/NETA 
group and the placebo group performed using a stratified version of the Mantel-Haenszel test 
statistic for sustained responder rates at Week 76 stratified by baseline mean menstrual blood 
loss in the pivotal study (< 225 mL vs. ≥ 225 mL), geographic region (North America vs. Other) 
and the duration of relugolix exposure prior to randomization (28 weeks vs. 52 weeks).  In this 
analysis, the sustained responder rate will be calculated as the Kaplan-Meier estimate of the 
cumulative probability of MBL volume < 80 mL through Week 76 (Day 169) using the Kaplan-
Meier method (see Section 7.3.1.1).  
The difference in sustained responder rates between the relugolix+E2/NETA and placebo group 
and its two-sided 95% CI will be provided.   
The study will be considered positive if the treatment effect for the primary endpoint is 
statistically significant with two-sided p-value < 0.05.)  
For each patient, event status (yes/no) and time to first event (MBL volume ≥ 80 mL) or 
censoring (if no event) during the randomized treatment period will be derived and used in 
Kaplan-Meier analysis.   
7.3.1.1. 
Kaplan-Meier Analysis  
The primary endpoint of sustained responder rate at Week 76 will be estimated based on the 
Kaplan-Meier (KM) survival functions of time to 1st relapse (MBL volume ≥80 mL) along with 
95% CI for sustained responder rate for each treatment group.   
The 95% CI for the KM estimation of the sustained responder rate at Week 76 (Day 169) is 
calculated using the exponential Greenwood formula via log-log transformation of the survival 
function.   
The 95% CI for treatment difference in sustained responder rates will be calculated via linear 
transformation of the difference in relapse free survival function with pooled variance, as follows: 
[(𝑆𝑅
̂ (𝑡) −𝑆𝑃
̂(𝑡)) −1.96√𝑉̂[𝑆𝑅
̂(𝑡) −𝑆𝑃
̂(𝑡)], (𝑆𝑅
̂ (𝑡) −𝑆𝑃
̂(𝑡)) + 1.96√𝑉̂[𝑆𝑅
̂(𝑡) −𝑆𝑃
̂(𝑡)] ]. 
Treatment difference in sustained responder rates at Week 76 between relugolix and placebo will 
be estimated along with 95% CI using the method described below.   
Variance of treatment difference will be calculated using the formula: 
                                                𝑉̂[𝑆𝑅
̂(𝑡) −𝑆𝑃
̂(𝑡)] = 𝑉̂[𝑆𝑅
̂(𝑡)] + 𝑉̂[𝑆𝑃
̂(𝑡)]; 


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Where each of the variance of the KM estimate will be calculated using the Greenwood’s formula  
𝑉̂[𝑆̂(𝑡)] = 𝑆̂(𝑡)2 ∑
𝑑𝑖
𝑛𝑖(𝑛𝑖−𝑑𝑖)
𝑡𝑖≤𝑡
  
where 𝑛𝑖 denotes the number of patients at risk at time 𝑡𝑖 and 𝑑𝑖 denotes the number of events 
observed at time 𝑡𝑖.  
P-value for testing treatment difference in sustained responder rates at Week 76 between 
relugolix+E2/NETA and placebo will be derived using an appropriate test statistic, as described 
in the following steps. 
Step A: The stratified test statistics via log-log transformation of the difference in survival curve 
at a fixed time point will be used to derive the -value (Klein et al. 2007).   
𝑥2 =
{∑
[log (−log (𝑆𝑅𝑠
̂ (𝑡))) −log (−log (𝑆𝑃𝑠
̂(𝑡)))]
𝑀
𝑠=1
}
2
∑
{
𝑉(𝑆𝑅𝑠
̂ (𝑡))
[𝑆𝑅𝑠
̂ (𝑡) log (𝑆𝑅𝑠
̂ (𝑡))]
2 +
𝑉(𝑆𝑃𝑠
̂(𝑡))
[𝑆𝑃𝑠
̂(𝑡) log (𝑆𝑃𝑠
̂(𝑡))]
2}
𝑀
𝑠=1
 
Where s is the sth stratum in the total of M strata and t = Week 76 (Day 169) in this case.  Each 
stratified test statistics at a fixed time under two samples follows a chi-square distribution with 
one-degree freedom.  
Step B:  If the stratified test statistics cannot be calculated due to event having not occurred in 
certain stratum, unstratified test will be used instead.   
Step C: If unstratified test is still not estimable, the stratified version of the Mantel-Haenszel test 
using pooled KM estimators in each stratum will be constructed as the following.  This test 
statistics follows a chi-square distribution with one-degree freedom. 
𝜒𝑀𝐻
2
=
{∑
𝑛𝑅𝑠𝑛𝑃𝑠
𝑛𝑅𝑠+ 𝑛𝐿𝑠
(
𝑀
𝑠=1
𝑆𝑅𝑠
̂ (𝑡) −𝑆𝑃𝑠
̂(𝑡))}
2
∑
𝑛𝑅𝑠𝑛𝑃𝑠
𝑀
𝑠=1
𝑉(𝑆𝑝𝑜𝑜𝑙𝑒𝑑𝑠
̂ (𝑡))
 
It is noted that sustained responder rate at Week 104 (Day 365) as a key secondary endpoint will 
be defined as the KM estimates from the same KM curves and will be analyzed using the same 
method as described above. 
7.3.1.2. 
 Censoring Rules   
The censoring rules in the Kaplan-Meier method are described as the following (see Table 8): 
• For patients with relapse (MBL volume ≥ 80 mL) during the randomized treatment 
period, they will be considered as having an event at the time of first relapse.  The time of 
first relapse is the date of the earliest menstrual bleeding days within the first FP 
collection visit window in which the MBL volume is ≥ 80 mL. 
• For patients who did not have relapse during the randomized treatment period and had 
complete FP collection at each scheduled visit during the randomized treatment period, 


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they will be considered as not having an event and will be censored at the last available 
FP collection visit date during the randomized treatment period. 
• For patients who did not have relapse during the randomized treatment period and had 
incomplete or missing FP collection during the randomized treatment period, they will be 
considered as censored using the following censoring rules: 
− If patients did not have FP collection after Week 64 (ie, have up to 3 FP collection 
visits through Week 64), they will be censored at the date of the last available FP 
collection visit if there are no consecutive visits with incomplete or missing FP 
collection; they will be censored at the date of the last available FP collection visit 
prior to the consecutive visits with incomplete or missing FP collections if there 
are two or more consecutive visits with incomplete or missing FP collections. 
− If patients had FP collection after Week 64  
▪ did not have incomplete or missing FP collections at consecutive visits, they 
will be censored at the last available FP collection date during the randomized 
treatment period. 
▪ had two or more consecutive visits with incomplete or missing FP collections, 
they will be censored at the last available FP collection visit date prior to the 
two consecutive visits during the randomized treatment period.  
The time to event or censoring will be summarized by the Kaplan-Meier method.  If the event 
time or censoring time is after the target (Day 365), Day 365 will be used as the event time or 
censoring time. 
A sensitivity analysis will be performed considering different censoring rules (see 
Section 7.3.4.3).  


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Table 8: 
Censoring Rules for Kaplan-Meier Analysis During Randomized Treatment 
Period  
Type of Patients 
Event 
Event 
Timea 
Censored 
Censoring Timea 
Patients who experienced a relapse 
(MBL ≥ 80 mL) 
Yes 
Date of first 
relapse 
No 
N/A 
Patients who did not experience a 
relapse and had complete FP 
collection  
No 
N/A 
Yes 
Date of last available FP collection visit 
Patients who did not have relapse 
and had incomplete or missing FP 
collection 
a. 
Patients did not have FP 
collection after Week 64  
b. Patients had FP collection 
after Week 64  
   i. No incomplete or missing FP 
collection at consecutive 
visits 
  ii. Incomplete or missing FP 
collection at two consecutive 
visits  
  iii. Incomplete or missing FP 
collection at three or more 
consecutive visits  
No 
N/A 
Yes 
a.  Use the date of last available FP 
collection visit if no consecutive visits 
with incomplete or missing FP collection;  
Use the date of last available FP 
collection visit prior to the consecutive 
visits with incomplete or missing FP 
collection. 
b.  See below  
   i. Date of last FP collection visit 
  ii. Date of last available FP collection visit 
prior to the two consecutive visits with 
incomplete or missing FP collection 
  iii. Date of last available FP collection visit 
prior to the three or more consecutive 
visits with incomplete or missing FP 
collection 
Abbreviations:  N/A = not applicable. 
a The reference point for event (or censoring) time is defined as from date of first dose of randomized study drug.  
 
7.3.2. 
Definitions Related to Menstrual Blood Loss for Each Feminine Product 
Collection Interval  
The data sources that will be used to support derivation of responder status for each FP collection 
interval include: 
• Menstrual blood loss volume determined by the alkaline hematin method; 
• Daily patient report of bleeding (yes/no) and use of FP (yes/no) captured in the paper 
patient diary;  
• The status of FP collection return (yes/no) recorded on the eCRF page at each visit with 
specific reasons captured when no product collection was returned.  
The total MBL volume is reported from the analysis of FP returned for each collection interval.  
An inventory of days (with dates) for which FP was collected and returned is also available.  
This inventory is aligned with patients’ reports of bleeding and FP use in the paper patient diary.  
The status of FP collection return, and specifically the reason for non-return of FP reported on 
the Feminine Product Collection eCRF page is used to support derivation of responder status 
(see Section 7.3.3 for details). 


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7.3.2.1. 
Menstrual Blood Loss Volume  
All returned FPs (validated, validated but unauthorized, or unvalidated products) collected at 
each visit will be analyzed by the alkaline hematin method to obtain the MBL volume.  The 
MBL volume measured over each FP collection interval will be used to determine responder 
status at that visit (see details below).  The vendor, KCAS, reports when unauthorized FPs 
(products not dispensed for use in the trial) have been returned.  KCAS also reports whether the 
unauthorized products have previously been validated for their analysis.  The report details MBL 
volumes for authorized, unauthorized but validated, and unauthorized and unvalidated products. 
7.3.2.2. 
Week 52/Baseline Menstrual Blood Loss Volume  
Week 52/Baseline MBL volume is defined as the last available MBL volume which was 
collected on or after the Week 44 in MVT-601-3003 and prior to the date of the first dose of 
randomized withdrawal study drug as assessed by the alkaline hematin method.  If a patient did 
not return any FPs and reported amenorrhea, Week 52/Baseline MBL volume is set to 0 mL.   
Although the responder status used to determine the patient’s eligibility for this study is based on 
Week 48 data (or Week 44 data if Week 48 data were not available at the time when eligibility 
was being assessed) in MVT-601-3003, the Week 52/Baseline MBL volume defined above will 
be used to establish the patient’s baseline for evaluation of menstrual blood loss of this study. 
In addition, baseline MBL volume for the retreatment period is defined as the highest value prior 
to the first dose of the retreatment drug.  This definition will be used for retreatment period 
related summaries.   
7.3.2.3. 
Feminine Product Collection Interval  
The FP collection interval at each visit is driven by types of bleeding patterns experienced by the 
patients, as described below: 
• For patients who continue to have cyclic bleeding, the length of the interval depends on 
the duration of the patient’s natural cycle;  
• Patients who report irregular, non-cyclic bleeding are instructed to collect and return all 
FP used between study visits, up to 35 days, as per the schedule of events; 
• For patients who report amenorrhea on the Feminine Product Collection eCRF page, an 
interval of last 35 days of treatment will be reviewed to ensure that reported amenorrhea 
is not due to incomplete collection.  
For patients who are in the midst of an episode of cyclic bleeding at the time of the FP collection 
visit (or the last visit in the randomized treatment period which is prior to Week 104), the visit 
window may be extended up to 7 days after Week 104 visit (or last visit) to ensure patients return 
all used FPs over that bleeding episode. 
Per protocol, all used FPs are to be collected at each visit and returned for analysis using the 
alkaline hematin method.  For patients who continue to have menstrual bleeding, study visits are 
timed such that the FPs used in the entire menstrual bleeding cycle are collected in one container 
provided at each visit.  


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7.3.2.4. 
Menstrual Blood Loss Volume for Each Feminine Product Collection Interval  
Menstrual blood loss volume for each FP collection interval is defined as the MBL volume 
obtained from the FP returned over the FP collection interval (or the FP collection interval 
between the two consecutive visits during the randomized treatment period which is prior to 
Week 104).  Sum of MBLs from multiple FP collection kegs (if any) within the same FP 
collection interval will be used as the total MBL for that visit.  The total MBL volume over each 
FP collection interval will be used to derive the responder status at that visit.    
If a patient did not return FP over the FP collection interval prior to retreatment and reported 
amenorrhea on the Feminine Product Return eCRF page, she will be considered as amenorrheic 
and her MBL volume will be assigned as 0 mL. 
If a patient did not return FP over the FP collection interval prior to retreatment and reported 
spotting on the Feminine Product Return eCRF page, her MBL volume will be assigned as 
<5 mL. 
7.3.2.5. 
Feminine Product Return Rate by Visit  
To quantify degree of compliance with FP collection during the randomized treatment period, the 
FPRR will be calculated based on the inventory of FP returned by day (dates) provided by the 
vendor, KCAS, the reason why the FP was not collected from the Feminine Product Collection 
eCFR page, and responses to the paper patient diary questions regarding bleeding experience and 
the use of FP obtained for the corresponding diary window (see Table 6).  Specifically: 
• For those who returned FP at a FP collection visit, the FPRR was calculated as the 
observed number of days with returned FPs (based on the inventory of FP received by 
KCAS) divided by the expected number of days with bleeding and use of product as 
reported on the patient’s paper diary within the FP collection interval (as defined above). 
FPRR =
observed ( No. of days with returned FP [per KCAS])
expected  (No. of days reported bleeding and use of FP [per Diary])  × 100 
• For those who did not return any FPs: 
o If the reason was “Amenorrheic” or “Patient only had Spotting that did not 
require the use of Sanitary Products” on the eCRF, their FPRR will be set to 
100% because the lack of menstruation obviates the need for FP collection.  
o If the reason was “Patient failed to collect Used Products per Protocol” on the 
eCRF, their FPRR was set to 0.   
o If the reason was “Retreatment Visit; No Product Collection Required” or 
“Successful Retreatment; No Product Collection Required” on the eCRF, their 
FPRR was set to 0. 
o If the reason is “Other”, their FPRR was set to 0.   
The texts specified for reason “Other” will be reviewed by the medical team to identify those 
which belong to any pre-defined reasons listed in the first three bullets above and the reason will 
thus be treated accordingly. 


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7.3.3. 
 Identifying Responder Status and Incomplete Feminine Product Collection at 
Each Visit   
For each schedule visit, responder (MBL volume < 80 mL) status and incomplete FP collection 
will be identified for each patient by checking compliance with FP collection against the 
patient’s paper diary, as measured by FPRR, and reasons for no FP collection (as displayed in 
Table 9). 
Table 9: 
Identifying Incomplete Feminine Product Collection and Derivation of 
Responder Status at Each Visit During Randomized Treatment Period 
FP 
Collection 
(Yes/No) 
Reason for  
No FP Collection (CRF 
page)  
Observed 
MBL 
Volume  
FPRR 
Incomplete FP 
collection  
Responder 
Status  
Yes 
 
N/A 
< 80 mL 
>80-100% 
Complete  
Yes 
N/A 
≥ 80 mL 
N/A 
N/A 
No 
N/A 
< 80 mL 
<= 80% 
Incomplete,  
Not acceptable 
Missing  
No  
 
Amenorrheic 
Set as 0 mL 
100% 
Complete  
Yes 
Patient only had spotting 
that did not require the use 
of sanitary products  
Set as 
4.99 mL 
100% 
Complete  
Yes 
Patient failed to collect 
used products per protocol  
Missing  
0% 
Incomplete  
Missing  
Retreatment visit; No 
product collection required  
N/A 
N/A 
N/A 
N/A 
Successful retreatment; No 
product collection required 
N/A 
N/A 
N/A 
N/A 
Other  
Missing  
0% 
Incomplete  
Missing  
Abbreviations:  FP = feminine product; FPRR = feminine product return rate; MBL = menstrual blood loss; N/A = 
not available.  
7.3.4. 
Sensitivity Analyses  
To assess the robustness of the primary analysis, the following sensitivity analyses of the 
primary endpoint (sustained responder rate) will be conducted at Week 76. 
7.3.4.1. 
Sensitivity Analysis 1  
To assess the potential impact of the length and full exposure of the treatment, the primary 
endpoint (sustained responder rate) will be analyzed for the Week 76 completers population as a 
sensitivity analysis as appropriate.  The Week 76 completers population is defined as patients in 
the mITT population who completed 24 weeks of treatment.   


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7.3.4.2. 
Sensitivity Analysis 2  
The primary endpoint will be analyzed on the Per-Protocol population as a sensitivity analysis, 
using the methods specified for the primary analysis (see definition of Per-Protocol population in 
Section 4.2.2). 
7.3.4.3. 
Sensitivity Analysis 3  
The primary endpoint will be analyzed on the mITT population as a sensitivity analysis, using 
different censoring rules for some of the patients who did not have relapse during the 
randomized treatment period and had incomplete or missing FP collection during the randomized 
treatment period, which are listed below.  Except the differences in the two situations listed 
below, the censoring rules in Table 8 will be used.  The differences are:    
• If patients did not have FP collection after Week 64 (ie, have <=3 FP collection visits), they 
will be considered as having an event at the date of the first visit with incomplete or missing 
FP collection during the randomized treatment period. 
• If patients had FP collection after Week 64 and had three or more consecutive visits with 
incomplete or missing FP collection, they will be considered as having an event at the date 
of the first visit of the three of more consecutive visits with incomplete or missing FP 
collection during the randomized treatment period.   
7.3.5. 
Subgroup Analyses  
Subgroup analyses of the primary efficacy endpoint of sustained responder rate comparing 
relugolix+E2/NETA and placebo will be performed to determine whether treatment effect is 
consistent across clinically meaningful subgroups.  The differences in sustained responder rate 
and corresponding 95% CIs (calculated via linear transformation of the difference in relapse free 
survival function with pooled variance) will be displayed in a forest plot.  Subgroups will include 
but not be limited to the following: baseline MBL volume in the pivotal study (< 225 mL vs. ≥ 
225 mL), geographic region (North America vs. Other), duration of exposure to relugolix prior to 
randomization (28 weeks vs. 52 weeks) as well as other baseline subgroups such as age, and 
race.  Details are provided in Table 10. 


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Table 10: 
Planned Subgroup Analyses  
Subgroup Name  
Subgroup Level 
Geographic region  
North America vs. Other 
Menstrual blood loss volume at Pivotal 
Baseline (mL) 
< 225 vs. ≥ 225 
< 120, 120 to < 160, 160 to < 225, ≥ 225 
Duration of exposure to relugolix prior to 
randomization (weeks) 
28 vs. 52  
Age category (years) at Pivotal Baseline 
< 40 vs. ≥ 40 
Race 
Black or African American vs. Other ; 
Black or African American, White, Other 
Volume of myoma at Pivotal Baseline (cm3) 
< 25 vs. ≥ 25 
Volume of uterus at Pivotal Baseline (cm3) 
< 300 vs. ≥ 300 
BMI (kg/m2) at Pivotal Baseline 
< 30 vs. ≥ 30 
< 25, 25 to < 30, 30 to < 35, 35 to <40, ≥ 40 
Maximum NRS score for uterine fibroid–
associated pain at Pivotal Baseline 
< 4 vs. ≥ 4 
Abbreviations:  BMI = body mass index; NRS = Numerical Rating Scale. 
7.4. 
Secondary Efficacy Endpoints  
Comparative statistics (p values, 95% CIs for differences) will be provided for treatment 
comparison of the relugolix group with the placebo group for secondary efficacy endpoints 
during randomized treatment period.   
7.4.1. 
Key Secondary Endpoints  
For testing whether relugolix+E2/NETA is statistically significantly superior to placebo for the 
primary efficacy endpoint as well as the three key secondary endpoints listed below, a fixed 
sequence testing procedure will be applied to maintain the family wise type I error rate.  Under 
this testing procedure, the primary endpoint will be tested first at a 2-sided 0.05 significance 
level.  If the p value for primary endpoint is < 0.05, the three key endpoints will be tested 
sequentially in the order depicted in Figure 1. 


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Figure 1: 
Fixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints  
 
Abbreviations:  EOT = end of treatment; MBL = menstrual blood loss. 
 
7.4.1.1. 
Time to Relapse (Menstrual Blood Loss Volume ≥ 80 mL)  
For the endpoint of time to MBL volume ≥ 80 mL (event) during the randomized treatment 
period, time-to-event will be defined as weeks from first dose of the randomized withdrawal 
study drug to first occurrence of MBL volume of ≥ 80 mL.  The corresponding menstruation 
start date will be considered as the event date.  Patients without an event will be censored by 
following the same censoring rules described in Section 7.3.1.2.  Kaplan-Meier methods will be 
used to describe the time to event (relapse) distributions for each study treatment group from 
which median time to event will be derived.  Hazard ratio (95%CI) of relugolix + E2/NETA to 
placebo for risk of relapse (MBL volume ≥ 80mL) will be provided using a proportional hazard 
model stratified by the stratification factors (pivotal study baseline MBL volume (< 225 ml vs. 
≥ 225 mL) and duration of exposure to relugolix (28 weeks vs. 52 weeks).  p-value for 
comparison of relugolix + E2/NETA to placebo based on the stratified log-rank test will be 
provided.   
7.4.1.2. 
Proportion of Patients Who Maintained a Menstrual Blood Loss Volume of 
< 80 mL at Week 104  
The proportion of patients who maintained a menstrual blood loss volume of < 80 mL by Week 
104 (52 weeks of the randomized treatment period) as measured by the alkaline hematin method 
will be analyzed using the same method as that for primary efficacy endpoint described in 
Section 7.3.  It is noted that sustained responder rate at Week 104 (Day 365) will be defined as 
the KM estimates from the same KM curves and will be analyzed using the same method as for 
the primary endpoint (see Section 7.3.1). 
No subgroup analysis will be performed for this secondary efficacy endpoint.   
The proportion of patients who maintained a menstrual blood loss volume of < 80 mL will also 
be summarized during the cumulative treatment period (including both randomized treatment 
period and the retreatment period).  


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The proportion of patients who had a menstrual blood loss volume of < 80 mL at a visit will also 
be summarized descriptively by visit during the cumulative treatment period (including both 
randomized treatment period and the retreatment period).  
7.4.1.3. 
Proportion of Patients Achieving or Maintaining Amenorrhea  
7.4.1.3.1. Determination of Amenorrhea  
Rules for determining amenorrhea in the randomized treatment period is defined as those who 
meet one of the following requirements for two consecutive visits (approximately 56 consecutive 
days).  Patients will be deemed to be amenorrheic during a particular visit window according to 
the following rules (see Table 11): 
• No FP returned due to reported amenorrhea;  
OR 
• No FP returned due to reported spotting or FP collection with a negligible observed MBL 
volume coupled with other data indicating infrequent non-cyclic bleeding/spotting as 
described in Table 11. 
 
If no FP collection because patient failed to collect used products per protocol or due to “Other” 
reason, the amenorrhea status will be missing.  If no FP collection due to retreatment visit or 
successful retreatment, the amenorrhea status is not applicable. 
Missing responses for menstrual bleeding questions in the paper diary will be treated as “No 
Bleeding” if paper diary compliance rate is > 70%.   


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Table 11: 
Rules for Determining Reported Amenorrhea by Visit  
Feminine Product Collection a 
Patient’s Paper Diary 
Amenorrhea 
Status 
No feminine product collection 
due to reported amenorrhea 
N/A, since paper diary entry is not required per 
protocol. 
Yes 
No feminine product collection 
due to reported spotting or 
feminine product collection with 
negligible observed MBL 
volume defined as <5 mL 
• Data indicating infrequent, non-cyclic 
bleeding/spotting defined as bleeding/spotting 
with feminine product use for no more than 3 
consecutive days and no more than 5 days 
bleeding total per visit window 
• Diary entry rate > 70% 
Yes 
Abbreviations:  MBL = menstrual blood loss; N/A = not applicable. 
a  There is no requirement for feminine product return rate, as the determination of amenorrhea is based on the 
Feminine Product Collection eCRF page and the diary response. 
 
7.4.1.3.2. Amenorrhea During the Randomized Treatment Period  
Patients achieving or maintaining amenorrhea during the randomized treatment period at 
Week 76/EOT (or at Week 104/EOT) are defined as those who meet the definition of 
amenorrhea at last two consecutive post-baseline visits prior to date of last dose of study drug 
during the randomized treatment period through Week 76 (or through Week 104) visit. 
A key secondary endpoint is the proportion of patients who achieved or maintained amenorrhea  
at Week 76/EOT during the randomized treatment period. 
Patients missing amenorrhea reporting for all visits in the study will not be considered as 
amenorrheic by Week 76 or Week 104.   
Proportion of patients achieving or maintaining amenorrhea at Week 76/EOT and at Week 
104/EOT will be summarized by treatment and treatment comparisons will be performed using a 
stratified Cochran-Mantel-Haenszel test. 
7.4.2. 
Other Secondary Endpoints  
7.4.2.1. 
Proportion of Patients Who Responded to Retreatment During the Retreatment 
Period  
Proportion of patients who responded (MBL volume of < 80 mL) to retreatment with open-label 
relugolix 40 mg +E2/NETA during the retreatment period among placebo patients whose MBL 
volume had returned to ≥ 80 mL during the randomized treatment period will be summarized 
descriptively.  The point estimate and its corresponding 95% CIs will be provided.  
The change and percent change in MBL volume from retreatment initiation will also be 
summarized descriptively as a continuous variable every 4 weeks after retreatment initiation 
during the retreatment period.   


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7.4.2.2. 
Change and Percent Change from Week 52/Baseline in Menstrual Blood Loss 
Volume During the Randomized Treatment Period  
The change (for all patients) and percent change (for patients who did not have amenorrhea at 
baseline) in MBL volume from Week 52/baseline will be summarized descriptively as a 
continuous variable at each visit during the randomized treatment period including Week 76 and 
Week 104 visits.  Observed MBL volume for each timepoint will be used to calculate change and 
percent change from Week 52/Baseline.  In addition, the change and percent change in MBL 
volume from Week 52/baseline will also be summarized descriptively as a continuous variable at 
each visit during the cumulative treatment period.   
For change and percent change in MBL volume, mixed-effects model will not be used to derive 
LS means (and 95% CIs) due to skewed distribution of MBL volumes (majority of patients 
experiencing amenorrhea with MBL volume set as 0 mL at baseline).  Descriptive statistics 
(medians and simple means) will be provided for each treatment group.  
Categorical summary of change in MBL volume will be provided by grouping patients into three 
categories: who had increase, no change, and decrease in MBL volume from Week52/Baseline 
over time by visit for cumulative treatment period.  A figure will also be provided to display the 
percentages for each category by treatment group every 12 weeks from Week 52/Baseline up to 
Week 104.    
Besides, the observed MBL values will be categorized into three categories: 0 mL, > 0 to 
< 80 mL, and ≥ 80 mL.  Shift tables will be provided to summarize Week 52/Baseline versus 
each post-baseline visit for the randomized treatment period and cumulative treatment period.  
Figures will also be provided to display the percentages for each category by treatment group at 
Week 52/Baseline, Week 76, and Week 104.    
7.4.2.3. 
Proportion of Patients Whose Menses Has Resumed  
This endpoint is defined only for patients who were amenorrheic (ie, had MBL volume of 0 mL 
at baseline).  
7.4.2.3.1. Determination of Resumption of Menses  
Patients who were previously amenorrheic will be deemed to resume the menses during a visit 
window according to the following rules: 
• FPs were collected and MBL volume was ≥ 5 mL; 
OR 
• FPs were collected and MBL volume was < 5 mL; however, there were more than 5 days 
and more than 3 consecutive days of bleeding with FP use during the visit window per 
the diary; 
OR  
• No FPs were returned because patient failed to collect used products per protocol; 
however, there were more than 5 days and more than 3 consecutive days of bleeding with 
FP use during the visit window per the diary; 
OR  


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• No FPs were returned due to other reasons that indicate menstruation occurred; also, 
there were more than 5 days and more than 3 consecutive days of bleeding with FP use 
during the visit window per the diary.    
 
These were also described in Table 12.  
Table 12 
Rules for Determining Resumption of Menses by Visit 
Feminine Product 
Collection 
Patient’s Paper Diary 
Resumption 
of Menses? 
Date of Resumption of 
Menses 
Feminine products were 
collected with observed 
MBL volume ≥ 5 mL 
N/A 
Yes 
Earliest menstruation date 
recorded in KCASa data for 
the corresponding feminine 
product collection  
Feminine products were 
collected with observed 
MBL volume < 5 mL 
> 5 days and > 3 
consecutive days of 
bleeding with feminine 
product use reported in 
paper diary 
Yes 
Earliest menstruation date 
recorded in KCASa data for 
the corresponding feminine 
product collection  
Feminine product collection 
not performed per protocol 
or no feminine product 
collection performed due to 
other reasons which indicate 
menstruation occurred. 
> 5 days and > 3 
consecutive days of 
bleeding with feminine 
product use reported in 
paper diary 
Yes 
Paper diary date of first 
episode of > 3 consecutive 
days of bleeding with 
feminine product use in 
timeframe corresponding to 
missed collection.  
a This date has been reconciled against the Menstruation Status data in EDC and is more reliable if irregular bleeding has been 
reported.  
Abbreviations:  MBL = menstrual blood loss; N/A = not applicable. 
7.4.2.3.2. Resumption of Menses During the Randomized Treatment Period  
Proportion of patients whose menses has resumed during the randomized treatment period 
among those who were amenorrheic at Week 52/Baseline will be summarized by treatment at 
Week 76 and at Week 104.  The point estimate and its corresponding 95% CIs will be provided 
based on the Kaplan-Meier method as described below in Section 7.4.2.4. 
7.4.2.4. 
Time to Resumption of Menses  
For time to resumption of menses among those who were amenorrheic at Week 52/Baseline, 
time-to-event will be defined as weeks from first dose of the Randomized Withdrawal study drug 
to first occurrence of the menses resumption during the randomized treatment period. Patients 
without an event will be censored at last assessment date prior to the last dose of randomized 
withdrawal study drug before Week 104.  
Kaplan-Meier methods will be used to describe the time to event distributions by Week 76 and 
by Week 104 for each study treatment arm.  Difference (95% CI) in the rate of menses 
resumption between the two treatment groups will be calculated at Week 76 and Week 104 based 
on the KM estimates. P-value from the unstratified log-rank test for treatment comparison in the 
KM rates at Week 76 and Week 104 will be provided.  See Section 7.1.3 for more details.   


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7.4.2.5. 
Proportion of Patients with Menstrual Blood Volume ≥ 80 mL at Any Timepoint 
During the 52-week Randomized Treatment Period  
Proportion of patients with menstrual blood volume ≥ 80 mL at any timepoint during the 
randomized treatment period will be summarized by visit based on the Kaplan-Meier estimates.  
The treatment differences (95% CI) in the proportions at Week 76 and at Week 104 will be 
provided using the analysis method described above in Section 7.4.1.1. 
7.4.2.6. 
Change and Percent Change from Week 52/Baseline in Hemoglobin  
The change and percent change from Week 52/Baseline in hemoglobin during the randomized 
treatment period will be summarized at each scheduled visit as described in Section 7.1.2.    
The change and percent change from Week 52/Baseline in hemoglobin during the cumulative 
treatment period will be summarized descriptively by visit.   
7.4.2.7. 
Proportion of Patients with Anemia or Below Lower Limit of Normal  
The proportion of patients with anemia (hemoglobin values ≤ 10.5 g/dL) during the randomized 
treatment period will be summarized by visit.  Similarly, the proportion of patients with 
hemoglobin values below the lower limit of normal (ie, < 11.6 g/dL) during the randomized 
treatment period will also be summarized by visit. 
The proportion of patients with hemoglobin ≤ 10.5 g/dL and with hemoglobin < 11.6 g/dL will 
also be summarized by visit for the cumulative treatment period. 
7.4.2.8. 
Change from Week 52/Baseline in SF-36v2 Scores  
Change from Week 52/Baseline in SF-36v2 scores of eight scales and two summary components 
during the randomized treatment period will be summarized using descriptive statistics.   The 
scores after the time of retreatment initiation with open-label relugolix + E2/NETA will not be 
included in the analysis for randomized treatment period.     
Change from Week 52/Baseline in SF-36v2 scores of eight scales and two summary components 
during the cumulative treatment period will be summarized by visit.   
Calculation of SF-36v2 Scale Scores  
The eight SF-36v2 scales, including Physical Functioning, Role-Physical, Bodily Pain, General 
Health, Vitality, Social Functioning, Role-Emotional, Mental Health, and Reported Health 
Transition will be calculated using the PRO CoRE™ Scoring Software provided by 
QualityMetric Incorporated, LLC.  The physical component summary (PCS) and mental 
component summary (MCS) scores will also be calculated using this software.   
PRO CoRE™ is a validated tool that an organization can use to score health-related quality of 
life data and feel confident that the data was scored correctly.  The eight SF-36v2 scales are 
normalized using mean scores and their SDs from the 2009 general US population, and then they 
are aggregated using weights from the 2009 general US population to obtain PCS and MCS.  
Finally, the normalized scores of the eight scales and two component summaries provided by the 
software will be used for analysis.  Higher scores indicate higher health related quality of life. 


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7.4.2.9. 
Change from Week 52/Baseline in PGA Score  
Change from Week52/Baseline in PGA for functions and symptoms during the randomized 
treatment period will be summarized using descriptive statistics.  The scores after the time of 
retreatment initiation with open-label relugolix + E2/NETA will not be included in the analysis 
for randomized treatment period.   
Categorical change from Week 52/Baseline at each visit will also be summarized for randomized 
treatment period and cumulative treatment period separately.  The PGA for function and 
symptoms will be evaluated using a 5-point response scale (eg, absent, mild, moderate, severe, 
and very severe).  To calculate change from Week 52/Baseline to Week 76 or Week 104, the 
numerical scores shown in Table 13 will be assigned to each response level. 
Table 13: 
Patient Global Assessment Numerical Scores 
Response Scale (Function) 
Response Scale (Symptoms) 
Numerical Score 
No limitation at all 
Not severe 
1 
Mild limitation 
Mildly severe 
2 
Moderate limitation 
Moderately severe  
3 
Quite a bit of limitation 
Very severe 
4 
Extreme limitation 
Extremely severe 
5 
 
For each item, the count and proportion of improvement by level or at least one level will be 
tabulated by treatment group and by visit.  The denominator for the proportion will be based on 
the number of patients who provided non-missing responses to the items. 
The change from Week 52/Baseline in PGA scores during the cumulative treatment period will 
be summarized descriptively by visit.   
7.4.2.10. Change from Week 52/Baseline in the WPAI-UF Scores  
Change from Week 52/Baseline in WPAI-UF scores during the randomized treatment period will 
be summarized using descriptive statistics. The scores after the time of retreatment initiation with 
open-label relugolix + E2/NETA will not be included in the analysis for randomized treatment 
period.   
Change from Week 52/Baseline in WPAI-UF scores during the cumulative treatment period will 
be summarized by visit.   
Calculation of WPAI-UF Scores  
WPAI-UF outcomes are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, ie, worse outcomes.  There are six questions in this 
questionnaire: 
1 = currently employed 
2 = hours missed due to uterine fibroid symptoms 


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3 = hours missed other reasons 
4 = hours actually worked 
5 = degree uterine fibroid symptoms affected productivity while working in past 7 days 
6 = degree uterine fibroid symptoms affected regular activities in past 7 days 
If a patient is not employed (ie, answered no to the first question), only question 6 needs to be 
answered.  
Four WPAI-UF scores will be calculated using the following algorithms (Reilly et al. 1993; 
Reilly Associates Health Outcomes Research website [http://www.reillyassociates.net]) and 
analyzed.  Multiply the scores by 100% to express them in percentages.  Higher percentages 
indicate that impairment due to Uterine Fibroids is worse.   
• Percent work time missed due to uterine fibroid symptoms: Q2 (Q2 + Q4)
⁄
× 100% 
• Percent impairment while working due to uterine fibroid symptoms: Q5 10
⁄
× 100% 
• Percent overall work impairment due to uterine fibroid symptoms:  
{Q2 (Q2 + Q4)
⁄
+ [1 −Q2 (Q2 + Q4)
⁄
] × (Q5 10
⁄
)} × 100% 
• Percent activity impairment due to uterine fibroid symptoms: Q6 10
⁄
× 100% 
 
7.4.2.11. Change from Week 52/Baseline in the UFS-QoL Score  
Change from Week 52/Baseline in the UFS-QoL Bleeding and Pelvic Discomfort (BPD) Scale 
score, UFS-QoL Symptom Severity Scale score, UFS-QoL Revised Activities Scale, UFS-QoL 
subscale scores, and total scores during the randomized treatment period will be summarized 
using descriptive statistics by treatment group and by visit.  The scores after the time of 
retreatment initiation with open-label relugolix + E2/NETA will not be included in the analysis 
for randomized treatment period.   
The change from Week 52/Baseline in UFS-QoL scores during the cumulative treatment period 
will be summarized by visit.  
In addition, the proportion of responders as measured by the BPD Scale score and Revised 
Activities Scale will be summarized, as described below. This analysis will be performed for 
randomized treatment period and cumulative treatment period separately. 
Calculation of UFS-QoL Symptom Severity Scale Score  
To calculate the Symptom Severity Scale score, a summed score is created for the items listed 
below and then the formula below the table is used to transform raw scores to a normalized score 
with a range of possible values from 0 to 100.  This provides Symptom Severity Scale scores, 
where higher scores are indicative of greater symptom severity and lower scores indicate lower 
symptom severity. 
 


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Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Symptom Severity 
Sum 1 – 8 
8, 40 
32 
 
Formula for Transformation of Symptom Severity Raw Scores: 
Transformed Scale = [(Actual raw score –  lowest possible raw score)
Possible raw score range
] × 100  
Calculation of UFS-QoL Bleeding and Pelvic Discomfort Scale Score  
The UFS-QoL BPD Scale has been derived from the UFS-QoL Symptoms Scale; the derivation 
and validation of this new scale can be found in the MVT-601-3001/3002 SAP.  The new scale 
consists of the following three symptoms proximal to uterine fibroids: 
• Heavy bleeding during your menstrual period (Q1) 
• Passing blood clots during your menstrual period (Q2) 
• Feeling tightness or pressure in your pelvic area (Q5) 
To calculate the score for the BPD Scale, a summed score of the items listed below is created 
and then the formula below the table is used to transform the raw score to a normalized score.  
This provides BPD Scale scores, where higher score values are indicative of greater symptom 
severity and lower scores will indicate minimal symptom severity (high scores = bad). 
 
Sub-Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Q1, Q2 and Q5 
Sum 1,2,5 
3, 15 
12 
Formula for Transformation of BPD Raw Scores:  
Transformed Scale = [(Actual raw score –  lowest possible raw score)
Possible raw score range
] × 100  
 
On the basis of transformed score for BPD Scale, change from Week 52/Baseline in the 
transformed score for BPD Scale at Week 76 and Week 104 will be defined as a secondary 
endpoint.  The proportion of patients who are responders (defined as meeting a meaningful 
change threshold from Week 52/Baseline in the BPD Scale) at Week 76 and Week 104 on the 
transformed score for the BPD Scale will be summarized for each treatment group.  The 
proposed responder threshold is a 20-point change.  Details in the determination of the 
meaningful change in the BPD Scale can be found in the MVT-601-3001/3002 SAP Appendix 4.   
As a descriptive assessment on robustness of the responder analysis, a plot of the cumulative 
distribution function (CDF) will be provided for each treatment group to display the change from 


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Week 52/Baseline to Week 76 and Week 104 in the transformed score for BPD Scale on the x-
axis and cumulative percentage of patients experiencing up to that change on the y-axis.  
Calculation of Other UFS-QoL Scale Scores and UFS-QoL Total Score  
For the other UFS-QoL scales (concern, activities, revised activities, energy/mood, control, self-
conscious, and sexual function), a summed score of the items listed below is created for each 
individual scale.  To calculate the UFS-QoL total score, the values for each individual scale are 
summed.  See Table 14 for details.  Using the formula below the table, all raw scores are 
transformed to normalized scores.  Higher scores are indicative of better health-related quality of 
life (high = good).  
For endpoints evaluating a single question, the raw score is used in the analysis.  The activity and 
revised activity domain scores will be summarized by treatment group. 
Table 14: 
Formulas for Scoring and Transforming UFS-QoL Scale Scores and UFS-
QoL Total Score  
Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Concern 
9+15+22+28+32 
5, 25 
20 
Activities 
10+11+13+19+20+27+29 
7, 35 
28 
Revised activities 
11+13+19+20+27 
5,25 
20 
Energy/mood 
12+17+23+24+25+31+35 
7, 35 
28 
Control 
14+16+26+30+34 
5, 25 
20 
Self-conscious 
18+21+33 
3, 15 
12 
Sexual function 
36+37 
2, 10 
8 
HRQL TOTAL 
Sum of 6 Subscale 
Scoresa  
29, 145 
116 
Abbreviations:  HRQL = health-related quality of life; UFS-QoL = Uterine Fibroid Symptom and Health-Related 
Quality of Life (Questionnaire). 
a HRQL Total includes following scales: concern, activities, energy/mood, control, self-conscious, and sexual 
function. 
Formula for Transformation of Raw Scores of Other Scale Scores:  
Transformed Scale = [(Highest possible raw score − Actual raw score)
Possible raw score range
] × 100  
For revised activities, the proportion of patients who are responders (defined as meeting a 
meaningful change from Week 52/Baseline in the revised activity score) at Week 76 and 
Week 104 will be analyzed similarly to that for the change in BPD Scale score for each treatment 
group.  The proposed responder threshold is a 20-point increase.  Details of the determination of 
the meaningful change in the Revised Activities Scale score can be found in the MVT-601-
3001/3002 SAP Appendix 5.   


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Missing Item Handling in UFS-QoL Score Calculation  
For any scale analyses, if < 50% of the scale items are missing, the scale should be retained using 
the mean scale score of the items present.  If ≥ 50% of the items are missing, no scale score 
should be calculated; the subscale score will be considered missing.   


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8. 
PHARMACODYNAMIC ANALYSES  
Pharmacodynamic data for the randomized withdrawal study consists of pre-dose estradiol serum 
concentration at Week 52/Baseline and Week 56 only.  Estradiol concentration data will be listed 
and summarized using descriptive statistics (including absolute and change from Week 
52/Baseline) by randomized withdrawal study treatment group at baseline and Week 56.  The 
number and percentage of patients with individual estradiol concentration values will be 
summarized by treatment group at baseline and Week 56 according to the following categories.   
• < 10 pg/mL, 10 to < 20 pg/mL, 20 to < 30 pg/mL, 30 to < 40 pg/mL, 40 to < 50 pg/mL, 
50 to < 60 pg/mL, 60 to < 70 pg/mL, and ≥ 70 pg/mL 
• < 20 pg/mL, 20 to < 50 pg/mL, and ≥ 50 pg/mL 
• < 20 pg/mL, 20 to < 60 pg/mL, and ≥ 60 pg/mL 
Estradiol concentration values below the limit of quantification will be set to half of the lower 
limit of quantification.   
Follicle-stimulating hormone concentrations were collected at Week 76 in patients who have 
been amenorrheic since randomization and the concentration data will be listed and summarized 
using descriptive statistics. 


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9. 
SAFETY ANALYSES  
Unless otherwise specified, safety analyses will be conducted using the safety population 
according to the actual treatment received by the patients in this randomized withdrawal study.   
9.1. 
Adverse Events  
Adverse events will be collected from the time of the first dose of randomized withdrawal study 
drug through the safety follow up visit approximately 30 days after the last dose of randomized 
withdrawal study drug (if no retreatment was initiated) or approximately 30 days after the last 
dose of retreatment drug (if the retreatment was initiated), or the date of initiation of another 
investigational agent or hormonal therapy (eg, elagolix, acotol) or surgical intervention (eg, 
uterine artery embolization), whichever occurs first.  Serious adverse events reported to the 
investigator after the safety reporting period should be reported to the sponsor if the investigator 
assesses the event as related to study drug.  
The severity of all treatment-emergent adverse events will be evaluated by the investigator based 
on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), 
v.5.0 dated 27 Nov 2017, and will be coded to preferred term and system organ class using 
MedDRA 24.0 or higher. 
A treatment-emergent adverse event for cumulative treatment period (including the randomized 
treatment and the retreatment periods) is defined as any adverse event that onsets or worsens 
after administration of the first dose of randomized withdrawal study drug.  
For patients who stayed on the randomized treatment till end of the study, a treatment-emergent 
adverse event for the randomized treatment period is defined as any adverse event that onsets or 
worsens after administration of the first dose of randomized withdrawal study drug.  For patients 
who had the retreatment drug initiated, any adverse event that onsets or worsens after 
administration of the first dose of randomized withdrawal study drug and prior to the initiation of 
the retreatment drug is defined as treatment-emergent adverse event for the randomized 
treatment period.   
For patients who started the retreatment drug, a treatment-emergent adverse event for the 
retreatment period is defined as any adverse event that onsets after the initiation of retreatment 
drug.   
Adverse event summaries will be based on treatment-emergent adverse events in the randomized 
withdrawal study, unless otherwise specified.  The summaries will mainly be done for the 
cumulative treatment period.  Some selected summaries may be provided for the randomized 
withdraw period and the retreatment period separately.  All adverse events will be listed in by-
patient listings.   
The following tabular summaries that include the number and percentage of patients will be 
provided for the cumulative treatment period: 
• Overview of adverse events; 
• All adverse events; 
− By SOC and PT; 


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− By decreasing frequency of PT; 
− By SOC, PT, and maximum severity; 
− Drug-related per investigator by SOC and PT; 
− By time to onset, SOC and PT; 
• Grade 3 or higher adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− Drug-related per investigator by SOC and PT; 
• Adverse events leading to study drug withdrawal; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events leading to dose interruption; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events resulting in fatal outcome; 
− By decreasing frequency of PT; 
• Serious adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− By SOC, PT, and maximum severity; 
− By SOC, PT, and relationship to study drug; 
• Adverse events of special interest or clinical interest (ALT or AST ≥ 3 × ULN); 
− By SOC, PT, and maximum severity; 
− By decreasing frequency of PT. 
• Adverse events with first onset during the randomized withdrawal study; 
− By SOC and PT; 
− By decreasing frequency of PT. 
Additionally, adverse event categories defined in Table 15 will be summarized by decreasing 
frequency of PT for the cumulative treatment period. 
The following tabular summaries that include the number and percentage of patients will be 
provided for the retreatment period: 
• Overview of adverse events; 


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• All adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− By time to onset, SOC and PT; 
• Grade 3 or higher adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events leading to study drug withdrawal; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Serious adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events of special clinical interest (ALT or AST ≥ 3 × ULN); 
− By decreasing frequency of PT. 
The adverse events which were ongoing at the time of randomization of the randomized 
withdrawal study will be summarized as specified below.  Such adverse events were collected 
during the pivotal study and LTE study and they are considered pre-existing conditions for the 
randomized withdrawal study.   
• All adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Grade 3 or higher adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
9.1.1. 
Relationship to Study Drug  
Adverse events will be classified as “related” to study treatment if the relationship was rated by 
the investigator as possibly related or probably related.  Adverse events related to any study drug 
component (relugolix or placebo and E2/NETA or placebo) will be considered as related to study 
drug.   
9.1.2. 
Severity of Adverse Event  
Grade 3 or higher adverse events will be summarized by SOC, PT, and/or maximum severity, 
relationship to study treatment.   


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9.1.3. 
Serious Adverse Event  
Serious adverse events will be summarized by SOC, PT, and/or maximum severity, relationship 
to study treatment. 
The data handling conventions for and the definition of a serious adverse event are discussed in 
this section.  All deaths during the study, including the post treatment follow-up period, and 
deaths that resulted from a process that began during the study, should be included in the 
analysis.  For more details, deaths occurring during the following time periods or under the 
following conditions should be considered:  
• Deaths occurring during participation in this randomized withdrawal study;  
• Deaths occurring after a patient leaves the study, or otherwise discontinues study 
drug, whether or not the patient completes the study to the nominal endpoint, if the 
death:  
− Is the result of a process initiated during the study or other drug exposure, 
regardless of when it actually occurs; or  
− Occurs within a time period that might reflect drug toxicity for a patient leaving a 
study or otherwise discontinuing drug.   
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug  
Adverse events leading to withdrawal of study drug are those adverse events collected from the 
adverse event eCRF pages with “drug withdrawn” as the action taken with study drug.   
Adverse events with “drug withdrawn” as action taken due to any one of the components of 
study drug will be considered as leading to withdrawal of study drug.   
9.1.5. 
Adverse Events Leading to Dose Interruption  
Adverse events leading to dose interruption are those adverse events collected from the adverse 
event eCRF pages with “drug interrupted” as their action taken with study drug.   
Adverse events with “drug interrupted” as action taken due to any one of the components of 
study drug will be considered as leading to dose interruption. 
9.1.6. 
Adverse Events Resulting to Fatal Outcome  
Adverse events resulting in a fatal outcome are those adverse events collected from the adverse 
event eCRF pages with “fatal” as their outcome.   
The fatal events, if any, will be provided in a by-subject listing. 
9.1.7. 
Other Safety Parameters of Interest  
In addition, other safety parameters of interest defined in Table 15 summarized by decreasing 
frequency of PT under each safety population.   


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Table 15: 
Other Safety Parameters of Interest  
Category 
Search Criteria 
Bone health related events  Osteoporosis/Osteopenia SMQ (broad) 
Fracture (custom SMQ):  All preferred terms including the term “fracture,” 
excluding “Tooth fracture” and “Fracture of penis” 
Hepatic transaminase 
elevations 
Drug-related hepatic disorders – comprehensive SMQ (narrow) 
Carbohydrate and lipid 
metabolic effects  
Dyslipidemia SMQ  
Hyperglycemia/new onset diabetes mellitus SMQ (narrow) 
Vasomotor symptoms 
The following five Preferred Terms will be included:  
• 
Hyperhidrosis;  
• 
Feeling hot; 
• 
Hot flush;  
• 
Night sweats; 
• 
Flushing. 
Mood disorders  
MedDRA Depression and Suicide/Self-Injury SMQ (broad)  
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA Query.   
9.1.8. 
Adverse Events of Clinical Interest  
Adverse Events of clinical interest in the randomized withdraw study are defined as any increase 
in ALT or AST ≥ 3 × ULN, which are reported as “Yes” for adverse events of clinical interest in 
the adverse event CRF. Adverse events of clinical interest will be summarized. 
9.2. 
Laboratory Data  
Laboratory parameters, including chemistry and hematology panels, specified as per protocol for 
the randomized withdrawal study, and collected from the central laboratory will be tabulated and 
presented in by-patient listings.  Local laboratory parameters will not be used for summary.  
Urinalysis and hepatitis virus serological test results will be provided in by-patient listing only.   
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 if she has laboratory values meeting each criterion.  Shift tables 
will be provided for each parameter, which is gradable by the CTCAE, to summarize 
Week 52/Baseline toxicity grade versus worst post-Baseline toxicity grade during this 
randomized withdrawal study.  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 Week 52/Baseline versus worst post-Baseline results during this 
randomized withdrawal study.  A shift table for selected parameters based on predefined 


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categories (refer to Appendix 1) will be provided to summarize Week 52/Baseline category 
versus post-baseline category in the randomized withdrawal study. The parameters include 
glucose, fasting glucose, HbA1c, low density cholesterol, and high-density cholesterol. 
Boxplots of laboratory values over time in the randomized withdrawal study, will be plotted for 
key laboratory parameters.  These laboratory parameters include, but are not limited to, 
hematology (hemoglobin, platelets, leukocytes, neutrophils), creatinine, glomerular filtration 
rate, and hepatic function panel (alanine aminotransferase [ALT], aspartate aminotransferase 
[AST], alkaline phosphatase [ALP], and total bilirubin). 
The change from Week 52/Baseline to each post-Baseline study visit will be presented by 
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 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 16. 
Table 16:  
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 ALT or AST ≥ 3  ULN + total bilirubin > 2  ULN  
ALT or AST, total bilirubin, 
and ALP 
ALT or AST ≥ 3 x ULN + total bilirubin > 2  ULN + ALP < 2  ULN 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
ULN = upper limit of normal. 
 
The number and percentage of patients with concurrent (defined as measurements on the same 
day) ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN will also be presented. 
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) by treatment group. 
9.3. 
Other Safety Analyses  
9.3.1. 
Electrocardiograms  
ECG was collected at unscheduled visit only besides at Week 52 (which was collected as part of 
the LTE study).  Overall ECG assessments will be listed. 


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9.3.2. 
Vital Signs and Body Weight  
Blood pressure (systolic and diastolic), heart rate, weight, and BMI will be summarized at 
Week 52/Baseline and each subsequent scheduled assessment by treatment group.  Change from 
Week 52/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. 
Potentially clinically significant abnormalities in vital signs are defined in Table 17, 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 17: 
Categories of Potentially Clinically Significant Abnormalities in Vital Signs  
Parameter 
Category 
Systolic blood pressure 
≥ 140 mmHg and greater than Week 52/Baseline 
≥ 180 mmHg and greater than Week 52/Baseline 
≤ 90 mmHg and less than Week 52/Baseline 
Increase of ≥ 20 mmHg from Week 52/Baseline 
Decrease of ≥ 20 mmHg from Week 52/Baseline 
Diastolic blood pressure  
≥ 90 mmHg and greater than Week 52/Baseline 
≥ 105 mmHg and greater than Week 52/Baseline 
≤ 50 mmHg and less than Week 52/Baseline 
Increase of ≥ 15 mmHg from Week 52/Baseline 
Decrease of ≥ 15 mmHg from Week 52/Baseline 
Heart rate 
≥ 120 bpm and greater than Week 52/Baseline 
< 45 bpm and less than Week 52/Baseline 
Increase of ≥ 15 bpm from Week 52/Baseline 
Decrease of ≥ 15 bpm from Week 52/Baseline 
Abbreviations:  bpm = beats per minute; mmHg = millimeters of mercury. 
 
Potentially clinically significant abnormalities in post-Baseline weight are to be summarized 
using the categories specified in Table 18.  Potentially clinically significant abnormalities in 
weight will also be flagged in by-patient listings. 


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Table 18: 
Categories of Potentially Clinically Significant Abnormalities in Weight 
Parameter 
Category 
Body weight 
Increase of ≥ 5% from Week 52/Baseline 
Increase of ≥ 10% from Week 52/Baseline 
Decrease of ≥ 5% from Week 52/Baseline 
Decrease of ≥ 10% from Week 52/Baseline 
 
9.3.3. 
Bone Mineral Density  
Corrected BMD data will be used for analysis as determined by the central radiology laboratory 
in the three prespecified anatomical locations:  lumbar spine (L1–L4), total hip, and femoral 
neck.   
9.3.3.1. 
Analysis Using Week 52/Baseline Bone Mineral Density as Baseline  
As defined in Section 4.3.6, the BMD at Week 52 of the extension study will be used as the 
Week 52/Baseline in the randomized withdrawal study as long as it was within 30 days of the 
first dose date of the randomized study drug.  If there are multiple BMD measurements at Week 
52 in the extension study, the one closest to the first dose date of the study drug will be used as 
Week 52/Baseline in the randomized withdrawal study.   
BMD at Week 52/Baseline and Week 104 visit will be summarized descriptively by treatment 
group and each measured anatomical location for all patients in the safety population.  
Percentage changes from Week 52/Baseline along with 95% CIs of mean percentage changes 
also will be summarized by treatment group and anatomical location.  Mean percentage change 
from Week 52/Baseline with its corresponding 95% CI will be plotted by visit, treatment group, 
and anatomical location.   
An analysis of covariance (ANCOVA) model will be used to assess BMD at Week 104.  The 
model will include treatment, stratification factors (menstrual blood loss volume at pivotal study 
baseline, and duration of relugolix exposure prior to randomization), race (African American 
versus Other) as fixed factors, and age at Week 52/Baseline, Week 52/Baseline BMD value, and 
BMI at Week 52/Baseline as covariates.  Least square means on each anatomical location will be 
presented and plotted with associated 95% CIs.  Taking into consideration of the BMD data 
collected for patients who prematurely discontinued prior to Week 104, the ANCOVA model 
analysis will also be performed similarly to assess BMD at Week 104/EOT.  
Categorical representation of percentage change from Week 52/Baseline to Week 104  (also 
Week 104/EOT) will be presented by the number and proportion of patients who had BMD 
increase > 0%, no change (0%), declines of ≤ 2%, >2% to 3%, > 3% to 5%, > 5% to 8%, and > 
8% by pivotal study treatment group and anatomical location.  The 95% CIs will be provided for 
the respective proportions.   
Categorical changes from Week 52/Baseline in overall BMD (defined as lumbar spine and total 
hip) also will be assessed..  Femoral neck evaluates a smaller area of bone mass than the total hip 
and is prone to lower precision in the measurement (Leslie et al. 2007; ISCD 2015).  Since 


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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. 
Corrected BMD Z-scores and its change from Week 52/Baseline will be summarized by 
treatment group, visit, and anatomical location with descriptive statistics including 95% CIs, and 
the number and percentage of patients with a corrected BMD Z-score < -2.0 will be presented by 
treatment group, visit, and anatomical location.  Additionally, categorical change from Week 
52/Baseline in Z-score will be summarized as ≥ 0, < 0 to -0.25, < -0.25 to -0.5, < -0.5 to -0.75, < 
-0.75 to -1, < -1 to -2 and < -2, by treatment group, visit and anatomical location. 
BMD percentage changes from Week 52/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 19.  
Table 19: 
Planned Subgroup Analyses for Bone Mineral Density 
Subgroup Name 
Subgroup Level 
Geographic region 
North America, Other 
Age category (years) at pivotal study 
baseline 
< 40, ≥ 40  
Race 
Black or African American, Other 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino  
BMI (kg/m2) at pivotal study baseline 
<30, ≥ 30  
Duration of exposure to relugolix prior 
to randomization (weeks)  
28, 52  
Abbreviations:  BMI = body mass index. 
 
9.3.3.2. 
Analysis Using the Pivotal Study Baseline Bone Mineral Density as Baseline  
For the visits in pivotal and extension studies, the visit window specified in the extension study 
SAP Table 3 will be used where the first dose of pivotal study drug was used as the reference.   
Percentage changes from pivotal study baseline along with 95% CIs of mean percentage changes 
since first dose of the pivotal study drug at all the timepoints when BMD was scheduled to be 
collected in a pivotal study, extension study and the randomized withdrawal study also will be 
summarized by treatment group and anatomical location.  Mean percentage change from pivotal 
study baseline with its corresponding 95% CI will be plotted by visit, treatment group, and 
anatomical location.   
Categorical representation of percentage change from pivotal study baseline to all the timepoints 
where BMD was scheduled to be collected since pivotal study baseline will be presented by the 
number and proportion of patients who had BMD increase > 0%, no change (0%), declines of ≤ 
2%, >2% to 3%, > 3% to 5%, > 5% to 8%, and > 8% by treatment group and anatomical 
location.  The 95% CIs will be provided for the respective proportions.   


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Categorical changes from pivotal baseline in overall BMD (defined as lumbar spine and total 
hip) also will be assessed at all the timepoints where BMD was scheduled to be collected since 
pivotal study baseline.   
Corrected BMD Z-scores and its change from pivotal study baseline will be summarized by 
treatment group, visit, and anatomical location with descriptive statistics including 95% CIs, and 
the number and percentage of patients with a corrected BMD Z-score < -2.0 will be presented by 
treatment group, visit, and anatomical location.  Additionally, categorical change from pivotal 
study baseline in Z-score will be summarized as ≥ 0, < 0 to -0.25, < -0.25 to -0.5, < -0.5 to -0.75, 
< -0.75 to -1, < -1 to -2 and < -2, by treatment group, visit and anatomical location. 
These analyses will be carried out by six combined analysis groups where the pivotal study 
treatment group, LTE study treatment and the randomized withdrawal study treatment group are 
considered (see the Table 20 below).  
In addition, to observe the long-term impact of relugolix + delayed E2/NETA on BMD loss, 
these analyses will be performed by the relugolix monotherapy status groups: patients who were 
previously treated with any relugolix + delayed E2/NETA (from Groups 3 and 4) and the rest of 
the patients (from Groups 1, 2, 5 and 6). 
9.3.3.3. 
Analysis Using Pivotal Week 12 BMD as Baseline  
To observe the long-term impact of relugolix+E2/NETA on BMD loss in dependent of 
hypoestrogenic effect caused by relugolix monotherapy, BMD at Week 12 in the pivotal studies 
will be used as baseline to calculate percent change in BMD for each patient.  Descriptive 
statistics will be provided for percent change from pivotal Week 12 in BMD by the six 
combination groups and as well as by the monotherapy status groups.    


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Table 20: 
Combined Analysis Groups for Bone Mineral Density 
Combined Analysis Group 
Pivotal Study  
Treatment Group 
Extension Study 
Treatment 
Randomized 
Withdrawal Study 
Treatment Group 
Group 1 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Group 2 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Placebo 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Placebo 
Group 3 
Relugolix + Delayed E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Relugolix + Delayed 
E2/NETA 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Group 4 
Relugolix + Delayed E2/NETA 
Relugolix + E2/NETA 
Placebo 
Relugolix + Delayed 
E2/NETA 
Relugolix + E2/NETA 
Placebo 
Group 5 
Placebo 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Placebo 
Relugolix + E2/NETA 
Relugolix + E2/NETA 
Group 6 
Placebo 
Relugolix + E2/NETA 
Placebo 
Placebo 
Relugolix + E2/NETA 
Placebo 
 
Patients who prematurely discontinued from the study treatment after Week 60 will undergo 
another bone densitometry scan at the safety follow-up visit.  Patients with a BMD loss of ≥ 7% 
at lumbar spine, total hip, or femoral neck at their Week 104/Early Termination visit relative to 
pivotal study baseline measurement will undergo another bone densitometry scan at 6 (± 1) 
months and follow-up to evaluate recovery per the protocol.  All available post-treatment follow-
up BMD data will be listed. BMD data collected during the additional safety follow-up period 
may be summarized and reported in an addendum to the CSR if deemed necessary. 


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9.3.4. 
Endometrial Biopsy and Transvaginal Ultrasound  
The endometrial biopsy procedure was performed only if required in this study and consensus 
readings were not performed.  The biopsy related information collected in the eCRF will be 
listed.   
Transvaginal ultrasound was to be performed at Week 52/Baseline visit and unscheduled visit in 
this study, and the results collected in the eCRF will be listed.   
  


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10. 
REFERENCES  
ISCD. ISCD 2015 Official Positions Brochure.pdf | Powered by Box [Internet]. 2015 [cited 2019 
Jun 11]. Available from: https://iscd.app.box.com/v/OP-ISCD-2015-Adult 
Klein JP, Logan B, Harhoff M, Andersen PK. Analyzing survival curves at a fixed point in time. 
Stat Med. 2007;26(24):4505–19.  
Leslie WD, Lix LM, Tsang JF, Caetano PA, Manitoba Bone Density Program. Single-site vs 
multisite bone density measurement for fracture prediction. Arch Intern Med. 2007 Aug 
13;167(15):1641–7.  
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument: PharmacoEconomics. 1993 Nov;4(5):353–65.  
 
 


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APPENDIX 1:  PRE-DEFINED CATEGORIES FOR LAB SHIFT TABLE  
Clinical Laboratory Parameter 
Category 
Fasting Glucose/Glucose 
Category 1 ( < 100 mg/dL) 
Category 2 (100 - 125 mg/dL) 
Category 3 (126 - 200 mg/dL) 
Category 4 ( > 200 mg/dL) 
HbA1C  
Category 1 (< 5.7%) 
Category 2 (5.7 – 6.4%) 
Category 3 (6.5 – 8%) 
Category 4 (8.1 – 9.4%) 
Category 5 (9.5 – 11%) 
Category 6 (> 11%) 
Total Cholesterol (CTCAE Grade) 
Grade 0 (≤ ULN) 
Grade 1 (> ULN – 300 mg/dL) 
Grade 2 (> 300 – 400 mg/dL) 
Grade 3 (> 400 – 500 mg/dL) 
Grade 4 (> 500 mg/dL) 
Low Density Cholesterol (NCEP ATP 
III Guidelines) 
Category 1 (< 100 mg/dL) 
Category 2 (100 – 129 mg/dL) 
Category 3 (130 – 159 mg/dL) 
Category 4 (160 – 189 mg/dL) 
Category 5 (≥ 190 mg/dL) 
High Density Cholesterol (NCEP ATP 
III Guidelines) 
Category 1 (< 40 mg/dL) 
Category 2 (40 – 59 mg/dL) 
Category 3 (≥ 60 mg/dL) 
Triglycerides (CTCAE Grade) 
Grade 0 (< 150 mg/dL) 
Grade 1 (150 – 300 mg/dL) 
Grade 2 (301 – 500 mg/dL) 
Grade 3 (501 – 1000 mg/dL) 
Grade 4 (> 1000 mg/dL) 
Abbreviations: HbA1c = Hemoglobin A1c; CTCAE = Common Terminology Criteria for Adverse Events; NCEP ATP III= 
National Cholesterol Education Program Adult Treatment Panel III; ULN= upper limit of normal. 
 
 


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APPENDIX 2:  LIST OF PRE-DEFINED THRESHOLDS 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 
  GFR < 15 mL/min per 1.73 m2 
  CR > 50% increase from BL 
  GFR ≥ 15 - < 30 mL/min per 1.73 m2 
 
  GFR ≥ 30 - < 60 mL/min per 1.73 m2 
 
  GFR ≥ 60 - < 90 mL/min per 1.73 m2 
 
  GFR ≥ 90 mL/min per 1.73 m2 
 
 


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Chemistry Laboratory 
Metabolic Parameters 
 
  Fasting Glucose 
Highest Postbaseline Glucose 
     < 100 mg/dL at BL 
   Gluc ≥ 200 mg/dL and > BL 
          < 100 mg/dL  
   Gluc ≥ 200 mg/dL and ≥ 126 mg/dL at BL 
          ≥ 100 - < 126 mg/dL  
   Gluc ≥ 500 mg/dL and > BL 
          ≥ 126 mg/dL  
   Gluc ≥ 500 mg/dL and ≥ 126 mg/dL at BL 
 
 
      ≥ 100 - < 126 mg/dL at BL 
Total CHOL > 200 mg/dL and > BL 
          < 100 mg/dL  
Total CHOL increase > 30 mg/dL from BL 
          ≥ 100 - < 126 mg/dL  
 
          ≥ 126 mg/dL  
 
 
 
     ≥ 126 mg/dL at BL 
HDL < LLN and < BL 
         < 100 mg/dL  
 
         ≥ 100 - < 126 mg/dL  
 
         ≥ 126 mg/dL  
 
 
LDL > ULN and > BL 
TRIG > ULN and > BL 
LDL 100 - < 130 mg/dL and > BL 
TRIG 150 - < 200 mg/dL and > BL 
LDL 130 - < 160 mg/dL and > BL 
TRIG 200 - < 500 mg/dL and > BL 
LDL 160 - < 190 mg/dL and > BL 
TRIG ≥ 500 mg/dL and > BL 
LDL ≥ 190 mg/dL and > BL 
 
 
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 
ALP > 5× ULN and > BL 
CK > 5× ULN and > BL 
ALP > 10× ULN and > BL 
CK > 10× ULN and > BL 
 
 


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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 
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; EOS = eosinophils; GFR = 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; NEUT = neutrophils; PHOS = phosphate; PLT 
= platelets; TRIG = triglycerides; ULN = upper limit of normal; WBC = white blood cell.