Clinical trial NCT03412890
Conditions: Heavy Menstrual Bleeding Uterine Fibroid
Keywords: Uterine Fibroid Heavy Menstrual Bleeding Menstrual Blood Volume
Sponsor: Myovant Sciences GmbH
Start date: 2017-10-19; Completion date: 2021-01-13
Enrollment: 477 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to determine the long-term efficacy and safety of relugolix 40 milligrams (mg) once daily co-administered with estradiol (E2) and norethindrone acetate (NETA) for 28 weeks on heavy menstrual bleeding associated with uterine fibroids in participants who previously completed a 24-week treatment period in one of the pivotal studies (MVT-601-3001 or MVT-601-3002).

Detailed description:
This study is an international phase 3 open-label, single-arm, long-term efficacy and safety extension study that enrolled eligible participants who have completed their participation in one of the phase 3 randomized, double-blind, placebo-controlled pivotal studies, MVT-601-3001 (LIBERTY 1 - NCT03049735) or MVT-601-3002 (LIBERTY 2 - NCT 03103087). All participants received relugolix 40 mg orally once daily co-administered with E2 (1 mg) and NETA (0.5 mg) for 28 weeks.

Approximately 600 women with heavy menstrual bleeding associated with uterine fibroids were to be enrolled, after having completed a 24-week treatment period in one of the pivotal studies. The objectives of the study were to evaluate long-term efficacy and safety through up to 52 weeks of treatment (including treatment during the pivotal study) of relugolix co-administered with E2/NETA.

Screening and baseline procedures were to be done at the same visit for this extension study (referred to as the "Week 24/Baseline Visit"), which coincided with the Week 24 Visit from the pivotal study and was to be defined as the date of completion of the last Week 24 procedure in the pivotal study. Participants will have received their last dose of study drug in the pivotal study on the day prior to the Week 24/Baseline Visit and were to receive their first dose of study drug for this extension study in the clinic after the participant was determined to be eligible for this extension study and provided informed consent to participate. The administration of the first dose of study drug for MVT-601-3003 was to define enrollment into this study. Study participants were to then take the open-label study treatment orally once daily for 28 weeks.

Arms: arm 1: Relugolix co-administered with E2/NETA for 28 weeks.
Interventions: intervention 1: Relugolix intervention 2: Estradiol/norethindrone acetate
Intervention descriptions: intervention 1: Relugolix 40-mg tablet administered orally once daily intervention 2: Capsule containing co-formulated tablet of E2 (1 mg) and NETA (0.5 mg) administered orally once daily

Protocol documents:
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1 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
LIBERTY EXTENSION:  An International Phase 3 
Open-Label, Single-Arm, Long-Term Efficacy and Safety 
Extension Study to Evaluate Relugolix Co-Administered with 
Low-Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3003 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
c/o Vischer AG 
Aeschenvorstadt 4 
CH-4010 Basel 
Switzerland 
Regulatory Identifier(s): 
Eudra CT # 2017-003310-74 
IND # 131161 
Version and 
Effective Date: 
Original:  08AUG-2017 
Amendment 1:  18 October 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-601-3003 
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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 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR STATEMENT ...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SYNOPSIS .............................................................................................9 
1.1. 
Schedule of Activities .................................................................................................16 
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 ..............................................................23 
4. 
INVESTIGATIONAL PLAN .....................................................................................26 
4.1. 
Overall Study Design ..................................................................................................26 
4.2. 
Discussion of Study Design, Including Dosing ..........................................................27 
4.3. 
Selection of Study Population ....................................................................................29 
4.3.1. 
Inclusion Criteria ........................................................................................................30 
4.3.2. 
Exclusion Criteria .......................................................................................................30 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number ..............32 
4.5. 
Removal of Patients from Therapy .............................................................................32 
4.6. 
Contraception/Pregnancy Avoidance .........................................................................33 
5. 
TREATMENTS ..........................................................................................................35 
5.1. 
Treatments Administered ............................................................................................35 
5.2. 
Identity of Investigational Product .............................................................................35 
5.2.1. 
Product Characteristics ...............................................................................................35 
5.3. 
Randomization and Stratification ...............................................................................35 
5.4. 
Directions for Administration .....................................................................................36 
5.5. 
Dose Reduction/Dose Administration ........................................................................36 
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5.6. 
Storage, Packaging, and Labeling ..............................................................................36 
5.7. 
Blinding ......................................................................................................................36 
5.8. 
Study Drug Accountability and Treatment Compliance ............................................37 
5.9. 
Prior and Concomitant Medications and Non-Drug Therapies ..................................37 
5.9.1. 
Prohibited Medications ...............................................................................................37 
5.9.2. 
Permitted Medications ................................................................................................40 
5.9.3. 
Prohibited Non-Drug Therapies .................................................................................40 
6. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
6.1. 
Schedule of Observations and Procedures ..................................................................41 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) ................................41 
6.3. 
Early Termination Visit and Follow-up Visit .............................................................42 
6.4. 
Continuation into Randomized Withdrawal Study .....................................................42 
6.5. 
Unscheduled Visits .....................................................................................................43 
6.6. 
Study Procedures ........................................................................................................43 
6.6.1. 
Efficacy-Related Procedures ......................................................................................43 
6.6.2. 
Safety-Related Procedures ..........................................................................................45 
7. 
SAFETY CONSIDERATIONS ..................................................................................49 
7.1. 
Adverse Event Definitions ..........................................................................................49 
7.1.1. 
Adverse Event .............................................................................................................49 
7.1.2. 
Serious Adverse Event ................................................................................................50 
7.2. 
Adverse Event Reporting ............................................................................................50 
7.2.1. 
Adverse Event Reporting Period ................................................................................51 
7.3. 
Assigning Causal Relationship to Study Drug ...........................................................52 
7.4. 
Assigning Severity Rating for Adverse Events ..........................................................52 
7.5. 
Adverse Events of Clinical Interest Reporting ...........................................................53 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities ......................................................................................................53 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities ............................................................................................54 
7.6. 
Serious Adverse Event Reporting ...............................................................................54 
7.7. 
Study Drug Overdose Management ............................................................................55 
7.8. 
Pregnancy Reporting ..................................................................................................56 
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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures .................................56 
7.10. Benefit/Risk Assessment ............................................................................................56 
8. 
DATA QUALITY ASSURANCE ..............................................................................59 
8.1. 
Clinical Procedures .....................................................................................................59 
8.2. 
Monitoring ..................................................................................................................59 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................60 
9.1. 
Randomization Methods .............................................................................................60 
9.2. 
Analysis Populations ..................................................................................................60 
9.3. 
Sample Size Estimation ..............................................................................................60 
9.4. 
Efficacy Analyses .......................................................................................................60 
9.5. 
Safety Analyses ..........................................................................................................62 
9.6. 
Pharmacodynamic Analyses .......................................................................................63 
9.7. 
Exploratory Analyses ..................................................................................................63 
10. 
RESPONSIBILITIES .................................................................................................64 
10.1. Investigator Responsibilities .......................................................................................64 
10.1.1. 
Good Clinical Practice ................................................................................................64 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................64 
10.1.3. 
Informed Consent .......................................................................................................64 
10.1.4. 
Confidentiality ............................................................................................................65 
10.1.5. 
Steering Committee ....................................................................................................65 
10.1.6. 
Study Files and Retention of Records ........................................................................65 
10.1.7. 
Electronic Case Report Forms ....................................................................................66 
10.1.8. 
Investigational Product Accountability ......................................................................66 
10.1.9. 
Inspections ..................................................................................................................67 
10.1.10. 
Protocol Compliance ..................................................................................................67 
10.2. Sponsor Responsibilities .............................................................................................67 
10.2.1. 
Protocol Modifications ...............................................................................................67 
10.2.2. 
Study Report ...............................................................................................................67 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ......................68 
10.3. Joint Investigator/Sponsor Responsibilities ................................................................68 
10.3.1. 
Access to Information Monitoring..............................................................................68 
10.3.2. 
Access to Information for Auditing or Inspections ....................................................68 
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10.3.3. 
Study Discontinuation ................................................................................................68 
10.3.4. 
Publications .................................................................................................................68 
11. 
REFERENCES ...........................................................................................................70 
APPENDICES ...............................................................................................................................72 
Appendix 1.Menorrhagia Impact Questionnaire ....................................................................73 
Appendix 2.Uterine Fibroid Symptom and Quality of Life Questionnaire ............................74 
Appendix 3.European Quality of Life Five-Dimension Five-Level Scale .............................77 
Appendix 4.Assessment of Abnormal Liver Tests .................................................................79 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Study MVT-601-3003 ......................................................16 
Table 2: 
Description of MVT-601-3003 Study Drugs ..............................................................35 
Table 3: 
Prohibited Medications ...............................................................................................37 
Table 4: 
Clinical Laboratory Tests ...........................................................................................46 
Table 5: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................53 
Table 6: 
Protocol Risk Assessment and Mitigation Strategies .................................................57 
 
Appendix Table 1 Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury ...........79 
Appendix Table 2 Investigations of Alternative Causes for Abnormal Liver Tests ...................80 
 
LIST OF FIGURES 
Figure 1: 
MVT-601-3003 Study Schematic ...............................................................................27 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Council on Harmonisation 
IEC 
institutional ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIQ 
Menorrhagia Impact Questionnaire 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT interval by the Fridericia correction 
RBC 
red blood cell 
SAP 
statistical analysis plan 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
LIBERTY EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Long-Term Efficacy and Safety Extension Study to Evaluate Relugolix 
Co-Administered with Low-Dose Estradiol and Norethindrone Acetate in 
Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number 
MVT-601-3003 
Location 
Multinational, including North and South America, Europe, and South Africa 
Study Centers 
Approximately 240 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with heavy menstrual bleeding 
associated with uterine fibroids 
Number of Patients 
Planned 
Approximately 600 
Study Objectives 
In women with heavy menstrual bleeding associated with uterine fibroids, the 
study objectives are as follows: 
 
Primary Efficacy Objective 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3001 or 
MVT-601-3002), on heavy menstrual bleeding associated with uterine 
fibroids 
 
Secondary Efficacy Objectives 
• 
To evaluate long-term efficacy of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3001 or 
MVT-601-3002), on the following: 
o Achievement/maintenance of amenorrhea; 
o Hemoglobin; 
o Changes in symptom severity and quality of life related to uterine 
fibroids as measured by the Uterine Fibroid Symptom and Health-
Related Quality of Life (UFS-QoL); 
o Impact of heavy menstrual bleeding on social, leisure, and physical 
activities as measured by the Menorrhagia Impact Questionnaire 
(MIQ); 
o Uterine volume; 
o Uterine fibroid volume. 
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Safety Objectives 
• 
To evaluate the safety of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for up to 52 weeks, among 
patients who previously completed a 24-week treatment period in one of 
the parent studies (MVT-601-3001 or MVT-601-3002), including: 
o Adverse events; 
o Changes in bone mineral density. 
 
Pharmacodynamic Objective 
• 
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily 
co-administered with low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously completed a 24-week 
treatment period in one of the parent studies (MVT-601-3001 or 
MVT-601-3002), on estradiol. 
 
Exploratory Objective 
• 
To evaluate the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate on patient-reported 
quality of life outcomes (European Quality of Life Five-Dimension Five-
Level Scale [EQ-5D-5L]) for up to 52 weeks among patients who 
previously completed a 24-week treatment period in one of the parent 
studies (MVT-601-3001 or MVT-601-3002). 
Study Design 
The LIBERTY EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety extension study that will enroll eligible patients who have completed their 
participation in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3001 or MVT-601-3002).  All patients will receive oral relugolix 40 mg once daily 
co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for  28 weeks.  
Approximately 600 women with heavy menstrual bleeding associated with uterine fibroids will be 
enrolled.  The objectives of the study are to evaluate long-term efficacy and safety through up to 
52 weeks of treatment (including treatment during the parent study) with relugolix co-administered 
with low-dose estradiol/norethindrone acetate. Eligible patients will have completed participation in 
one of the parent studies and consented to participate in this extension study.  Screening and baseline 
procedures will be done at the same visit for this extension study (referred to as the “Week 24/Baseline 
visit” in this study), which coincides with the Week 24 visit from the parent study and will be defined 
as the date of completion of the last Week 24 procedure in the parent study.  The Week 24/Baseline 
visit will include vital signs, physical examination, laboratory assessments, a 12-lead electrocardiogram 
(ECG), bone densitometry, patient-reported outcome assessments, transvaginal ultrasound, and 
endometrial biopsy (if required).  When Week 24 procedures in the parent study have been completed, 
the investigator will assess patient eligibility for participation in the open-label extension study.  The 
eligibility assessment will be based on data available at the Week 24/Baseline visit.  No 
MVT-601-3003 study procedures will be performed until the consent form for this extension study is 
signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  The administration of the first dose of study drug for MVT-601-3003 will define 
enrollment into this study.  Study participants will then take the open-label study treatment (relugolix 
40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once daily for 
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28 weeks.  Patients will complete daily paper diaries to record menstrual bleeding and feminine product 
use. 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment of 
bone mineral density via dual-energy x-ray absorptiometry (DXA).  Quality of life questionnaires will 
be completed according to the Schedule of Activities (Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, 
and transvaginal ultrasound. 
At the Week 52 visit or at an Early Termination visit occurring on or after Week 36, patients with a 
bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip relative to the parent study 
Baseline measurement will undergo another bone densitometry scan at 6 (± 1) months.  If Early 
Termination occurs prior to Week 36, follow-up bone densitometry will be performed according to the 
requirements of the parent study. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption (eg, 
medical procedure or medications) will be contacted again by telephone 3 (+ 0.5) months after the 
Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 visit, 
then the Follow-up visit and the follow-up procedures performed under this protocol, including the 
follow-up bone densitometry scan at 6 (± 1) months and status of menstruation recover, may be waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1. Completed 24 weeks of study drug treatment and study participation in either MVT-601-3001 or 
MVT-601-3002; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or 
study-specific procedures for MVT-601-3003; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures for 
this study may be done under the informed consent for the parent study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within 
the study period, including during the Safety Follow-Up period; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
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5. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment period and for at least 30 days after the 
last dose of study drug.  However, the patient is not required to use the specified nonhormonal 
contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the Week 24/Baseline 
visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at 
least 4 months prior to the Week 24/Baseline visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of 
post-Essure syndrome; 
c. Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
nonhormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
 
Exclusion Criteria:  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 (MVT-601-3001 or MVT-601-3002); 
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 (eg, bilateral hip 
replacement, spinal hardware in the lumbar spine); 
3. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study 
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA 
assessment of bone mineral density; 
4. Anticipated to use any prohibited medications as detailed in Section 5.9.1; 
5. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to 
the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or norethindrone 
acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
6. Has current active liver disease from any cause; 
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7. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
syndromes, etc).  Psoriasis not requiring or anticipated to require systemic therapy is permitted; 
8. Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or any 
subsequent visit in one of the parent studies (MVT-601-3001 or MVT-601-3002): 
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); 
9. Is currently pregnant or lactating, or intends to become pregnant during the study period or within 
1 month after the last dose of study drug, or plans to donate ova during the study period or within 
2 months after the last dose of study drug; 
10. Has a decline in presenting visual acuity score as defined below (unless explained by refractive 
error or approved by the Sponsor): 
a. 90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the parent study 
Baseline visit; OR 
b. The presenting visual acuity score has decreased by 10 or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  visual acuity score must have been obtained with corrective lenses, if applicable; 
11. 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. 
12. Met a withdrawal criterion in the parent study (MVT-601-3001 or MVT-601-3002). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 28 weeks (Open-Label 
Treatment period). 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made 
between the parent study Baseline and the end of the extension study 
(Week 52) for the following parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg 
norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in 
the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for the extension 
study for all change from baseline-related endpoints.  The menstrual blood 
loss during the screening period of the parent study will establish the patient’s 
baseline for both the parent study and the extension study. 
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Primary Efficacy Endpoint 
• 
Proportion of women who achieve or maintain a menstrual blood loss 
volume of < 80 mL AND at least a 50% reduction from parent study 
Baseline to the last 35 days of treatment, as measured by the alkaline 
hematin method. 
 
Secondary Efficacy Endpoints 
• 
Time to achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from parent study Baseline menstrual blood loss volume as 
measured by the alkaline hematin method; 
• 
Change from parent study Baseline to Week 52 in menstrual blood loss; 
• 
Proportion of women who achieve or maintain amenorrhea over the last 
35 days of treatment; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at parent study Baseline who achieve an increase of ≥ 1 g/dL from parent 
study Baseline at Week 52; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at parent study Baseline who achieve a normal hemoglobin at Week 52; 
• 
Change from parent study Baseline to Week 52 in hemoglobin; 
• 
Change from parent study Baseline to Week 52 in the Uterine Fibroid 
Scale – Symptom Severity; 
• 
Change from parent study Baseline to Week 52 in the Uterine Fibroid 
Scale – Health-related Quality of Life subscales and total score; 
• 
Change from parent study Baseline to Week 52 in the MIQ score for 
physical activities; 
• 
Change from parent study Baseline to Week 52 in the MIQ score for 
social and leisure activities; 
• 
Change from parent study Baseline to Week 52 in uterine volume; 
• 
Change from parent study Baseline to Week 52 in uterine fibroid volume. 
 
Safety Endpoints 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline to Week 52 in bone 
mineral density at the lumbar spine (L1-L4), femoral neck, and total hip as 
assessed by DXA. 
 
Pharmacodynamic Endpoint 
• 
Change from parent study Baseline to Week 52 in pre-dose concentrations 
of serum estradiol. 
 
Exploratory Endpoint 
• 
Change from parent study Baseline to Week 52 in the EQ-5D-5L. 
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Groups A, B, and C) for the Intent-to-Treat Population.  The analyses methods for efficacy 
endpoints are similar to those used for the parent studies, unless otherwise specified in the statistical 
analysis plan (SAP). 
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The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoint 
(responder rate defined as proportion of women who achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from parent study Baseline in menstrual blood loss volume over 
the last 35 days of treatment) will be calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, and transvaginal 
ultrasound.  Safety data analyses will use data from all patients from the parent studies who receive any 
amount of study drug (ie, from parent study Baseline to Week 52). 
Drug exposure will be summarized by descriptive statistics.  Severity of all treatment-emergent adverse 
events will be evaluated by the investigator based on the National Cancer Institute’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 parent study Baseline results to each of the subsequent visits will be produced. 
Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  The absolute, 
change, and percent change from parent study Baseline and Z-scores will be summarized by visit and 
parent study treatment group. 
The mean percentage change at Week 52 from parent study Baseline in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3001 
or MVT-601-3002) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, the 
relugolix add-back treatment arm will be considered to have successfully prevented bone mineral 
density loss. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3001 or MVT-601-3002) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 600 patients (75% of the total of 
780 patients who will be randomized into the parent studies) will participate in this study. 
 
 
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1.1. 
Schedule of Activities 
Table 1: 
Schedule of Activities for Study MVT-601-3003 
PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/-3002) 
Week 24/Baseline 
(Week 24 of Parent Study; 
Baseline of Extension 
Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
– 10 to + 20 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
- 
- 3 to + 18 
Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
 
 
X 
 
 
 
X 
Xh 
 
Complete Physical Examination 
Xg 
 
 
 
 
 
 
X 
 
 
Visual Acuityi 
Xg 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-Directed Physical 
Examinationj 
 
X 
X 
X 
X 
X 
X 
 
Xh 
X 
12-Lead ECGk 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Clinical Laboratory Testsl 
Xg,m 
X 
X 
X 
X 
X 
X 
Xm 
Xh 
X 
Pharmacodynamics Samplen 
Xg,m 
 
 
 
 
 
 
Xm 
Xh,m 
 
Urinalysis 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
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PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/-3002) 
Week 24/Baseline 
(Week 24 of Parent Study; 
Baseline of Extension 
Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-scheduledb 
Follow-Upc 
(~30 days after 
last dose of 
study drug) 
Visit Window (days) 
Parent Study Day 169 
– 10 to + 20 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
- 
- 3 to + 18 
Transvaginal Ultrasoundo 
Xg 
 
 
 
 
 
 
Xp 
Xh 
 
Bone Densitometryq 
Xg 
 
 
X 
 
 
 
Xp,r 
Xh 
 
Endometrial Biopsy 
Xg,s 
 
 
 
 
 
 
Xp 
Xh 
 
Dispense Study Treatment 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Patient Paper Diaryt 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense Feminine Products 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Feminine Product Collection and 
Venous Blood Sampleu 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose in Clinicv 
Xw 
 
 
 
 
 
 
X 
Xh 
 
Daily Self-Administration of Study 
Treatmentv 
 
X 
 
 
 
MIQx 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
UFS-QoL Questionnairex 
Xg 
 
 
X 
 
 
 
X 
Xh 
 
EQ-5D-5L Questionnairex 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Adverse Event Collectiony 
Xz 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation Recovery 
 
 
 
 
 
 
 
 
 
Xaa 
 
 
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BP, blood pressure; ECG, electrocardiogram; EQ-5D-5L, European Quality of Life Five-Dimension Five-Level Scale; HR, heart rate; MIQ, Menorrhagia Impact Questionnaire; 
UFS-QoL, Uterine Fibroid Symptom and Health-Related Quality of Life 
a The week 52 visit must occur on or after the 1-year anniversary of Study Day 1 in the parent study.  The timing of the visit should also be at least 28 weeks 
(± 10 days) from the actual date of the Week 24/Baseline visit. 
b Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents. 
c The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 visit. 
d May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3003 is defined by 
administration of the first dose of MVT-601-3003 study drug. 
e Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up period.  Concomitant 
medications with start date prior to the first dose of study drug for MVT-601-3003 should be reported as concomitant medications in the parent study 
(MVT-601-3001 or MVT-601-3002).  Concomitant medications initiated during the MVT-601-3001 or MVT-60-3002 studies and ongoing at the time of the 
first dose in Study MVT-601-3003 will be recorded in the electronic case report form. 
f Concomitant medications are recorded both for the parent study and for MVT-601-3003 at the Week 24/Baseline visit.   (See footnote c for further details). 
g This is a parent study (MVT-601-3001 or MVT-601-3002) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3003 and is 
covered under the informed consent for the parent study. 
h The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal 
laboratory test). 
i See parent study protocols (MVT-601-3001 or MVT-601-3002) for instructions on testing visual acuity. 
j The exam may include a gynecologic examination, if indicated based on signs and symptoms. 
k The 12-lead ECGs will be submitted for central reading. 
l Clinical laboratory tests at each visit include clinical chemistries and a complete blood count.  At the Week 24/Baseline visit and Week 52 visit, additional tests 
include:  fasting (at least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
m Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period. 
n Pharmacodynamic samples:  For Week 24/Baseline samples, see the parent protocol (MVT-601-3001 or MVT-601-3002).  At Week 52/Early Termination, 
collect samples for analysis of estradiol concentrations only.  On days when pharmacodynamic samples are collected, administer the study treatment after the 
pharmacodynamic sample collections are completed. 
o Transvaginal ultrasound, with or without transabdominal ultrasound and with or without saline or gel contrast, is performed to determine uterine and myoma 
volumes and endometrial thickness 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.  Note:  Transvaginal ultrasound is required.  
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. 
p This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier.  However, the 
procedure may be done if it will aid in the evaluation of an ongoing adverse event. 
q Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
r At the Week 52 visit or at an Early Termination visit occurring on or after Week 36, patients with a bone mineral density loss of > 3 relative to the parent study 
Baseline measurement will undergo a follow-up bone densitometry scan at 6 (± 1) months and will be contacted to question them about medications and conditions 
(eg, pregnancy) that might affect bone mineral density through the time of follow-up bone densitometry.  If Early Termination occurs prior to Week 36, follow-up 
bone densitometry will be performed according to the requirements of the parent study.  The follow-up bone densitometry will be submitted for central reading. 
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s Endometrial biopsies are to be performed per instructions in the parent study.  See the Laboratory Manual for guidance on handling and shipping the biopsy 
sample to the central laboratory for analysis.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who 
participated in MVT-601-3001 (see MVT-601-3001 protocol for details) and in some patients who participated in MVT-601-3002 (see MVT-601-3002 
protocol for details). 
t Patients enter diary information on menstruation status and feminine product use daily starting on the day of the Week 24/Baseline Visit. 
u A venous blood sample (for hemoglobin) must be collected each time feminine products are collected to be sent to the central laboratory conducting the 
alkaline hematin assessment.  The site must document the start and stop dates of the patient’s menses corresponding to the collected feminine products. 
v Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  The first dose of study 
drug for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed.  The last dose of study 
drug will be taken in the clinic during the Week 52/Early Termination visit. 
w Pregnancy test must be negative before the study drug dose is administered. 
x The patient will enter her response(s) into an electronic tablet device at the site. 
y Collect adverse events from the time that the first dose of study drug for MVT-601-3003 is administered.  Adverse events with onset prior to the first dose of 
study drug for MVT-601-3003 should be reported as an adverse event in the parent study (MVT-601-3001 or MVT-601-3002).  If events originating in the 
parent study are ongoing at the time of the first dose of study drug for MVT-601-3003, please see the Study Reference Manual for instructions for recording the 
follow-up status. 
z Adverse events are collected for both the parent study and for MVT-601-3003 at the Week 24/Baseline visit (see footnote v for further details). 
aa Patients whose menses have not resumed as of the Follow-up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted again by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and questioned about factors 
that may affect resumption of menses. 
 
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2. 
INTRODUCTION 
2.1. 
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 25% 
of women of reproductive age.  While the majority of uterine fibroids are asymptomatic, 
approximately 25% of women with fibroids develop symptoms requiring treatment.  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 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, 
and more than 200,000 hysterectomies are 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 
medicine that can decrease the symptoms of uterine fibroids and can be safely administered so 
that women have an option other than surgical procedures such as myomectomy and 
hysterectomy. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix investigator brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once daily oral medication for the treatment of 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 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. 
Relugolix antagonizes the human GnRH receptors present on the gonadotropin-secreting cells of 
the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
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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 treated with relugolix had substantial reductions in 
reproductive organ weights of both female and male mice, suggesting that relugolix may 
suppress blood estrogen and testosterone levels, respectively.  Orally administered relugolix 
suppressed the hypothalamic-pituitary axis in castrated cynomolgus monkeys at doses of 
1 mg/kg and higher. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this extension study are to evaluate long-term efficacy and safety through up to 
52 weeks of treatment (including 24 weeks of treatment during the parent study) of relugolix 
co-administered with low-dose estradiol and norethindrone acetate. 
Descriptive assessments of efficacy and safety will be made between the parent study Baseline 
and the end of the extension study (Week 52) on the extension study population, defined as 
patients who enrolled in MVT-601-3003 (ie, who received at least 1 dose of study drug in the 
extension study), for the following parent study treatment groups: 
• Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent 
study; 
• Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg 
estradiol and 0.5 mg norethindrone acetate in the parent study; 
• Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for the extension study for all 
change from baseline-related endpoints.  The menstrual blood loss during the screening period of 
the parent study will establish the patient’s baseline for both the parent study and the extension 
study. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate for 
up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies (MVT-601-
3001 or MVT-601-3002), on heavy menstrual 
bleeding associated with uterine fibroids. 
• 
Proportion of women who achieve or 
maintain a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
parent study Baseline to the last 35 days of 
treatment, as measured by the alkaline 
hematin method. 
Secondary Efficacy 
• 
To evaluate long-term efficacy of relugolix 
40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate for 
up to 52 weeks, among patients who 
previously completed a 24-week treatment 
period in one of the parent studies (MVT-601-
3001 or MVT-601-3002), on the following: 
o Achievement/maintenance of amenorrhea; 
o Hemoglobin; 
o Changes in symptom severity and quality 
of life related to uterine fibroids as 
measured by the Uterine Fibroid 
• 
Time to achieve a menstrual blood loss 
volume of < 80 mL AND at least a 50% 
reduction from parent study Baseline 
menstrual blood loss volume as measured by 
the alkaline hematin method; 
• 
Change from parent study Baseline to 
Week 52 in menstrual blood loss; 
• 
Proportion of women who achieve or 
maintain amenorrhea over the last 35 days of 
treatment; 
• 
Proportion of women with a hemoglobin 
below the lower limit of normal at parent 
study Baseline who achieve an increase of 
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Objective(s) 
Endpoint(s) 
Symptom and Health-Related Quality of 
Life (UFS-QoL); 
o Impact of heavy menstrual bleeding on 
social, leisure, and physical activities as 
measured by the Menorrhagia Impact 
Questionnaire (MIQ); 
o Uterine volume; 
o Uterine fibroid volume. 
≥ 1 g/dL from parent study Baseline at 
Week 52; 
• 
Proportion of women with a hemoglobin 
below the lower limit of normal at parent 
study Baseline who achieve a normal 
hemoglobin at Week 52; 
• 
Change from parent study Baseline to 
Week 52 in hemoglobin; 
• 
Change from parent study Baseline to 
Week 52 in the Uterine Fibroid Scale – 
Symptom Severity; 
• 
Change from parent study Baseline to 
Week 52 in the Uterine Fibroid Scale – 
Health-related Quality of Life subscales and 
total score; 
• 
Change from parent study Baseline to 
Week 52 in the MIQ score for physical 
activities; 
• 
Change from parent study Baseline to 
Week 52 in the MIQ score for social and 
leisure activities; 
• 
Change from parent study Baseline to 
Week 52 in uterine volume; 
• 
Change from parent study Baseline to 
Week 52 in uterine fibroid volume. 
Safety 
• 
To evaluate the safety of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate for up to 
52 weeks, among patients who previously 
completed a 24-week treatment period in one 
of the parent studies (MVT-601-3001 or 
MVT-601-3002), including: 
o Adverse events; 
o Changes in bone mineral density. 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline 
to Week 52 in bone mineral density at the 
lumbar spine (L1-L4), femoral neck, and total 
hip as assessed by dual-energy x-ray 
absorptiometry (DXA). 
Pharmacodynamic 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone 
acetate for up to 52 weeks, among patients 
who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3001 or MVT-601-3002), on 
estradiol. 
• 
Change from parent study Baseline to 
Week 52 in pre-dose concentrations of serum 
estradiol. 
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Objective(s) 
Endpoint(s) 
Exploratory 
• 
To evaluate the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate on patient-
reported quality of life outcomes (European 
Quality of Life Five-Dimension Five-Level 
Scale [EQ-5D-5L]) for up to 52 weeks among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3001 or MVT-601-3002). 
• 
Change from parent study Baseline to 
Week 52 in the EQ-5D-5L. 
 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The LIBERTY EXTENSION study (MVT-601-3003) is an international phase 3 open-label, 
single-arm, long-term efficacy and safety extension study that will enroll eligible patients who 
have completed their participation in one of the phase 3 randomized, double-blind, placebo-
controlled parent studies (MVT-601-3001 or MVT-601-3002).  All patients will receive oral 
relugolix 40 mg once daily co-administered with low-dose estradiol 1.0 mg and norethindrone 
acetate 0.5 mg for  28 weeks.  Approximately 600 women with heavy menstrual bleeding 
associated with uterine fibroids will be enrolled.  The objectives of the study are to evaluate 
long-term efficacy and safety through up to 52 weeks of treatment (including treatment during 
the parent study) with relugolix co-administered with low-dose estradiol/norethindrone acetate.  
Eligible patients will have completed participation in one of the parent studies and consented to 
participate in this extension study.  Screening and baseline procedures will be done at the same 
visit for this extension study (referred to as the “Week 24/Baseline visit” in this study), which 
coincides with the Week 24 visit from the parent study and will be defined as the date of 
completion of the last Week 24 procedure in the parent study.  The Week 24/Baseline visit will 
include vital signs, physical examination, laboratory assessments, a 12-lead electrocardiogram 
(ECG), bone densitometry, patient-reported outcome assessments, transvaginal ultrasound, and 
endometrial biopsy (if required).  When Week 24 procedures in the parent study have been 
completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 
24/Baseline visit.  No MVT-601-3003 study procedures will be performed until the consent form 
for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  The administration of the first dose of study drug for 
MVT-601-3003 will define enrollment into this study.  Study participants will then take the 
open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 28 weeks.  Patients will complete daily paper 
diaries to record menstrual bleeding and feminine product use. 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment 
of bone mineral density via DXA.  Quality of life questionnaires will be completed according to 
the Schedule of Activities (Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with 
DXA, and transvaginal ultrasound. 
At the Week 52 visit or at an Early Termination visit occurring on or after Week 36, patients 
with a bone mineral density loss of > 3 relative to the parent study Baseline measurement will 
undergo a follow-up bone densitometry scan at 6 (± 1) months and will be contacted to question 
them about medications and conditions (eg, pregnancy) that might affect bone mineral density 
through the time of follow-up bone densitometry.  If Early Termination occurs prior to Week 36, 
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follow-up bone densitometry will be performed according to the requirements of the parent 
study.  The follow-up bone densitometry will be submitted for central reading. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
of resumption (eg, medical procedure or medications) will be contacted again by telephone 
3 (+ 0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided Figure 1 . 
Figure 1: 
MVT-601-3003 Study Schematic 
 
4.2. 
Discussion of Study Design, Including Dosing 
The LIBERTY EXTENSION study (MVT-601-3003) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3001 and MVT-601-3002) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with heavy menstrual bleeding associated with 
uterine fibroids.  This 28-week extension study provides additional efficacy and safety data up to 
52 weeks to demonstrate the benefit and safety of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate (0.5 mg).  The primary objective of the study is to 
assess long-term efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks on reduction in heavy menstrual bleeding, the most 
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common and burdensome symptom of uterine fibroids.  The study will also evaluate safety of 
relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who previously completed a 24-week treatment period in one 
of the parent studies (MVT-601-3001 or MVT-601-3002), including adverse events and change 
in bone mineral density. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily (N = 101) suppressed 
estradiol levels to below 20 pg/mL in the majority of women, and results were similar to those in 
the group of women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the 
relugolix 40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary 
endpoint of the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 
demonstrated the 40 mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from heavy menstrual bleeding in a high enough percentage of women to 
move forward into phase 3 clinical development and, based on the DXA data from the phase 2 
study, are not expected to prevent bone mineral density loss in a significant majority of women 
over 52 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 52 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in heavy menstrual blood loss.  
It is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Kliovance® SmPC, 2016].  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 this phase 3 study is currently approved in the US as long-term 
hormone replacement therapy to prevent bone loss and alleviate vasomotor symptoms in 
postmenopausal women [Kliovance SmPC, 2016]. 
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A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 
lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Kliovance SmPC, 2016]) would not provide sufficient serum estradiol concentrations to protect 
against the loss of bone mineral density resulting from the hypoestrogenic state induced by once 
daily administration of relugolix 40 mg. 
The doses of estradiol and norethindrone acetate used in this study (1.0 mg and 0.5 mg, 
respectively) were used in the parent studies (MVT-601-3001 and MVT-601-3002) and represent 
less than one fifth the estrogenic effects of an oral contraceptive pill containing 30 µg of ethinyl 
estradiol.  Therefore, this low-dose hormonal add-back therapy is added solely to improve the 
safety of relugolix therapy, and it is expected to have either a neutral or a marginal detrimental 
effect on efficacy, while mitigating the side effects of relugolix on bone mineral density loss and 
vasomotor symptoms. 
In summary, relugolix at a dose of 40 mg once daily resulted in a marked decrease in the heavy 
menstrual bleeding associated with uterine fibroids in a majority of women in a well-designed 
large phase 2 study.  However, its administration was associated with a degree of bone mineral 
density loss unacceptable for long-term treatment.  This phase 3 study extension study will 
assess long-term efficacy and safety of relugolix 40 mg co-administered with low-dose of 
estradiol and norethindrone acetate to decrease heavy menstrual bleeding associated with uterine 
fibroids and to prevent the bone mineral density loss and ameliorate some of the other side 
effects of a hypoestrogenic state such as hot flushes. 
This open-label extension study will allow for a description of long-term efficacy data and safety 
for an additional 28 weeks of treatment, providing approximately 1 year of efficacy and safety 
data from the women originally randomized to relugolix in studies (MVT-601-3001 and 
MVT-601-3002).  This study design will allow eligible patients with heavy menstrual bleeding 
associated with uterine fibroids, who were randomized to placebo in the parent study, to receive 
relugolix co-administered with low-dose hormonal add-back therapy during the extension. 
4.3. 
Selection of Study Population 
The study population will include approximately 600 women who have completed one of the 
parent studies (MVT-601-3001 or MVT-601-3002) to this extension study and meet all 
eligibility criteria for this study.  Patients enrolled in the parent studies were premenopausal 
women with heavy menstrual bleeding associated with uterine fibroids (≥ 80 mL per cycle for 
2 cycles or ≥ 160 mL for 1 cycle as measured by the alkaline hematin method during the 
screening period). 
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Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor. 
4.3.1. 
Inclusion Criteria 
A woman will be eligible for enrollment in this study only if all of the following inclusion 
criteria apply and have been met at the time of the Week 24/Baseline visit, unless otherwise 
specified: 
1. Completed 24 weeks of study drug treatment and study participation in either 
MVT-601-3001 or MVT-601-3002; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures for MVT-601-3003; 
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures 
for this study may be done under the informed consent for the parent study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine 
fibroids within the study period, including during the Safety Follow-Up period; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment period and for at least 30 days 
after the last dose of study drug.  However, the patient is not required to use the specified 
nonhormonal contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
c. Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of nonhormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
4.3.2. 
Exclusion Criteria 
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 (MVT-601-3001 or MVT-601-3002); 
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 
(eg, bilateral hip replacement, spinal hardware in the lumbar spine); 
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3. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent 
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 
24 DXA assessment of bone mineral density; 
4. Anticipated to use any prohibited medications as detailed in Section 5.9.1; 
5. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
6. Has current active liver disease from any cause; 
7. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc).  Psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
8. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or any subsequent visit in one of the parent studies (MVT-601-3001 or MVT-601-
3002): 
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); 
9. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
10. Has a decline in presenting visual acuity score as defined below (unless explained by 
refractive error or approved by the Sponsor): 
a. 90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the 
parent study Baseline visit; OR 
b. The presenting visual acuity score has decreased by 10 or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  visual acuity score must have been obtained with corrective lenses, if applicable; 
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11. 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. 
12. Met a withdrawal criterion in the parent study (MVT-601-3001 or MVT-601-3002). 
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 parent study.  This extension study is a single-arm study, and 
thus all eligible patients are assigned to the same treatment group of relugolix 40 mg 
co-administered with low-dose of estradiol and norethindrone acetate (see Section 5.1 for 
treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 52 visit defines completion of the study.  Patients may withdraw 
consent to participate in the study and discontinue treatment at any time for any reason.  
Investigators or the medical monitor may remove patients from therapy under this protocol for 
reasons of safety and/or lack of compliance as discussed below.  Patients removed from therapy 
for any reason will undergo the assessments for the Early Termination visit (see the Week 52 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication). 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• Any adverse event that is intolerable to the patient and that cannot be ameliorated by 
the use of adequate medical intervention, or that in the opinion of the investigator or 
medical monitor would lead to undue risk to the patient if dosing continued; 
• If it is discovered after enrollment that a patient failed to meet protocol entry criteria 
and continued participation poses an unacceptable risk to the patient’s health; 
• If the following liver test abnormalities develop, study drug should be discontinued 
immediately with appropriate clinical follow-up (including repeat laboratory tests, 
until a patient’s laboratory profile has returned to normal/baseline status): 
− ALT or AST > 8 x ULN; or 
− ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
− ALT or AST > 3 x ULN in conjunction with elevated total bilirubin > 2 x ULN or 
international normalized ratio (INR) > 1.5; or 
− ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%); 
• QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec 
read by a cardiologist; 
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• Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial 
biopsy; 
• If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or 
femoral neck compared with the parent study Baseline; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  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). 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous noncompliance.  In cases where the patient does not return for the rescheduled visit 
or cannot be reached to reschedule the missed visit, the site should make every effort to regain 
contact with the patient.  The site should attempt at least three documented telephone calls and if 
necessary a certified letter to the patient’s last known mailing address so that they can 
appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up.” 
4.6. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones for contraception are excluded, and 
patients must agree to use nonhormonal contraception throughout the study unless any of the 
following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure) at least 4 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
• Has a nonhormonal intrauterine device (eg, Paragard) placed in the uterus; 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of nonhormonal contraception as described below; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods 
do not apply are: 
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• Condom (male or female condom) with or without spermicide (cream, spray, foam, 
gel, suppository, or polymer film); 
• Diaphragm with spermicide (condom may or may not be used); 
• Cervical cap with spermicide (condom may or may not be used); or 
• Vaginal sponge impregnated with spermicide used with a condom. 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed at monthly intervals during the study (including just 
prior to receiving the first dose of study drug), and patients will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures.  Patients who become 
pregnant during the study will be withdrawn from the study and followed for pregnancy outcome 
(see Section 7.8). 
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5. 
TREATMENTS 
5.1. 
Treatments Administered 
In this extension study, all patients will receive the following open-label oral study treatment: 
• 28 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg 
estradiol and 0.5 mg norethindrone acetate. 
Each patient will be instructed to take one tablet and one capsule per day. 
Table 2: 
Description of MVT-601-3003 Study Drugs 
Name of Investigational 
Product 
Relugolix 
Estradiol / Norethindrone 
Acetate 
Formulation Description 
Round film-coated pink tablet 
A Swedish orange, over-
encapsulated round film-coated 
white tablet with back-fill 
material 
Dosage Form 
Tablet 
Capsule 
Unit Dose Strength 
40 mg 
Estradiol 1.0 mg / norethindrone 
acetate 0.5 mg 
Route of Administration/ 
Duration 
Oral once daily/ 
28 weeks 
Oral once daily/ 
28 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) and norethindrone acetate (0.5 mg) is a fixed-dose combination product. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using common 
excipients. 
The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
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5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
On Week 24/Baseline and Week 52 clinic visit days, study drug will be administered in the clinic 
rather than at home (see Schedule of Activities in Section 1.1). 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Study drug can be held for a period of up to 2 weeks for evaluation and treatment of an adverse 
event.  Patients may subsequently be re-started on study drug with the written approval of the 
sponsor (or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20°C to 25°C with excursion to 15°C to 30°C permitted until it is used or 
returned to the sponsor (or designee).  Study drug should be stored protected from light.  A daily 
temperature log of the drug storage area must be maintained every working day.  Study drug 
must be stored under the conditions specified on the label, and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Further guidance and information for final 
disposition of unused study drug are provided in the Study Reference Manual.  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. 
Relugolix 40 mg will be supplied to the study site in blister cards co-packaged with the 
estradiol/norethindrone acetate. 
5.7. 
Blinding 
Blinding is not applicable for this open-label extension study. 
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5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused and used study drug to each study visit.  Study drug 
accountability will be conducted and results will be recorded.  If a patient is persistently 
noncompliant with the study treatment (ie, failure to take 80% or more of the scheduled doses 
after the last visit or compliance values over 120%), it may be appropriate to withdraw the 
patient from the study.  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 3 provides examples of prohibited drug categories; however, it is not a comprehensive list 
of all restricted medications.  Drugs and drug classes in Table 3 are prohibited at any time during 
the study through the Follow-Up visit, except as noted in the table.  Consult the medical monitor 
if there is any uncertainty regarding patient use of a particular drug or drug class. 
Table 3: 
Prohibited Medications 
Drug Class 
Examples 
Comments 
Bisphosphonates 
alendronate 
etidronate 
zolendronic 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 
 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
 
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Drug Class 
Examples 
Comments 
Hormonal Contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
Nova Ring 
 
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 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 
Study drug may be held for a period of 
up to 2 weeks with medical monitor 
approval if short-term treatment with one 
of these medications is required (eg, to 
treat an infection). 
Moderate and Strong 
P-glycoprotein Inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
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 allowed 
 
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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 24/Baseline visit to the Week 52/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. 
5.9.2.2. 
Iron Therapy 
Women who enter the extension 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 a 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 24/Baseline visit until the patient’s final study visit unless urgently needed for patient 
safety. 
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6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities (see 
Section 1.1).  Study procedures are briefly described within Section 6.6.  Further details of the 
procedures are provided in the Study Reference Manual. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 2 periods:  Open-Label Treatment 
period and Safety Follow-Up period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3001 or MVT-601-3002 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study, and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• Informed consent; 
• Record concomitant medications; 
• Dispense study treatment; 
• Dispense feminine products and paper diary with instructions to begin recording 
information daily;Take study drug dose in clinic; and 
• Record adverse events, if any. 
Patients will commence taking their open-label treatment once daily, beginning on the day of the 
Week 24/Baseline visit and continuing through the Week 52 visit.  Following the 
Week 24/Baseline visit, on-treatment study visits will occur at Weeks 28, 32, 36, 40, 44, 48, and 
52. 
At each post-Week24/Baseline visit, patients will return their feminine products for alkaline 
hematin testing.  The paper diary will be reviewed at each visit.  A venous blood sample (for 
hemoglobin) must be collected each time feminine products are collected to be sent to the central 
laboratory conducting the alkaline hematin assessment.  The site must document the start and 
stop dates of the patient’s menses corresponding to the collected feminine products. 
Safety monitoring including physical examination, ECGs, clinical laboratory tests, pregnancy 
tests, and adverse event collection will occur at each visit.  Bone densitometry will occur at the 
Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  A transvaginal ultrasound 
(with or without a transabdominal ultrasound) will be performed at Week 24/Baseline and 
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Week 52/Early Termination.  An endometrial biopsy will have been performed at the parent 
study Week 24 visit for all patients who participated in MVT-601-3001 (see MVT-601-3001 
protocol for details) and in some patients who participated in MVT-601-3002 (see MVT-601-
3002 protocol for details). 
Study drug compliance will be reviewed at each visit. 
Fasting (other than water) for at least 8 hours is required prior to blood sampling on 
Week 24/Baseline and Week 52/Early Termination visits and for 1 hour after administration of 
the study drug in the clinic.  Laboratory requisitions must indicate whether or not the patient was 
not fasted for their chemistry and lipid testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 52 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 52; however, for 
patients whose last dose of study drug is during Week 32 or earlier, the following procedures do 
not need to be performed:  transvaginal ultrasound (with or without a transabdominal 
ultrasound), bone densitometry, and endometrial biopsy.  These procedures may be performed at 
the investigator’s discretion if they aid in follow-up of ongoing adverse events. 
Patients (including those who complete the Week 52 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
uterine fibroids, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 52 visit, then the Follow-up visit may be 
waived. 
The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the Follow-
up visit. 
At an Early Termination visit occurring on or after Week 36, patients with a bone mineral 
density loss of > 3 relative to the parent study Baseline measurement will undergo a follow-up 
bone densitometry scan at 6 (± 1) months and will be contacted to question them about 
medications and conditions (eg, pregnancy) that might affect bone mineral density through the 
time of follow-up bone densitometry.  If Early Termination occurs prior to Week 36, follow-up 
bone densitometry will be performed according to the requirements of the parent study.  The 
follow-up bone densitometry will be submitted for central reading. 
6.4. 
Continuation into Randomized Withdrawal Study 
Eligible patients may enter the 52-week randomized withdrawal study (MVT-601-035), which is 
conducted under a separate protocol.  Patients will provide separate informed consent to 
participate for Study MVT-601-035, which will enroll patients who responded to study treatment 
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in this study and randomize them to receive relugolix 40 mg co-administered with 1 mg estradiol 
and 0.5 mg norethindrone acetate, or placebo. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
investigator.  The date and reason for the Unscheduled visit should be recorded in the 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 needed.  See 
the Schedule of Activities (Section 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. 
6.6. 
Study Procedures 
6.6.1. 
Efficacy-Related Procedures 
6.6.1.1. 
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 collected at each visit until the patient completes 
treatment or terminates participation from the study prior to completing treatment.  The site must 
document the start and stop dates of the patient’s menses corresponding to the collected feminine 
products.  Each time the patient submits her feminine products from a menstrual cycle for 
analysis, a venous blood sample will be collected and sent to the laboratory.  Details regarding 
materials, process, and requirements for the menstrual blood loss collection will be provided in 
the Study Reference Manual. 
6.6.1.2. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal ultrasound will be performed for all subjects.  Once the transvaginal ultrasound is 
done, a transabdominal ultrasound, with or without saline or gel contrast, may also be done if the 
uterus cannot be adequately imaged on transvaginal ultrasound; for example, due to enlarged 
size.  Transvaginal ultrasound, with or without transabdominal ultrasound, is performed to 
determine uterine and myoma volumes and endometrial thickness.  To avoid inter-observer and 
inter-device variations, a single operator will be assigned to a patient and will perform each of 
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the ultrasound scans using the same device as far as possible; this single operator should be the 
same, if possible, as 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 x D2 x D3 x π / 6 
Where: 
D1 = the longest diameter of the myoma or uterus (unit of length:  cm) 
D2 = the longest diameter of the myoma or uterus that is perpendicular to D1 (unit of 
length:  cm) 
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.  
The largest myoma among those measurable at the Screening 1 visit of the parent study (see the 
MVT-601-3001 or MVT-601-3002 protocol) will continue to be measured throughout the 
extension study. 
Endometrial thickness will be locally assessed and recorded.  Saline or gel contrast may be used 
to supplement sonographic assessment of the endometrium, as needed. 
6.6.1.3. 
Endometrial Biopsy 
Per the parent study MVT-601-3001 protocol, an endometrial biopsy is performed for all 
subjects at the Week 24 visit, whereas per the parent study MVT-601-3002 protocol, an 
endometrial biopsy is performed at the Week 24 visit only if indicated (endometrial thickness at 
any location is ≥ 4 mm or if any other endometrial abnormality is visualized on the Week 24 
ultrasound).  If the required Week 24 biopsy is inadequate for diagnosis, it should be repeated, 
and a sample submitted to the central laboratory.  If the second sample is inadequate, ensure an 
endometrial thickness has been reported from the Week 24 transvaginal ultrasound and contact 
the medical monitor to review the findings.  Patients who have endometrial hyperplasia or 
endometrial carcinoma, will be withdrawn from study drug treatment and followed per 
instructions in the parent study protocol. 
Additional assessment of the effects of relugolix co-administered with low-dose estradiol and 
norethindrone acetate on the endometrium will be performed at Week 52 and submitted to the 
central laboratory.  If the Week 52 biopsy specimen is inadequate, the endometrial thickness 
reported at the Week 52 transvaginal ultrasound will be used to determine if further action is 
required: 
• Endometrial thickness ≤ 5 mm – no further action required. 
• Endometrial thickness > 5 mm at any location or any other endometrial abnormality – 
repeat endometrial sampling.  Contact medical monitor if second specimen is 
inadequate for diagnosis. 
Patients who decline endometrial sampling at Week 52 will not be prohibited from participating 
in the randomized withdrawal study. 
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Unscheduled endometrial biopsies may also be performed when medically indicated and as 
deemed necessary by the investigator.  The investigator should obtain approval from the sponsor 
to perform an unscheduled endometrial biopsy, unless urgently indicated.  Additional consent is 
not required in this circumstance. 
6.6.1.4. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum estradiol will be collected pre-dose at 
the visits indicated in the study Schedule of Activities (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory. 
6.6.1.5. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire was designed to measure a women’s self-assessment of 
menstrual blood loss and its impact on her social and leisure activities, physical activities, and 
ability to work (see Appendix 1).  The MIQ has undergone psychometric validation.  Patients 
will complete the MIQ at each study visit during the Open-Label Treatment period.  Patients will 
complete the MIQ at each visit at the site before other study procedures, such as blood draws and 
physical examinations, are performed. 
6.6.1.6. 
Uterine Fibroid Symptom – Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life score is used to evaluate the 
symptom severity and the quality of life of patients with uterine fibroids (see Appendix 1).  
Patients will complete the UFS-QoL questionnaire at the site at the Week 24/Baseline visit, 
Week 36, and Week 52/Early Termination visit before other study procedures, such as blood 
draws and physical examinations, are performed. 
6.6.1.7. 
European Quality of Life Five-Dimension Five-Level Scale 
The European Quality of Life Five-Dimension Five-Level Scale is a standardized instrument for 
use as a measure of health outcomes (see Appendix 2).  Mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression are each assessed on 5-point categorical scales ranging 
from “no problem” to “severe problem.” 
Patients will complete the EQ-5D-5L questionnaire at the site at the Week 24/Baseline visit and 
the Week 52/Early Termination visit before other study procedures, such as blood draws and 
physical examinations, are performed. 
6.6.1.8. 
Patient Diary 
All women enrolled in the study will be provided with a patient paper diary, along with detailed 
instructions for its use.  Patients will use the daily diary to record menstrual bleeding and use of 
feminine products.  The diary will be reviewed by study staff at each visit. 
6.6.2. 
Safety-Related Procedures 
6.6.2.1. 
Weight 
Patients should have weight measured while wearing indoor clothing and with shoes removed. 
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6.6.2.2. 
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. 
6.6.2.3. 
Physical and Gynecologic Examinations 
A complete physical examination will include head, ears, eyes, nose, mouth, thyroid, skin, heart 
and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.  All 
subsequent physical examinations should focus on signs and symptoms reported by the patient to 
assess for clinically significant changes from previous assessments. 
6.6.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities (see Section 1.1).  Laboratory 
requisition forms must be completed and samples must be clearly labelled with the Patient 
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 safety 
parameters will be provided to the site by the central laboratory.  The samples collected for 
clinical laboratory tests are listed in Table 4 . 
Table 4: 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatinine Kinase 
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 
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 
 
 
 
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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. 
6.6.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at Week 24 visit in the parent study and at the Week 52/Early 
Termination 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. 
6.6.2.6. 
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 used at each site and operated in the same 
scan mode for all scans for an individual patient, and should be the same as used for the patient 
during the parent study (MVT-601-3001 or MVT-601-3002).  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 subject will be monitored by a central radiology 
laboratory over the course of the study. 
Patients who experience a bone mineral density loss from the parent study Baseline of ≥ 7% at 
any of the anatomical sites assessed will be discontinued from the extension study.  Patients 
should be assessed for secondary causes of bone loss if determined necessary by the investigator 
and followed up to resolution if bone mineral density loss is determined by the investigator to be 
related to study drug. 
At Week 52 or an Early Termination visit occurring on or after Week 36, patients with a bone 
mineral density loss of > 3% at lumbar spine or total hip relative to parent study Baseline 
measurement will undergo another bone densitometry scan at 6 (± 1) months and will be 
contacted to obtain information about medications and conditions (eg, pregnancy) that might 
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affect bone mineral density through the time of the follow-up bone densitometry.  If Early 
Termination occurs prior to Week 36, follow-up bone densitometry will be performed according 
to the requirements of the parent study.  The follow-up bone densitometry will be submitted for 
central reading. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the follow-up bone densitometry scan at 6 (± 1) months conducted under this 
protocol may be waived. 
6.6.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the electronic case 
report form (eCRF).  Patients whose menses has not resumed as of the Follow-Up visit for whom 
there is no explanation for the lack of resumption (eg, medical procedure or medications) will be 
contacted again by telephone 3 (+ 0.5) months after the Follow-Up visit to determine if menses 
has resumed and will be asked about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), ECGs, bone mineral density assessments, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
Adverse event:  An adverse event is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or 
duration of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately); and 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least 
one of the following criteria: 
− Induces clinical signs or symptoms; 
− Requires active intervention; 
− Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an adverse event; 
• Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• Situations where an untoward medical event has not occurred (eg, planned 
hospitalization for an elective procedure, with elective defined as known or planned 
at the time of signing of the informed consent); 
• 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 
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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: 
1. Results in death; 
2. 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. 
3. Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from the Week 24/Baseline visit is 
not considered an adverse event. 
4. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect; 
6. 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 
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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 or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
each sign and symptom as an individual adverse event. 
Overdose and pregnancy in the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for uterine fibroids, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  Serious adverse events reported to the investigator after the 
safety reporting period should be reported to the sponsor if the investigator assesses the event as 
related to the study drug treatment. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
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7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
following definitions are to be used for the relationship of the adverse event to study drug: 
• Probably related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely attributed to 
concurrent disease or other drugs or chemicals, and that follows a clinically 
reasonable response on readministration (rechallenge) or withdrawal (dechallenge). 
• Possibly related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug but that could also be 
explained by concurrent disease or other drugs or chemicals.  Information on drug 
withdrawal may be lacking or unclear. 
• Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable and/or 
in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
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 5 should 
be used to determine the grade severity. 
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Table 5: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE  
Grade
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
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 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 3. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
•
ALT or AST > 8 x ULN; or
•
ALT or AST > 5 x ULN and persists for more than 2 weeks; or
•
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or 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 24/Baseline values.  The investigator and sponsor must discuss and agree with any 
decision to rechallenge. 
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Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 0 0 3 
A me n d me nt 1, 1 8 Oct o ber 2 0 1 8 
M y o va nt Scie nces G m b H  
5 4 
C O N FI D E N TI A L  
Rec halle n ge s h o ul d n ot o cc ur w h e n  t he eti ol o g y of t he li ver test a b n or malities is c o nsi dere d 
p ossi bl y dr u g i n d uce d. 
7. 5. 2.  
Criteri a f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g i n Ass oci ati o n w it h Li ver 
Test A b n or m aliti es  
St u d y dr u g treat me nt s h o ul d be disc o nti n ue d per m a ne ntl y if all of t he f oll o wi n g 4 criteria are 
met (ie,  p ote ntial se ver e dr u g-i n d uce d li ver i nj ur y/ H y’s la w cas e):  
1.  A S T or A L T i ncr eases t o ≥ 3 x U L N; A N D  
2.  T otal bilir u bi n i ncreases t o >  2 x U L N or I N R >  1. 5; A N D 
3.  Al kali ne p h os p hatase v al ue d oes n ot reac h 2 x U L N ; A N D 
4.  N o alter nati ve ca use e x plai ns t he c o m bi nati o n of t he a b o ve la b orat or y a b n or malities; 
i m p orta nt alter nati ve ca uses i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g: 
a. He pat o biliar y tract diseas e ; 
b.  Viral he patitis (e g, he p atitis A/ B/ C/ D/ E, E pstei n -Barr vir us) ; 
c. E x p os ure t o he pat ot o xic a ge nts/ dr u gs or he p at ot o xi ns, i ncl u di n g her b al a n d dietar y 
s u p ple me nts, pla nts, a n d m us hr o o ms; 
d.  Alc o h olic he patitis ; 
e. N o nalc o h olic steat o he p atitis;  
f. A ut oi m m u ne he patitis.  
If a n alter nati ve ca use for he pat ot o xicit y is i de ntifi e d, t he n it s h o ul d be deter mi ne d ( base d o n t he 
se verit y of t he he p at ot o xicit y or e ve nt) w h et her st u d y dr u g treat me nt sh o ul d be wit h hel d or 
per ma ne ntl y disc o nti n ue d as a p pr o priat e f or t he s afet y of t he p atie nt. 
7. 6.  
Seri o us A d verse E ve nt Re p orti n g  
Usi n g a Safet y Re p ort  F or m, all seri o us a d vers e e v e nts m ust be re p orte d wit hi n 2 4  h o urs of t he 
st u d y site pers o n nel’s k n o wle d ge of t he e ve nt , re gar dless of t h e i n vesti gat or assess me nt of t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g. 
T he c o ntact i nf or mati o n f or s u b missi o n of seri o us a d verse e ve nts , a d v erse e ve nts of cli nical 
i nterest, a n d e v e nts of o v er d ose is a vaila bl e o n t he seri o us a d vers e ev e nt re p ort f or m  a n d is as 
f oll o ws: 
Se n d c o m plete d S af et y Re p ort  F or ms t o Q ui ntilesI M S S afet y: 
Site L oc ati o n 
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber 
( Sec o n d ar y re p orti n g met h o d) 
All st u d y  sites 
 
 
 
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P P D
P P D


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 0 0 3 
A me n d me nt 1, 1 8 Oct o ber 2 0 1 8 
M y o va nt Scie nces G m b H  
5 5 
C O N FI D E N TI A L  
F or q uesti o ns o n Seri o us A d verse E ve nt /A d vers e E ve nt of Cli nic al I nterest  re p orti n g, 
ple ase c all : 
•  N ort h/ S o ut h A merica :  
 
•  E ur o pe, Asia, Pacific, a n d Africa:  see re gi o n-s pecific p h o ne n u m bers acc o m pa n yi n g 
t he Safet y Re p ort  F or m  
T he i nitial re p ort s h o ul d i ncl u de: 
•  St u d y n u m b er ( M V T - 6 0 1- 3 0 0 3); 
•  Site a d dress  a n d n u m ber; 
•  I n v esti gat or na me; 
•  Patie nt I de ntifi cati o n N u m ber, se x, a n d a ge; 
•  Details of st u d y dr u g a d mi nistrati o n ; 
•  T he date of t h e re p ort ; 
•  A descri pti o n of t he seri o us a d verse e ve nt (e ve nt t er m, seri o us ness of t h e e ve nt , date 
of o nset, i nte nsit y); 
•  Ca usal relati o ns hi p t o t he st u d y dr u g. 
If t he patie nt die d, t he re p ort s h o ul d i ncl u de t he ca use of deat h as t he e v e nt ter m ( wit h deat h as 
o utc o me) a n d w h et her or n ot t he e ve nt lea di n g t o deat h was relate d t o st u d y dr u g treat me nt, as 
well as t he a ut o ps y fi n di n gs if a v aila ble.  
D o n ot dela y re p orti n g a s us pecte d seri o us a d vers e e ve nt i n or der t o o btai n a d diti o nal 
i nf or mati o n.  A n y a d diti o nal i nf or mati o n, if c ollect e d, ca n b e re p orte d as a f oll o w- u p t o t he 
i nitial re p ort.  All seri o us a d verse e ve nts will be f oll o we d u ntil res ol uti o n, u ntil t he e ve nt has 
sta bilize d, a n d/ or reac h e d a ne w bas eli ne.  All seri o us a d verse e ve nts c o nti n ui n g at t he 
c o m pleti o n of t he st u d y m ust be assesse d or f oll o we d t o deter mi ne o utc o m e. 
7. 7.  
St u d y Dr u g  O ver d ose  M a n a ge me nt  
T he m e dical m o nit or m ust be c o ntacte d i n t he e ve nt of a n y st u d y dr u g o ver d ose. 
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of st u d y dr u g, t o or b y 
a st u d y p atie n t, at a d ose a b o ve t hat assi g ne d t o t h at i n di vi d ual patie n t acc or di n g t o t he st u d y 
pr ot oc ol. 
F or t his st u d y, a n y d ose of rel u g oli x > 8 0 m g  wit hi n a 2 4- h o ur wi n d o w is a n o ver d ose a n d a n y 
d ose of estra di ol/ n oret hi n dr o ne acetate > 2 x t he pr ot oc ol d ose is a n o ver d os e (ie, m ore t h a n 
2 ca ps ules  ta ke n wit hi n a 2 4- h o ur wi n d o w).  T h ere is n o k n o w n a nti d ote f or a n o ver d os e. 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or or treati n g p h ysicia n s h o ul d: 
•  C o ntact t he m e dical m o nit or i m me diatel y;  
•  Cl osel y m o nit or t he patie n t f or a d vers e e v e nts  a n d la b orat or y a b n or malities ; 
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• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form according to Section 7.6, whether or not the 
overdose is associated with an adverse event; 
• If possible, obtain a plasma sample for pharmacokinetic analysis within 2 days from 
the date of the last dose of study drug if requested by the medical monitor 
(determined on a case-by-case basis); 
• Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy 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 this 
information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures 
Section 6.6.2 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 (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on the heavy menstrual bleeding associated with uterine 
fibroids.  Low-dose hormonal add-back therapy with estradiol and norethindrone acetate will be 
evaluated for maintenance of bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT 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 
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the addition of estradiol/norethindrone acetate.  Summaries of findings from both nonclinical and 
clinical studies conducted with relugolix can be found in the current version of the investigator 
brochure. 
The risk assessment and mitigation strategy for this protocol are outlined in Table 6 . 
Table 6: 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
and Week 52/Early 
Termination visits with 
specified discontinuation and 
follow-up criteria and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
period will be reported 
within 24 hours of study 
personnel awareness. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Phospholipidosis 
Data from nonclinical studies in rats and 
monkeys showed histopathological 
changes consistent with PLD.  PLD by 
itself is not adverse.  No clinical evidence 
of relugolix-related PLD-associated 
toxicity has been observed nor was there a 
clinically meaningful increase in a 
biomarker of PLD assessed in phase 2 
clinical studies. 
Patients with significant 
underlying medical 
conditions are excluded. 
Routine safety monitoring 
including laboratory 
assessments, ECGs, and 
assessment of adverse 
events, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
Metabolic Changes 
Metabolic changes (insulin resistance, 
dyslipidemia, and increased weight) with 
increased risk of diabetes are a potential 
risk of the hypoestrogenic state induced by 
relugolix. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each visit. 
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8. 
DATA QUALITY ASSURANCE 
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the Study 
Reference Manual with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice (GCP) regulations.  By signing this protocol, the investigator grants permission 
to Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-
site monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and GCP.  The study monitor should have access to 
laboratory test results and any other source records and data needed to verify the entries on the 
eCRF.  The investigator agrees to cooperate with the study monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved.  For this study, patient data will be 
entered into a sponsor-approved electronic database and combined with data provided from other 
sources in validated datasets then transmitted electronically to the sponsor (or designee). 
Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
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9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  Continuous data will be summarized by 
means, standard deviations, medians, maximum, minimum, and number of patients.  Categorical 
data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 28 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the Intent-to-Treat Population, defined as all patients 
who were randomized in a parent study and who have received any amount of study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of study drug. 
The analyses methods for safety and efficacy endpoints are similar to those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the numbers of patients 
who have completed either parent study (MVT-601-3001 or MVT-601-3002) and who are 
eligible and willing to participate in this study.  It is estimated that approximately 600 patients 
(75% of 780 patients who will be randomized in total into the parent studies) will participate in 
this extension study. 
9.4. 
Efficacy Analyses 
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies. 
• Proportion of women who achieve or maintain a menstrual blood loss volume of < 80 
mL AND at least a 50% reduction from parent study Baseline to the last 35 days of 
treatment, as measured by the alkaline hematin method. 
• Time to achieve a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction from parent study Baseline menstrual blood loss volume as measured by the 
alkaline hematin method; 
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• Change from parent study Baseline to Week 52 in menstrual blood loss; 
• Proportion of women who achieve or maintain amenorrhea over the last 35 days of 
treatment; 
• Proportion of women with a hemoglobin below the lower limit of normal at parent 
study Baseline who achieve an increase of ≥ 1 g/dL from parent study Baseline at 
Week 52; 
• Proportion of women with a hemoglobin below the lower limit of normal at parent 
study Baseline who achieve a normal hemoglobin at Week 52; 
• Change from parent study Baseline to Week 52 in hemoglobin; 
• Change from parent study Baseline to Week 52 in the Uterine Fibroid Scale – 
Symptom Severity; 
• Change from parent study Baseline to Week 52 in the Uterine Fibroid Scale – Health-
related Quality of Life subscales and total score; 
• Change from parent study Baseline to Week 52 in the MIQ score for physical 
activities; 
• Change from parent study Baseline to Week 52 in the MIQ score for social and 
leisure activities; 
• Change from parent study Baseline to Week 52 in uterine volume; 
• Change from parent study Baseline to Week 52 in uterine fibroid volume. 
The point estimate and 2-sided 95% confidence interval (CI) for the responder rate (defined as 
proportion of women who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from the parent study Baseline in menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method), will be calculated for each 
parent study treatment group. 
Baseline menstrual blood loss is defined as the average menstrual blood loss from the two 
Screening menstrual cycles used to meet the inclusion criteria prior to the date of the first dose of 
study drug in the parent study as assessed by the alkaline hematin method.  The menstrual blood 
loss during the last on-treatment cycle (Week 52) is the total menstrual blood loss during the last 
35 days on treatment as assessed by the alkaline hematin method. 
Patients from Group C, who discontinue the extension study before Week 32 (28 days) will be 
considered non-responders. 
For the endpoints of time to achieving a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from parent study Baseline menstrual blood loss volume, time to event will be 
defined as weeks from randomization in the parent study to first occurrence of the event as 
assessed by the alkaline hematin method.  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 parent study treatment arm. 
Descriptive statistics will be provided for changes in menstrual blood loss, hemoglobin, Uterine 
Fibroid Scale – Symptom Severity, Menorrhagia Impact Questionnaire Score, Numerical Rating 
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Scale score for uterine fibroid-associated pain, uterine volume, and uterine fibroid volume to 
parent study Baseline. 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, and 12-lead ECGs. 
The treatment-emergent period will be defined as the period of time from the first dose date of 
study drug in the parent study 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 parent study Baseline versus post-baseline results.  All data will be listed and 
summarized by visit.  The change from parent study Baseline to each post-baseline study visit 
will be presented by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  ECGs will also be read 
centrally.  The distributions of QTc interval will be summarized at each visit.  All data will be 
listed and summarized by visit.  The change from parent study Baseline to each post-baseline 
study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
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Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for % change at Week 52 
from parent study Baseline in bone mineral density will be provided based on mixed effects 
model (assumed missing at random) for each parent study treatment group. 
All data will be listed and summarized by visit.  The change, percent change from parent study 
Baseline to Weeks 36 and 52 and associated 95% CIs will be presented by the parent study 
treatment group for each bone mineral density parameter.  The number and percentage of 
patients meeting a bone mineral density decline of at least 4%, 5%, 6%, or 7% by body area 
(lumbar spine, total hip, or femoral neck) will be estimated with 95% CIs by the parent study 
treatment group. 
Additional analyses will be performed to 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. 
Pharmacodynamic Analyses 
The change from the parent study Baseline to Week 52 in pre-dose concentrations of serum 
estradiol will be summarized.  Percentage of patients with concentrations of serum estradiol 
levels < 10 pg/mL and < 20 pg/mL will be provided. 
9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed: 
• Change from parent study Baseline to Week 52 in the European Quality of Life Five-
Dimension Five-Level scale. 
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10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Council on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a US investigational new drug 
application, the investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR 312), subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, are adhered to.  These 
standards are consistent with the requirements of the European Community Directive 
2001/20/EC. 
Since this is a “covered” clinical study, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical study is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.”  This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with the sponsor, or proprietary interests in the drug being studied.  This 
documentation must be provided before participation of the investigator and any sub-
investigator.  The investigator and sub-investigator agree to notify the sponsor of any change in 
reportable interests during the study and for 1 year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient. 
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10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the investigator brochure, protocol, eCRFs and other study forms, the investigational drug, and 
any other study information, remain the sole and exclusive property of the sponsor during the 
conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
10.1.5. 
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 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: 
a. Patient identification (name, date of birth, gender); 
b. Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
c. Participation in the study (including study number); 
d. Study discussed and date of informed consent; 
e. Dates of all visits; 
f. Documentation that protocol-specific procedures were performed; 
g. Results of efficacy parameters, as required by the protocol; 
h. Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
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i. Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
j. Concomitant medication (including start and end date); and 
k. Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified.  
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with the sponsor.  The investigator must 
notify the sponsor before destroying any clinical study records. 
Clinical study documentation includes the investigator brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, decoding procedures for blinded studies, 
curriculum vitae and all training records of study site personnel, and all correspondence 
pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
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 (ie, 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 
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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. 
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 
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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. 
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). 
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The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 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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11. 
REFERENCES 
ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of 
Leiomyomas. Obstetrics & Gynecology 2008;112(2 Part 1):387-400. 
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 Auguest 2017. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. American 
Journal of Obstetrics and Gynecology 1992;166(2):740-5. 
Cardozo ER. The estimated annual cost of uterine leiomyomata in the United States. American 
Journal of Obstetrics and Gynecology 2012;206(3):0092-0100. 
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://www.effectivehealthcare.ahrq.gov/ehc/products/152/642/DEcIDE31_UterineFibro
id_03-07-2011.pdf. Accessed: 03 August 2017. 
Hallberg L, Nilsson L. Determination of menstrual blood loss. Scand J Clin Lab Invest. 
1964;16(2):244–248. 
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. 
Kliovance Summary of Product Characteristics (SmPC).  Novo Nordisk Limited, Sussex, UK.  
Revised March 2016. 
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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. Clinical Practice. Uterine Fibroids. N Engl J Med. 2015;372(17):1646-55. 
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 
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APPENDIX 1. MENORRHAGIA IMPACT QUESTIONNAIRE 
In addition to the MIQ items listed in the table, patients describe all activities that were limited 
by excessive bleeding (MIQ item 5). 
Copyright ©, Ferring B.V., all rights reserved. 
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APPENDIX 2. UTERINE FIBROID SYMPTOM AND QUALITY OF LIFE 
QUESTIONNAIRE 
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APPENDIX 3. EUROPEAN QUALITY OF LIFE FIVE-DIMENSION 
FIVE-LEVEL SCALE 
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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
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APPENDIX 4. ASSESSMENT OF ABNORMAL LIVER TESTS 
Study drug treatment (relugolix co-administered with low-dose estradiol and norethindrone 
acetate) should be withheld for any liver test abnormality listed in Section 7.5.1, pending 
investigation of alternative causes of liver injury.  Follow-up should continue until the liver test 
abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations in 
Appendix Table 2.  If close monitoring is not possible, study drug should be withheld even if the 
results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]), Alkaline 
Phosphatase, and INR Tests 
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities 
improve 
If ALT or AST ≥ 3 × ULN and total 
bilirubin and INR are normal  
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve 
AND the patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international 
normalized ratio; ULN, upper limit of normal 
a. 
Review frequency of monitoring with medical monitor for an individual patient, in case of 
questions. 
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Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
• 
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and 
fever); 
• 
Prior and concurrent disease or illnesses; 
• 
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or 
coworkers, etc) and/or industrial chemical agents; 
• 
Prior and concurrent use of alcohol, recreational drugs, and special diets; 
• 
Concomitant use of medications (including nonprescription medicines and herbal and dietary 
supplements), plants and mushrooms; 
• 
Physical examination. 
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
• 
Repeat liver tests as per Appendix Table 1a; 
• 
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat 
liver tests; 
• 
CBC with differential to assess for eosinophilia; 
• 
Serum acetaminophen (paracetamol) concentration; 
• 
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus; 
• 
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune 
hepatitis, etc; 
• 
Serology for celiac disease; 
• 
Appropriate liver imaging; 
• 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or 
gastroenterologist). 
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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1 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
LIBERTY EXTENSION:  An International Phase 3 Open-
Label, Single-Arm, Long-Term Efficacy and Safety Extension 
Study to Evaluate Relugolix Co-Administered with Low-Dose 
Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3003 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
c/o Vischer AG 
Aeschenvorstadt 4 
CH-4010 Basel 
Switzerland 
Regulatory Identifier(s): 
Eudra CT # 2017-003310-74 
IND # 131161 
Version and 
Effective Date: 
Original 
Effective:  08-AUG-2017 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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Pa ge 8 3
M V T- 6 0 1- 3 0 0 3 C S R - A p pe n di x 1 6. 1. 1. Pr ot oc ol a n d Pr ot oc ol A me n d me nts
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Clinical Study Protocol:  MVT-601-3003 
 
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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 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR STATEMENT ...................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SYNOPSIS .............................................................................................9 
1.1. 
Schedule of Activities .................................................................................................16 
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 ..............................................................23 
4. 
INVESTIGATIONAL PLAN .....................................................................................26 
4.1. 
Overall Study Design ..................................................................................................26 
4.2. 
Discussion of Study Design, Including Dosing ..........................................................27 
4.3. 
Selection of Study Population ....................................................................................29 
4.3.1. 
Inclusion Criteria ........................................................................................................30 
4.3.2. 
Exclusion Criteria .......................................................................................................30 
4.4. 
Method of Assigning Patients to Treatment Group and Patient ID Number ..............32 
4.5. 
Removal of Patients from Therapy .............................................................................32 
4.6. 
Contraception/Pregnancy Avoidance .........................................................................33 
5. 
TREATMENTS ..........................................................................................................35 
5.1. 
Treatments Administered ............................................................................................35 
5.2. 
Identity of Investigational Product .............................................................................35 
5.2.1. 
Product Characteristics ...............................................................................................35 
5.3. 
Randomization and Stratification ...............................................................................35 
5.4. 
Directions for Administration .....................................................................................36 
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5.5. 
Dose Reduction/Dose Administration ........................................................................36 
5.6. 
Storage, Packaging, and Labeling ..............................................................................36 
5.7. 
Blinding ......................................................................................................................37 
5.8. 
Study Drug Accountability and Treatment Compliance ............................................37 
5.9. 
Prior and Concomitant Medications and Non-Drug Therapies ..................................37 
5.9.1. 
Prohibited Medications ...............................................................................................37 
5.9.2. 
Permitted Medications ................................................................................................39 
5.9.3. 
Prohibited Non-Drug Therapies .................................................................................40 
6. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
6.1. 
Schedule of Observations and Procedures ..................................................................41 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) ................................41 
6.3. 
Early Termination Visit and Follow-up Visit .............................................................42 
6.4. 
Unscheduled Visits .....................................................................................................42 
6.5. 
Study Procedures ........................................................................................................43 
6.5.1. 
Efficacy-Related Procedures ......................................................................................43 
6.5.2. 
Safety-Related Procedures ..........................................................................................45 
7. 
SAFETY CONSIDERATIONS ..................................................................................48 
7.1. 
Adverse Event Definitions ..........................................................................................48 
7.1.1. 
Adverse Event .............................................................................................................48 
7.1.2. 
Serious Adverse Event ................................................................................................49 
7.2. 
Adverse Event Reporting ............................................................................................50 
7.2.1. 
Adverse Event Reporting Period ................................................................................50 
7.3. 
Assigning Causal Relationship to Study Drug ...........................................................51 
7.4. 
Assigning Severity Rating for Adverse Events ..........................................................51 
7.5. 
Adverse Events of Clinical Interest Reporting ...........................................................52 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities ......................................................................................................52 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities ............................................................................................53 
7.6. 
Serious Adverse Event Reporting ...............................................................................53 
7.7. 
Study Drug Overdose Management ............................................................................54 
7.8. 
Pregnancy Reporting ..................................................................................................55 
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7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, 
Electrocardiograms, and Bone Mineral Density Measures ........................................55 
7.10. 
Benefit/Risk Assessment ............................................................................................55 
8. 
DATA QUALITY ASSURANCE ..............................................................................58 
8.1. 
Clinical Procedures .....................................................................................................58 
8.2. 
Monitoring ..................................................................................................................58 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................59 
9.1. 
Randomization Methods .............................................................................................59 
9.2. 
Analysis Populations ..................................................................................................59 
9.3. 
Sample Size Estimation ..............................................................................................59 
9.4. 
Efficacy Analyses .......................................................................................................59 
9.5. 
Safety Analyses ..........................................................................................................61 
9.6. 
Pharmacodynamic Analyses .......................................................................................62 
9.7. 
Exploratory Analyses ..................................................................................................62 
10. 
RESPONSIBILITIES .................................................................................................63 
10.1. 
Investigator Responsibilities .......................................................................................63 
10.1.1. 
Good Clinical Practice ................................................................................................63 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................63 
10.1.3. 
Informed Consent .......................................................................................................63 
10.1.4. 
Confidentiality ............................................................................................................64 
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 ......................................................................66 
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 ...............................................................................................................67 
10.2.3. 
Posting of Information on Publically Available Clinical Trial Registers ...................67 
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 
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10.3.3. 
Study Discontinuation ................................................................................................67 
10.3.4. 
Publications .................................................................................................................67 
11.
REFERENCES ...........................................................................................................69
APPENDICES ...............................................................................................................................71 
Appendix 1. Menorrhagia Impact Questionnaire ........................................................................71 
Appendix 2. Uterine Fibroid Symptom and Quality of Life Questionnaire................................72 
Appendix 3. European Quality of Life Five-Dimension Five-Level Scale.................................75 
Appendix 4. Assessment of Abnormal Liver Tests.....................................................................77 
LIST OF TABLES 
Table 1-1 Schedule of Activities for Study MVT-601-3003 ......................................................16 
Table 5-1 Description of MVT-601-3003 Study Drugs ..............................................................35 
Table 5-2 Prohibited Medications ...............................................................................................37 
Table 6-1 Clinical Laboratory Tests ...........................................................................................46 
Table 7-1 Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................52 
Table 7-2 Protocol Risk Assessment and Mitigation Strategies .................................................56 
Appendix 4 Table 1 Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .........77 
Appendix 4 Table 2 Investigations of Alternative Causes for Abnormal Liver Tests ................78 
LIST OF FIGURES 
Figure 4-1 MVT-601-3003 Study Schematic ...............................................................................27 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dihyroepiandrosterone 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
gonadotropin-releasing hormone 
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 
MIQ 
Menorrhagia Impact Questionnaire 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT interval by the Fridericia correction 
RBC 
red blood cell 
SAP 
statistical analysis plan 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cells 
 
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1.
PROTOCOL SYNOPSIS
Study Title 
LIBERTY EXTENSION:  An International Phase 3 Open-Label, Single-Arm, 
Long-Term Efficacy and Safety Extension Study to Evaluate Relugolix 
Co-Administered with Low-Dose Estradiol and Norethindrone Acetate in 
Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number 
MVT-601-3003 
Location 
Multinational, including North and South America, Europe, and South Africa 
Study Centers 
Approximately 240 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 51 years diagnosed with heavy menstrual bleeding 
associated with uterine fibroids 
Number of Patients 
Planned 
Approximately 600 
Study Objectives 
In women with heavy menstrual bleeding associated with uterine fibroids, the 
study objectives are as follows: 
Primary Efficacy Objective 
•
To evaluate long-term efficacy of relugolix 40 mg once daily
co-administered with low-dose estradiol and norethindrone acetate for up
to 52 weeks, among patients who previously completed a 24-week
treatment period in one of the parent studies (MVT-601-3001 or
MVT-601-3002), on heavy menstrual bleeding associated with uterine
fibroids
Secondary Efficacy Objectives 
•
To evaluate long-term efficacy of relugolix 40 mg once daily
co-administered with low-dose estradiol and norethindrone acetate for up
to 52 weeks, among patients who previously completed a 24-week
treatment period in one of the parent studies (MVT-601-3001 or
MVT-601-3002), on the following:
o
Achievement/maintenance of amenorrhea;
o
Hemoglobin;
o
Changes in symptom severity and quality of life related to uterine
fibroids as measured by the Uterine Fibroid Symptom and Health-
Related Quality of Life (UFS-QoL);
o
Impact of heavy menstrual bleeding on social, leisure, and physical
activities as measured by the Menorrhagia Impact Questionnaire
(MIQ);
o
Uterine volume;
o
Uterine fibroid volume.
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Safety Objectives 
•
To evaluate the safety of relugolix 40 mg once daily co-administered with
low-dose estradiol and norethindrone acetate for up to 52 weeks, among
patients who previously completed a 24-week treatment period in one of
the parent studies (MVT-601-3001 or MVT-601-3002), including:
o
Adverse events;
o
Changes in bone mineral density.
Pharmacodynamic Objective 
•
To evaluate the pharmacodynamic effects of relugolix 40 mg once daily
co-administered with low-dose estradiol and norethindrone acetate for up
to 52 weeks, among patients who previously completed a 24-week
treatment period in one of the parent studies (MVT-601-3001 or
MVT-601-3002), on estradiol.
Exploratory Objective 
•
To evaluate the benefit of relugolix 40 mg once daily co-administered
with low-dose estradiol and norethindrone acetate on patient-reported
quality of life outcomes (European Quality of Life Five-Dimension Five-
Level Scale [EQ-5D-5L]) for up to 52 weeks among patients who
previously completed a 24-week treatment period in one of the parent
studies (MVT-601-3001 or MVT-601-3002).
Study Design 
The LIBERTY EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety extension study that will enroll eligible patients who have completed their 
participation in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3001 or MVT-601-3002).  All patients will receive oral relugolix 40 mg once daily 
co-administered with low-dose estradiol 1.0 mg and norethindrone acetate 0.5 mg for up to 28 weeks.  
Approximately 600 women with heavy menstrual bleeding associated with uterine fibroids will be 
enrolled.  The objectives of the study are to evaluate long-term efficacy and safety through up to 
52 weeks of treatment (including treatment during the parent study) with relugolix co-administered 
with low-dose estradiol/norethindrone acetate. Eligible patients will have completed participation in 
one of the parent studies and consented to participate in this extension study. Screening and baseline 
procedures will be done at the same visit for this extension study (referred to as the “Week 24/Baseline 
visit” in this study), which coincides with the Week 24 visit from the parent study, and will be defined 
as the date of completion of the last Week 24 procedure in the parent study. The Week 24/Baseline visit 
will include vital signs, physical examination, laboratory assessments, a 12-lead electrocardiogram 
(ECG), bone densitometry, patient-reported outcome assessments, transvaginal ultrasound, and 
endometrial biopsy (if required). When Week 24 procedures in the parent study have been completed, 
the investigator will assess patient eligibility for participation in the open-label extension study.  The 
eligibility assessment will be based on data available at the Week 24/Baseline visit.  No 
MVT-601-3003 study procedures will be performed until the consent form for this extension study is 
signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in the 
clinic after the patient is determined to be eligible for this extension study and has provided informed 
consent to participate.  The administration of the first dose of study drug for MVT-601-3003 will define 
enrollment into this study.  Study participants will then take the open-label study treatment (relugolix 
40 mg co-administered with estradiol 1.0 mg and norethindrone acetate 0.5 mg) orally once daily for 
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28 weeks. 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment of 
bone mineral density via dual-energy x-ray absorptiometry (DXA).  Quality of life questionnaires will 
be completed according to the Schedule of Activities (Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, 
and transvaginal ultrasound. 
Patients with a bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit relative to the parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (± 1) months. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose menses has 
not resumed as of the Follow-Up visit for whom there is no explanation for the lack of resumption (eg, 
medical procedure or medications) will be contacted again by telephone 3 (+ 0.5) months after the 
Follow-Up visit to determine if menses has resumed and will be asked about factors that may affect 
resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 visit, 
then the Follow-up visit and the follow-up procedures performed under this protocol, including the 
follow-up bone densitometry scan at 6 (± 1) months and status of menstruation recover, may be waived. 
Inclusion/Exclusion Criteria 
Inclusion Criteria:  A woman will be eligible for enrollment in this study only if all of the following 
inclusion criteria apply and have been met at the time of the Week 24/Baseline visit: 
1.
Completed 24 weeks of study drug treatment and study participation in either MVT-601-3001 or
MVT-601-3002;
2.
Has voluntarily signed and dated the informed consent form prior to initiation of any screening or
study-specific procedures for MVT-601-3003;
Note:  Procedures conducted as part of the parent study that also serve as baseline procedures for
this study may be done under the informed consent for the parent study;
3.
Is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids within
the study period, including during the Safety Follow-Up period;
4.
Has a negative urine pregnancy test at the Week 24/Baseline visit;
5.
Agrees to continue to use acceptable nonhormonal contraceptive methods as described in
Section 4.6 consistently during the Open-Label Treatment period and for at least 30 days after the
last dose of study drug.  However, the patient is not required to use the specified nonhormonal
contraceptive methods if she:
a.
Has a sexual partner(s) who was vasectomized at least 6 months prior to the Week 24/Baseline
visit;
b.
Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at
least 4 months prior to the Week 24/Baseline visit (patients with Essure must have prior
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence of
post-Essure syndrome;
c.
Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus;
d.
Is not sexually active with men; periodic sexual relationship(s) with men requires the use of
nonhormonal contraception as noted above;
e.
Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic
abstinence is not acceptable.
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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 (MVT-601-3001 or MVT-601-3002);
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 (eg, bilateral hip
replacement, spinal hardware in the lumbar spine);
3.
Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent study
Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 24 DXA
assessment of bone mineral density;
4.
Anticipated to use any prohibited medications as detailed in Section 5.9.1;
5.
Has any contraindication to treatment with low-dose estradiol and norethindrone acetate,
including:
a.
Known, suspected, or history of breast cancer;
b.
Known or suspected estrogen-dependent neoplasia;
c.
Active deep vein thrombosis or pulmonary embolism, or history of these conditions prior to
the Week 24/Baseline visit;
d.
History of or active arterial thromboembolic disease, including stroke and myocardial
infarction;
e.
Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or norethindrone
acetate;
f.
Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia
disorders, including Factor V Leiden;
g.
Migraine with aura;
h.
History of porphyria;
6.
Has current active liver disease from any cause;
7.
Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s syndrome,
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic
syndromes, etc).  Psoriasis not requiring or anticipated to require systemic therapy is permitted;
8.
Had any of the following clinical laboratory abnormalities at the parent study Week 20 visit or any
subsequent visit in one of the parent studies (MVT-601-3001 or MVT-601-3002):
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);
9.
Is currently pregnant or lactating, or intends to become pregnant during the study period or within
1 month after the last dose of study drug, or plans to donate ova during the study period or within
2 months after the last dose of study drug;
10. Has a decline in presenting visual acuity score as defined below (unless explained by refractive
error or approved by the Sponsor):
a.
90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the parent study
Baseline visit; OR
b.
The presenting visual acuity score has decreased by 10 or more points at the
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Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  visual acuity score must have been obtained with corrective lenses, if applicable; 
11. 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. 
12. Met a withdrawal criterion in the parent study (MVT-601-3001 or MVT-601-3002). 
Dose and Route of 
Administration 
Test Product (all patients) 
• 
Relugolix 40 mg tablet will be co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The low-dose hormonal 
add-back therapy will be over-encapsulated.  Study treatment will be 
administered on an empty stomach. 
Duration of 
Treatment 
Study treatment will be self-administered for 28 weeks (Open-Label 
Treatment period). 
Criteria for 
Evaluation 
Descriptive assessments of long-term efficacy and safety will be made 
between the parent study Baseline and the end of the extension study 
(Week 52) for the following parent study treatment groups: 
• 
Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg 
once daily co-administered with 1.0 mg estradiol and 0.5 mg 
norethindrone acetate in the parent study; 
• 
Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg 
once daily followed by 12 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in 
the parent study; 
• 
Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for the extension 
study for all change from baseline-related endpoints.  The menstrual blood 
loss during the screening period of the parent study will establish the patient’s 
baseline for both the parent study and the extension study. 
 
Primary Efficacy Endpoint 
• 
Proportion of women who achieve or maintain a menstrual blood loss 
volume of < 80 mL AND at least a 50% reduction from parent study 
Baseline to the last 35 days of treatment, as measured by the alkaline 
hematin method. 
 
Secondary Efficacy Endpoints 
• 
Time to achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from parent study Baseline menstrual blood loss volume as 
measured by the alkaline hematin method; 
• 
Change from parent study Baseline to Week 52 in menstrual blood loss; 
• 
Proportion of women who achieve or maintain amenorrhea over the last 
35 days of treatment; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at parent study Baseline who achieve an increase of ≥ 1 g/dL from parent 
study Baseline at Week 52; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at parent study Baseline who achieve a normal hemoglobin at Week 52; 
• 
Change from parent study Baseline to Week 52 in hemoglobin; 
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•
Change from parent study Baseline to Week 52 in the Uterine Fibroid
Scale – Symptom Severity;
•
Change from parent study Baseline to Week 52 in the Uterine Fibroid
Scale – Health-related Quality of Life subscales and total score;
•
Change from parent study Baseline to Week 52 in the MIQ score for
physical activities;
•
Change from parent study Baseline to Week 52 in the MIQ score for
social and leisure activities;
•
Change from parent study Baseline to Week 52 in uterine volume;
•
Change from parent study Baseline to Week 52 in uterine fibroid volume.
Safety Endpoints 
•
Incidence of adverse events;
•
Percent change from the parent study Baseline to Week 52 in bone
mineral density at the lumbar spine (L1-L4), femoral neck, and total hip as
assessed by DXA.
Pharmacodynamic Endpoint 
•
Change from parent study Baseline to Week 52 in pre-dose concentrations
of serum estradiol.
Exploratory Endpoint 
•
Change from parent study Baseline to Week 52 in the EQ-5D-5L.
Statistical Methods 
Efficacy and safety data will be analyzed using descriptive statistics by the originally randomized 
treatment groups.  There will be no between-treatment group comparisons for the extension study data. 
Efficacy 
Efficacy data will be summarized by the original randomized treatment group assigned in the parent 
study (ie, Groups A, B, and C) for the Intent-to-Treat Population.  The analyses methods for efficacy 
endpoints are similar to those used for the parent studies, unless otherwise specified in the statistical 
analysis plan (SAP). 
The point estimate and 2-sided 95% confidence interval (CI) for the primary efficacy endpoint 
(responder rate defined as proportion of women who achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from parent study Baseline in menstrual blood loss volume over 
the last 35 days of treatment) will be calculated. 
The methods for analyzing the additional efficacy endpoints are described in the SAP. 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs and weight, physical 
examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with DXA, and transvaginal 
ultrasound.  Safety data analyses will use data from all patients from the parent studies who receive any 
amount of study drug (ie, from parent study Baseline to Week 52). 
Drug exposure will be summarized by descriptive statistics.  Severity of all treatment-emergent adverse 
events will be evaluated by the investigator based on the National Cancer Institute’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 parent study Baseline results to each of the subsequent visits will be produced. 
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Bone mineral density will be evaluated in all patients at the lumbar spine (L1-L4), femoral neck, and 
total hip at the Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  The absolute, 
change, and percent change from parent study Baseline and Z-scores will be summarized by visit and 
parent study treatment group. 
The mean percentage change at Week 52 from parent study Baseline in bone mineral density and 
corresponding 95% CI will be provided for each treatment group.  For patients who were randomized 
to 24 weeks of treatment with relugolix and add-back in the parent studies (Group A in MVT-601-3001 
or MVT-601-3002) and enrolled in the extension study, the lower bound of the 95% CI for mean 
percentage change at Week 52 from parent study Baseline in bone mineral density lumbar spine 
(L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to evaluate 
magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound is > -2.2%, the 
relugolix add-back treatment arm will be considered to have successfully prevented bone mineral 
density loss. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the number of patients who 
have completed a parent study (MVT-601-3001 or MVT-601-3002) and who are eligible and willing to 
participate in the extension study.  It is estimated that approximately 600 patients (75% of the total of 
780 patients who will be randomized into the parent studies) will participate in this study. 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3003 
PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/-3002) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 – 10 to + 20 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
- 
- 3 to + 18 
Informed Consent 
Xd 
 
 
 
 
 
 
 
 
 
Review Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medicationse 
Xf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, 
Temperature) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Weight 
Xg 
 
 
X 
 
 
 
X 
Xh 
 
Complete Physical Exam 
Xg 
 
 
 
 
 
 
X 
 
 
Visual Acuityi 
Xg 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-
Directed Physical Examj 
 
X 
X 
X 
X 
X 
X 
 
Xh 
X 
12-Lead ECGk 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Clinical Laboratory Testsl 
Xg,m 
X 
X 
X 
X 
X 
X 
Xm 
Xh 
X 
Pharmacodynamics 
Samplen 
Xg,m 
 
 
 
 
 
 
Xm 
Xh,m 
 
Urinalysis 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Pregnancy Test (Urine) 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
Transvaginal Ultrasoundo 
Xg 
 
 
 
 
 
 
Xp 
Xh 
 
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PERIOD 
OPEN-LABEL TREATMENT 
SAFETY 
FOLLOW-UP 
VISIT NAME 
(Timing is relative to 
MVT-601-3001/-3002) 
Week 24/Baseline 
(Week 24 of Parent 
Study; Baseline of 
Extension Study) 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 52a 
(or Early 
Termination of 
Study Drug) 
Un-
scheduledb 
Follow-Upc 
(~30 days 
after last dose 
of study drug) 
Visit Window (days) 
Parent Study Day 
169 – 10 to + 20 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
- 
- 3 to + 18 
Bone Densitometryq 
Xg 
 
 
X 
 
 
 
Xp,r 
Xh 
 
Endometrial Biopsy 
Xg,s 
 
 
 
 
 
 
 
Xh 
 
Dispense Study 
Treatment 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Dispense Feminine 
Products 
X 
X 
X 
X 
X 
X 
X 
 
Xh 
 
Feminine Product 
Collection and Venous 
Blood Samplet 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Treatment Compliance 
 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Take Study Drug Dose in 
Clinicu 
Xv 
 
 
 
 
 
 
X 
Xh 
 
Daily Self-Administration 
of Study Treatmentu 
 
X 
 
 
 
MIQw 
Xg 
X 
X 
X 
X 
X 
X 
X 
Xh 
X 
UFS-QoL Questionnairew 
Xg 
 
 
X 
 
 
 
X 
Xh 
 
EQ-5D-5L 
Questionnairew 
Xg 
 
 
 
 
 
 
X 
Xh 
 
Adverse Event 
Collectionx 
Xy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
Xz 
Abbreviations:  BP, blood pressure; ECG, electrocardiogram; EQ-5D-5L, European Quality of Life Five-Dimension Five-Level Scale; HR, heart rate; MIQ, Menorrhagia Impact 
Questionnaire; UFS-QoL, Uterine Fibroid Symptom and Health-Related Quality of Life 
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a. 
The Week 52 visit should occur on or after the 1-year anniversary of Study Day 1 of the parent study. 
b. Unscheduled visits may be conducted at the investigator’s discretion when needed.  The reason for the visit will be captured in the source documents. 
c. 
The Follow-up visit may be waived if the patient enrolls directly into another relugolix clinical study upon completion of the Week 52 visit. 
d. May be signed up to 30 days prior to the Week 24/Baseline visit or during the Week 24/Baseline visit.  Enrollment in MVT-601-3003 is defined by 
administration of the first dose of MVT-601-3003 study drug. 
e. 
Record all prescription and nonprescription drug and supplements taken from the Week 24/Baseline visit through the Safety Follow-Up period.  
Concomitant medications with start date prior to the first dose of study drug for MVT-601-3003 should be reported as concomitant medications in the parent 
study (MVT-601-3001 or MVT-601-3002).  If concomitant medication is ongoing at the time of the first dose of study drug for MVT-601-3003, please see 
the Study Reference Manual for instructions for recording the follow-up status. 
f. 
Concomitant medications are recorded both for the parent study and for MVT-601-3003 at the Week 24/Baseline visit.  (See footnote e for further details). 
g. This is a parent study (MVT-601-3001 or MVT-601-3002) Week 24 procedure that serves as the Week 24/Baseline procedure for MVT-601-3003 and is 
covered under the informed consent for the parent study. 
h. The indicated procedure may be performed at the Unscheduled visit based on the purpose of the visit (eg, follow-up for an adverse event or abnormal 
laboratory test). 
i. 
See parent study protocols (MVT-601-3001 or MVT-601-3002) for instructions on testing visual acuity. 
j. 
The exam may include a gynecologic examination, if indicated based on signs and symptoms. 
k. The 12-lead ECGs will be submitted for central reading. 
l. 
Clinical laboratory tests at each visit include clinical chemistries and a complete blood count.  At the Week 24/Baseline visit and Week 52 visit, additional 
tests include:  fasting (at least 8 hours) glucose, lipid profile, and hemoglobin A1c. 
m. Samples should be obtained in a fasted state (at least 8 hours).  Water is allowed during the fasting period. 
n. Pharmacodynamic samples:  For Week 24/Baseline samples, see the parent protocol (MVT-601-3001 or MVT-601-3002).  At Week 52/Early Termination, 
collect samples for analysis of estradiol concentrations only.  On days when pharmacodynamic samples are collected, administer the study treatment after 
the pharmacodynamic sample collections are completed. 
o. 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.  Note:  Transvaginal ultrasound is required.  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. 
p. This procedure is not required at the Early Termination visit in patients whose last dose of study drug was taken during Week 32 or earlier.  However, the 
procedure may be done if it will aid in the evaluation of an ongoing adverse event. 
q. Bone densitometry (L1-L4, total hip, femoral neck) will be submitted for central reading. 
r. 
Patients with a bone mineral density loss of > 3% at their Week 52/Early Termination visit relative to parent study Baseline measurement will undergo a 
follow-up bone densitometry scan at 6 (± 1) months and will be contacted to question them about medications and conditions (eg, pregnancy) that might 
affect bone mineral density through the time of follow-up bone densitometry.  The follow-up bone densitometry will be submitted for central reading. 
s. 
Endometrial biopsies are to be done per instructions in the parent study.  See the Laboratory Manual for guidance on handling and shipping the biopsy 
sample to the central laboratory for analysis.  An endometrial biopsy will have been performed at the parent study Week 24 visit for all patients who 
participated in MVT-601-3001 (see MVT-601-3001 protocol for details) and in some patients who participated in MVT-601-3002 (see MVT-601-3002 
protocol for details). 
t. 
A venous blood sample (for hemoglobin) must be collected each time feminine products are collected to be sent to the central laboratory conducting the 
alkaline hematin assessment.  The site must document the start and stop dates of the patient’s menses corresponding to the collected feminine products. 
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u. Patients will take the first dose of the study drug for this study once daily starting with the Week 24/Baseline visit (taken at the visit).  The first dose of study 
drug for this extension study must not be taken until all parent study Week 24 procedures such as laboratory tests have been completed.  The last dose of 
study drug will be taken in the clinic during the Week 52/Early Termination visit. 
v. Pregnancy test must be negative before the study drug dose is administered. 
w. The patient will enter her response(s) into an electronic tablet device at the site. 
x. Collect adverse events from the time that the first dose of study drug for MVT-601-3003 is administered.  Adverse events with onset prior to the first dose of 
study drug for MVT-601-3003 should be reported as an adverse event in the parent study (MVT-601-3001 or MVT-601-3002).  If events originating in the 
parent study are ongoing at the time of the first dose of study drug for MVT-601-3003, please see the Study Reference Manual for instructions for recording 
the follow-up status. 
y. Adverse events are collected for both the parent study and for MVT-601-3003 at the Week 24/Baseline visit (see footnote x for further details). 
z. 
Patients whose menses have not resumed as of the Follow-up visit for whom there is no explanation for the lack of resumption (eg, medical procedure or 
medications) will be contacted again by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and questioned about 
factors that may affect resumption of menses. 
 
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2. 
INTRODUCTION 
2.1. 
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 25% 
of women of reproductive age.  While the majority of uterine fibroids are asymptomatic, 
approximately 25% of women with fibroids develop symptoms requiring treatment.  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 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, 
and more than 200,000 hysterectomies are 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 
medicine that can decrease the symptoms of uterine fibroids and can be safely administered so 
that women have an option other than surgical procedures such as myomectomy and 
hysterectomy. 
2.2. 
Relugolix 
Summaries of nonclinical toxicology and previous human experience with relugolix, including 
results of phase 1 and phase 2 studies in women with uterine fibroids or endometriosis and in 
men with prostate cancer, are provided in the current relugolix investigator brochure, along with 
a full discussion of the safety profile of relugolix. 
2.2.1. 
Indication 
Relugolix co-administered with low-dose estradiol and norethindrone acetate is being developed 
as a once daily oral medication for the treatment of 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 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. 
Relugolix antagonizes the human GnRH receptors present on the gonadotropin-secreting cells of 
the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
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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 treated with relugolix had substantial reductions in 
reproductive organ weights of both female and male mice, suggesting that relugolix may 
suppress blood estrogen and testosterone levels, respectively.  Orally administered relugolix 
suppressed the hypothalamic-pituitary axis in castrated cynomolgus monkeys at doses of 
1 mg/kg and higher. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
The objectives of this extension study are to evaluate long-term efficacy and safety through up to 
52 weeks of treatment (including 24 weeks of treatment during the parent study) of relugolix 
co-administered with low-dose estradiol and norethindrone acetate. 
Descriptive assessments of efficacy and safety will be made between the parent study Baseline 
and the end of the extension study (Week 52) on the extension study population, defined as 
patients who enrolled in MVT-601-3003 (ie, who received at least 1 dose of study drug in the 
extension study), for the following parent study treatment groups: 
• Parent Study Group A:  Randomized to 24 weeks of oral relugolix 40 mg once daily 
co-administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate in the parent 
study; 
• Parent Study Group B:  Randomized to 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with 1.0 mg 
estradiol and 0.5 mg norethindrone acetate in the parent study; 
• Parent Study Group C:  Randomized to placebo in the parent study. 
The parent study Baseline will be used as the reference point for the extension study for all 
change from baseline-related endpoints.  The menstrual blood loss during the screening period of 
the parent study will establish the patient’s baseline for both the parent study and the extension 
study. 
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Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks, 
among patients who previously completed a 24-
week treatment period in one of the parent studies 
(MVT-601-3001 or MVT-601-3002), on heavy 
menstrual bleeding associated with uterine 
fibroids. 
• 
Proportion of women who achieve or maintain a 
menstrual blood loss volume of < 80 mL AND at 
least a 50% reduction from parent study Baseline 
to the last 35 days of treatment, as measured by the 
alkaline hematin method. 
Secondary Efficacy 
• 
To evaluate long-term efficacy of relugolix 40 mg 
once daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks, 
among patients who previously completed a 24-
week treatment period in one of the parent studies 
(MVT-601-3001 or MVT-601-3002), on the 
following: 
o 
Achievement/maintenance of amenorrhea; 
o 
Hemoglobin; 
o 
Changes in symptom severity and quality of 
life related to uterine fibroids as measured by 
the Uterine Fibroid Symptom and Health-
Related Quality of Life (UFS-QoL); 
o 
Impact of heavy menstrual bleeding on social, 
leisure, and physical activities as measured by 
the Menorrhagia Impact Questionnaire (MIQ); 
o 
Uterine volume; 
o 
Uterine fibroid volume. 
• 
Time to achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
parent study Baseline menstrual blood loss volume 
as measured by the alkaline hematin method; 
• 
Change from parent study Baseline to Week 52 in 
menstrual blood loss; 
• 
Proportion of women who achieve or maintain 
amenorrhea over the last 35 days of treatment; 
• 
Proportion of women with a hemoglobin below the 
lower limit of normal at parent study Baseline who 
achieve an increase of ≥ 1 g/dL from parent study 
Baseline at Week 52; 
• 
Proportion of women with a hemoglobin below the 
lower limit of normal at parent study Baseline who 
achieve a normal hemoglobin at Week 52; 
• 
Change from parent study Baseline to Week 52 in 
hemoglobin; 
• 
Change from parent study Baseline to Week 52 in 
the Uterine Fibroid Scale – Symptom Severity; 
• 
Change from parent study Baseline to Week 52 in 
the Uterine Fibroid Scale – Health-related Quality 
of Life subscales and total score; 
• 
Change from parent study Baseline to Week 52 in 
the MIQ score for physical activities; 
• 
Change from parent study Baseline to Week 52 in 
the MIQ score for social and leisure activities; 
• 
Change from parent study Baseline to Week 52 in 
uterine volume; 
• 
Change from parent study Baseline to Week 52 in 
uterine fibroid volume. 
Safety 
• 
To evaluate the safety of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate for up to 52 weeks, among 
patients who previously completed a 24-week 
treatment period in one of the parent studies 
(MVT-601-3001 or MVT-601-3002), including: 
o 
Adverse events; 
o 
Changes in bone mineral density. 
• 
Incidence of adverse events; 
• 
Percent change from the parent study Baseline to 
Week 52 in bone mineral density at the lumbar 
spine (L1-L4), femoral neck, and total hip as 
assessed by dual-energy x-ray absorptiometry 
(DXA). 
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Objective(s) 
Endpoint(s) 
Pharmacodynamic 
• 
To evaluate the pharmacodynamic effects of 
relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate for up 
to 52 weeks, among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3001 or MVT-601-
3002), on estradiol. 
• 
Change from parent study Baseline to Week 52 in 
pre-dose concentrations of serum estradiol. 
Exploratory 
• 
To evaluate the benefit of relugolix 40 mg once 
daily co-administered with low-dose estradiol and 
norethindrone acetate on patient-reported quality of 
life outcomes (European Quality of Life Five-
Dimension Five-Level Scale [EQ-5D-5L]) for up 
to 52 weeks among patients who previously 
completed a 24-week treatment period in one of 
the parent studies (MVT-601-3001 or MVT-601-
3002). 
• 
Change from parent study Baseline to Week 52 in 
the EQ-5D-5L. 
 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
The LIBERTY EXTENSION study (MVT-601-3003) is an international phase 3 open-label, 
single-arm, long-term efficacy and safety extension study that will enroll eligible patients who 
have completed their participation in one of the phase 3 randomized, double-blind, placebo-
controlled parent studies (MVT-601-3001 or MVT-601-3002).  All patients will receive oral 
relugolix 40 mg once daily co-administered with low-dose estradiol 1.0 mg and norethindrone 
acetate 0.5 mg for up to 28 weeks.  Approximately 600 women with heavy menstrual bleeding 
associated with uterine fibroids will be enrolled.  The objectives of the study are to evaluate 
long-term efficacy and safety through up to 52 weeks of treatment (including treatment during 
the parent study) with relugolix co-administered with low-dose estradiol/norethindrone acetate.  
Eligible patients will have completed participation in one of the parent studies and consented to 
participate in this extension study.  Screening and baseline procedures will be done at the same 
visit for this extension study (referred to as the “Week 24/Baseline visit” in this study), which 
coincides with the Week 24 visit from the parent study, and will be defined as the date of 
completion of the last Week 24 procedure in the parent study.  The Week 24/Baseline visit will 
include vital signs, physical examination, laboratory assessments, a 12-lead electrocardiogram 
(ECG), bone densitometry, patient-reported outcome assessments, transvaginal ultrasound, and 
endometrial biopsy (if required).  When Week 24 procedures in the parent study have been 
completed, the investigator will assess patient eligibility for participation in the open-label 
extension study.  The eligibility assessment will be based on data available at the Week 
24/Baseline visit.  No MVT-601-3003 study procedures will be performed until the consent form 
for this extension study is signed. 
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  The administration of the first dose of study drug for 
MVT-601-3003 will define enrollment into this study.  Study participants will then take the 
open-label study treatment (relugolix 40 mg co-administered with estradiol 1.0 mg and 
norethindrone acetate 0.5 mg) orally once daily for 28 weeks. 
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment 
of bone mineral density via DXA.  Quality of life questionnaires will be completed according to 
the Schedule of Activities (Section 1.1). 
Safety will be assessed throughout the study by the monitoring of adverse events, vital signs and 
weight, physical examinations, clinical laboratory tests, 12-lead ECG, bone mineral density with 
DXA, and transvaginal ultrasound. 
Patients with a bone mineral density loss of > 3% at the lumbar spine (L1-L4) or total hip at their 
Week 52/Early Termination visit relative to the parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (± 1) months. 
Status of menstruation recovery will be documented at the Follow-up visit.  Patients whose 
menses has not resumed as of the Follow-Up visit for whom there is no explanation for the lack 
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of resumption (eg, medical procedure or medications) will be contacted again by telephone 
3 (+ 0.5) months after the Follow-Up visit to determine if menses has resumed and will be asked 
about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the Follow-up visit and the follow-up procedures performed under this 
protocol, including the follow-up bone densitometry scan at 6 (± 1) months and status of 
menstruation recover, may be waived. 
A schematic of the overall study design is provided as Figure 4-1. 
Figure 4-1 
MVT-601-3003 Study Schematic 
 
 
4.2. 
Discussion of Study Design, Including Dosing 
The LIBERTY EXTENSION study (MVT-601-3003) is an extension of 2 replicate, 24-week 
phase 3 studies (MVT-601-3001 and MVT-601-3002) designed to establish the efficacy and 
safety of relugolix 40 mg once daily in women with heavy menstrual bleeding associated with 
uterine fibroids.  This 28-week extension study provides additional efficacy and safety data up to 
52 weeks to demonstrate the benefit and safety of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate (0.5 mg).  The primary objective of the study is to 
assess long-term efficacy of relugolix 40 mg once daily co-administered with low-dose estradiol 
and norethindrone acetate for up to 52 weeks on reduction in heavy menstrual bleeding, the most 
common and burdensome symptom of uterine fibroids.  The study will also evaluate safety of 
relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
for up to 52 weeks, among patients who previously completed a 24-week treatment period in one 
of the parent studies (MVT-601-3001 or MVT-601-3002), including adverse events and change 
in bone mineral density. 
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The dose of relugolix for phase 3 evaluation is 40 mg once daily.  Data from a phase 2 study in 
women with endometriosis demonstrated relugolix 40 mg once daily (N = 101) suppressed 
estradiol levels to below 20 pg/mL in the majority of women, and results were similar to those in 
the group of women treated with leuprolide subcutaneous injection, 3.75 mg.  Women in both the 
relugolix 40 mg and the leuprolide groups had similar reductions in pelvic pain, the primary 
endpoint of the study.  Finally, a phase 2 study of doses of relugolix 10, 20, or 40 mg once daily 
administered to women with heavy menstrual bleeding associated with uterine fibroids 
demonstrated the 40 mg dose provided the most reduction in menstrual blood loss and was the 
optimal dose to move forward into phase 3 development based on efficacy data. 
However, data on bone mineral density from DXA scanning in both phase 2 studies of 
premenopausal women with endometriosis or uterine fibroids demonstrated relugolix 40 mg 
once daily resulted in a degree of bone mineral density loss that is only acceptable for short-term 
dosing.  To mitigate this known adverse consequence of estrogen suppression, relugolix will be 
co-administered with 1 mg estradiol and 0.5 mg norethindrone acetate in this phase 3 clinical 
study.  This low-dose hormonal therapy is currently approved for long-term use to prevent bone 
mineral density loss and vasomotor symptoms in postmenopausal women.  Although relugolix 
doses of 20 mg and 10 mg once daily had less bone mineral density loss, these doses did not 
provide adequate relief from heavy menstrual bleeding in a high enough percentage of women to 
move forward into phase 3 clinical development and, based on the DXA data from the phase 2 
study, are not expected to prevent bone mineral density loss in a significant majority of women 
over 52 weeks of treatment. 
The co-administration of hormonal add-back therapy to relugolix aims to restore estradiol 
concentrations to a range that alleviates the adverse impact of the hypoestrogenic state on bone 
mineral density through 52 weeks of treatment, as well as on vasomotor symptoms such as hot 
flushes, but without substantial effect on the beneficial decrease in heavy menstrual blood loss.  
It is well known that bone is exquisitely sensitive to estrogen and low-doses of estrogen are 
sufficient to prevent bone mineral density loss in a hypoestrogenic state [Barbieri, 1992].  The 
combination of estradiol with a progestin is commonly used for long-term hormonal add-back 
therapy to reduce the risk of developing endometrial hyperplasia, which can occur with 
unopposed estrogen therapy [Activella US Prescribing Information, 2013].  A variety of add-
back hormonal therapies have been evaluated in combination with GnRH agonists and 
antagonists over the last 20 years [Archer, 2015; Chwalisz, 2012; Franke, 2000; Hornstein, 1998; 
Morris, 2008; Simpson, 2015; Wu, 2014; Zupi, 2004], and a combination of estradiol and 
norethindrone acetate has been used as add-back therapy in prior clinical studies with leuprolide 
(a GnRH agonist) and more recently, the GnRH antagonist elagolix, in each case reducing bone 
mineral density loss and the incidence of hot flushes without a significant impact on the decrease 
in menstrual blood loss [Archer, 2015; Lee, 2016; Franke, 2000].  The estradiol/norethindrone 
acetate combination proposed for evaluation in this phase 3 study is currently approved in the US 
as long-term hormone replacement therapy to prevent bone loss and alleviate vasomotor 
symptoms in postmenopausal women [Activella US Prescribing Information, 2013]. 
A 6-week study in healthy premenopausal women administered oral relugolix 40 mg once daily 
alone or relugolix 40 mg once daily in combination with 1 mg estradiol and 0.5 mg 
norethindrone acetate demonstrated that this dose of add-back therapy maintains serum estradiol 
in the 25 to 50 pg/mL range, the range historically shown to reduce loss of bone mineral density 
[Barbieri, 1992].  Serum N- and C-telopeptide concentrations were also maintained at near 
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baseline levels with the addition of the add-back therapy, suggesting reduced bone resorption 
compared to the group receiving relugolix alone.  Hot flush rate was also considerably reduced 
with the addition of add-back therapy.  The estrogenic metabolite of norethindrone acetate, 
ethinyl estradiol, was below the limit of quantitation in almost all pharmacokinetic samples 
collected, and therefore, will not be assessed in this phase 3 study.  These data also confirm that 
lower doses of estradiol/norethindrone acetate (such as the 0.5 mg/0.1 mg combination tablet 
[Activella US Prescribing Information, 2013]) would not provide sufficient serum estradiol 
concentrations to protect against the loss of bone mineral density resulting from the 
hypoestrogenic state induced by once daily administration of relugolix 40 mg. 
The doses of estradiol and norethindrone acetate used in this study (1.0 mg and 0.5 mg, 
respectively) were used in the parent studies (MVT-601-3001 and MVT-601-3002) and represent 
less than one fifth the estrogenic effects of an oral contraceptive pill containing 30 µg of ethinyl 
estradiol.  Therefore, this low-dose hormonal add-back therapy is added solely to improve the 
safety of relugolix therapy, and it is expected to have either a neutral or a marginal detrimental 
effect on efficacy, while mitigating the side effects of relugolix on bone mineral density loss and 
vasomotor symptoms. 
In summary, relugolix at a dose of 40 mg once daily resulted in a marked decrease in the heavy 
menstrual bleeding associated with uterine fibroids in a majority of women in a well-designed 
large phase 2 study.  However, its administration was associated with a degree of bone mineral 
density loss unacceptable for long-term treatment.  This phase 3 study extension study will 
assess long-term efficacy and safety of relugolix 40 mg co-administered with low-dose of 
estradiol and norethindrone acetate to decrease heavy menstrual bleeding associated with uterine 
fibroids and to prevent the bone mineral density loss and ameliorate some of the other side 
effects of a hypoestrogenic state such as hot flushes. 
This open-label extension study will allow for a description of long-term efficacy data and safety 
for an additional 28 weeks of treatment, providing approximately 1 year of efficacy and safety 
data from the women originally randomized to relugolix in studies (MVT-601-3001 and 
MVT-601-3002).  This study design will allow eligible patients with heavy menstrual bleeding 
associated with uterine fibroids, who were randomized to placebo in the parent study, to receive 
relugolix co-administered with low-dose hormonal add-back therapy during the extension. 
4.3. 
Selection of Study Population 
The study population will include approximately 600 women who have completed one of the 
parent studies (MVT-601-3001 or MVT-601-3002) to this extension study and meet all 
eligibility criteria for this study.  Patients enrolled in the parent studies were premenopausal 
women with heavy menstrual bleeding associated with uterine fibroids (≥ 80 mL per cycle for 
2 cycles or ≥ 160 mL for 1 cycle as measured by the alkaline hematin method during the 
screening period). 
Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.  Any questions 
regarding patient eligibility and entry criteria should be discussed with the medical monitor. 
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4.3.1. 
Inclusion Criteria 
A woman will be eligible for enrollment in this study only if all of the following inclusion 
criteria apply and have been met at the time of the Week 24/Baseline visit, unless otherwise 
specified: 
1. Completed 24 weeks of study drug treatment and study participation in either 
MVT-601-3001 or MVT-601-3002; 
2. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures for MVT-601-3003; 
Note:  Procedures conducted as part of the parent study that also serve as baseline 
procedures for this study may be done under the informed consent for the parent study; 
3. Is not expected to undergo gynecological surgery or ablation procedures for uterine 
fibroids within the study period, including during the Safety Follow-Up period; 
4. Has a negative urine pregnancy test at the Week 24/Baseline visit; 
5. Agrees to continue to use acceptable nonhormonal contraceptive methods as described in 
Section 4.6 consistently during the Open-Label Treatment period and for at least 30 days 
after the last dose of study drug.  However, the patient is not required to use the specified 
nonhormonal contraceptive methods if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
c. Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus; 
d. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of nonhormonal contraception as noted above; 
e. Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
4.3.2. 
Exclusion Criteria 
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 (MVT-601-3001 or MVT-601-3002); 
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 
(eg, bilateral hip replacement, spinal hardware in the lumbar spine); 
3. Has a Z-score < -2.0 or has a ≥ 7% decrease in bone mineral density from the parent 
study Baseline at lumbar spine, total hip, or femoral neck based on the parent study Week 
24 DXA assessment of bone mineral density; 
4. Anticipated to use any prohibited medications as detailed in Section 5.9.1; 
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5. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
including: 
a. Known, suspected, or history of breast cancer; 
b. Known or suspected estrogen-dependent neoplasia; 
c. Active deep vein thrombosis or pulmonary embolism, or history of these conditions 
prior to the Week 24/Baseline visit; 
d. History of or active arterial thromboembolic disease, including stroke and myocardial 
infarction; 
e. Known anaphylactic reaction or angioedema or hypersensitivity to estradiol or 
norethindrone acetate; 
f. Known protein C, protein S, or antithrombin deficiency, or other known 
thrombophilia disorders, including Factor V Leiden; 
g. Migraine with aura; 
h. History of porphyria; 
6. Has current active liver disease from any cause; 
7. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren’s 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic 
arthritis, vasculitic syndromes, etc).  Psoriasis not requiring or anticipated to require 
systemic therapy is permitted; 
8. Had any of the following clinical laboratory abnormalities at the parent study Week 20 
visit or any subsequent visit in one of the parent studies (MVT-601-3001 or MVT-601-
3002): 
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); 
9. Is currently pregnant or lactating, or intends to become pregnant during the study period 
or within 1 month after the last dose of study drug, or plans to donate ova during the 
study period or within 2 months after the last dose of study drug; 
10. Has a decline in presenting visual acuity score as defined below (unless explained by 
refractive error or approved by the Sponsor): 
a. 90 or lower and 5 or more points lower at Week 24/Baseline visit relative to the 
parent study Baseline visit; OR 
b. The presenting visual acuity score has decreased by 10 or more points at the 
Week 24/Baseline visit relative to the parent study Baseline visit; 
Note:  visual acuity score must have been obtained with corrective lenses, if applicable; 
11. 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. 
12. Met a withdrawal criterion in the parent study (MVT-601-3001 or MVT-601-3002). 
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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 parent study.  This extension study is a single-arm study, and 
thus all eligible patients are assigned to the same treatment group of relugolix 40 mg 
co-administered with low-dose of estradiol and norethindrone acetate (see Section 5.1 for 
treatment details). 
4.5. 
Removal of Patients from Therapy 
Completion of the Week 52 visit defines completion of the study.  Patients may withdraw 
consent to participate in the study and discontinue treatment at any time for any reason.  
Investigators or the medical monitor may remove patients from therapy under this protocol for 
reasons of safety and/or lack of compliance as discussed below.  Patients removed from therapy 
for any reason will undergo the assessments for the Early Termination visit (see the Week 52 
visit on the Schedule of Activities, Section 1.1) and will have a Follow-up visit to assess safety 
approximately 30 days after the end of study drug treatment (ie, after the patient’s last dose of 
study medication). 
The following safety and/or compliance events will result in the removal of patients from therapy 
either permanently or until the etiology of the problem has been identified and resolved: 
• Any adverse event that is intolerable to the patient and that cannot be ameliorated by 
the use of adequate medical intervention, or that in the opinion of the investigator or 
medical monitor would lead to undue risk to the patient if dosing continued; 
• If it is discovered after enrollment that a patient failed to meet protocol entry criteria 
and continued participation poses an unacceptable risk to the patient’s health; 
• If the following liver test abnormalities develop, study drug should be discontinued 
immediately with appropriate clinical follow-up (including repeat laboratory tests, 
until a patient’s laboratory profile has returned to normal/baseline status): 
o ALT or AST > 8 x ULN; or 
o ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
o ALT or AST > 3 x ULN in conjunction with elevated total bilirubin > 2 x ULN or 
international normalized ratio (INR) > 1.5; or 
o ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%); 
• QT interval by the Fridericia correction (QTcF) prolongation of more than 500 msec 
read by a cardiologist; 
• Evidence of endometrial hyperplasia or endometrial carcinoma on endometrial 
biopsy; 
• If the patient has a ≥ 7% loss of bone mineral density at lumbar spine, total hip, or 
femoral neck compared with the parent study Baseline; 
• If the patient, in the opinion of the investigator or the medical monitor, is grossly 
noncompliant with the protocol’s requirements.  This may include < 75% compliance 
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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). 
Should a patient fail to attend the clinic for a required study visit within the protocol-defined 
window, the site should attempt to contact the patient and reschedule the missed visit as soon as 
possible.  The site should also counsel the patient on the importance of maintaining the assigned 
visit schedule and determine whether the patient can and/or should continue in the study based 
on previous noncompliance.  In cases where the patient does not return for the rescheduled visit 
or cannot be reached to reschedule the missed visit, the site should make every effort to regain 
contact with the patient.  The site should attempt at least three documented telephone calls and if 
necessary a certified letter to the patient’s last known mailing address so that they can 
appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up.” 
4.6. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones for contraception are excluded, and 
patients must agree to use nonhormonal contraception throughout the study unless any of the 
following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
Week 24/Baseline visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™) at least 4 months prior to the Week 24/Baseline visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram) and there 
must be no evidence of post-Essure syndrome; 
• Has a nonhormonal intrauterine device (eg, Paragard®) placed in the uterus; 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of nonhormonal contraception as described below; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods do 
not apply are: 
• Condom (male or female condom) with or without spermicide (cream, spray, foam, 
gel, suppository, or polymer film); 
• Diaphragm with spermicide (condom may or may not be used); 
• Cervical cap with spermicide (condom may or may not be used); or 
• Vaginal sponge impregnated with spermicide used with a condom. 
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Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm with signing of the consent form that they understand 
the requirements for avoidance of pregnancy during the course of the study.  Patients may not 
donate ova during the course of the study and for 2 months following the last dose of study drug. 
A patient may start hormonal contraception 4 weeks after her last study dose of study drug 
provided her menstrual cycle has returned. 
Urine pregnancy tests will be performed at monthly intervals during the study (including just 
prior to receiving the first dose of study drug), and patients will receive continued guidance with 
respect to the avoidance of pregnancy as part of the study procedures.  Patients who become 
pregnant during the study will be withdrawn from the study and followed for pregnancy outcome 
(see Section 7.8). 
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5.
TREATMENTS
5.1. 
Treatments Administered
In this extension study, all patients will receive the following open-label oral study treatment: 
•
28 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg
estradiol and 0.5 mg norethindrone acetate.
Each patient will be instructed to take one tablet and one capsule per day. 
Table 5-1 
Description of MVT-601-3003 Study Drugs 
Name of Investigational 
Product 
Relugolix 
Estradiol / Norethindrone 
Acetate 
Formulation Description 
Round film-coated pink tablet 
A Swedish orange, over-
encapsulated round film-coated 
white tablet with back-fill 
material 
Dosage Form 
Tablet 
Capsule 
Unit Dose Strength 
40 mg 
Estradiol 1.0 mg / norethindrone 
acetate 0.5 mg 
Route of Administration/ 
Duration 
Oral once daily/ 
28 weeks 
Oral once daily/ 
28 weeks 
5.2. 
Identity of Investigational Product 
Relugolix has the chemical name 1-(4-{1-[(2,6-difluorophenyl)methyl]-5-
[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-
d]pyrimidin-6-yl}phenyl)-3-methoxyurea.
Estradiol (1.0 mg) and norethindrone acetate (0.5 mg) is a fixed-dose combination product. 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using common 
excipients. 
The fixed-dose combination tablet of estradiol 1.0 mg and norethindrone acetate 0.5 mg is 
encapsulated in a gelatin capsule with sufficient common back-fill material. 
5.3. 
Randomization and Stratification 
This extension study is a single-arm, open-label study, and thus, patients are not randomized or 
stratified upon enrollment in this study. 
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5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
The study treatment should be taken in the fasted state (other than water, tea, or coffee) in the 
morning, at least 1 hour before breakfast.  If dosing is missed in the morning for any reason, the 
study treatment may be taken later in the day, under fasting conditions, at least 1 hour before or 
2 hours after eating a meal.  The study treatment should be taken as close as possible to the same 
time of morning each day. 
On Week 24/Baseline and Week 52 clinic visit days, study drug will be administered in the clinic 
rather than at home (see Schedule of Activities in Section 1.1). 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Study drug can be held for a period of up to 2 weeks for evaluation and treatment of an adverse 
event.  Patients may subsequently be re-started on study drug with the written approval of the 
sponsor (or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20°C to 25°C with excursion to 15°C to 30°C permitted until it is used or 
returned to the sponsor (or designee).  Study drug should be stored protected from light.  A daily 
temperature log of the drug storage area must be maintained every working day.  Study drug 
must be stored under the conditions specified on the label, and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Further guidance and information for final 
disposition of unused study drug are provided in the Study Reference Manual.  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. 
Relugolix 40 mg will be supplied to the study site in blister cards co-packaged with the 
estradiol/norethindrone acetate. 
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5.7. 
Blinding 
Blinding is not applicable for this open-label extension study. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should bring all unused and used study drug to each study visit.  Study drug 
accountability will be conducted and results will be recorded.  If a patient is persistently 
noncompliant with the study treatment (ie, failure to take 80% or more of the scheduled doses 
after the last visit or compliance values over 120%), it may be appropriate to withdraw the 
patient from the study.  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 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 
zolendronic 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 
Note: All other anticonvulsants are 
allowed 
Aromatase Inhibitors 
anastrozole 
letrozole 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethynyl estradiol 
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Table 5-2 
Prohibited Medications (Continued) 
Hormonal 
Contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
Nova Ring 
Selective Estrogen 
Receptor Modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
Selective Progesterone 
Receptor Modulators  
mifepristone 
ulipristal acetate 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
Intrauterine Devices 
levonorgestrel 
copper 
Bone Agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction. 
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.  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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Table 5-2 
Prohibited Medications (Continued) 
P-glycoprotein Inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavir 
Study drug may be held for a period 
of up to 2 weeks with medical 
monitor approval if short-term 
treatment with one of these 
medications is required (eg, to treat 
an infection). 
Moderate and Strong 
P-glycoprotein Inhibitors 
amiodarone 
azithromycina 
captoprilb 
carvedilol 
clarithromycina 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
erapamilv 
Study drug may be held for a period 
of up to 2 weeks with medical 
monitor approval if short-term 
treatment with one of these 
medications is required (eg, to treat 
an infection). 
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.
Clopidogrel is allowed
5.9.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded, including the drug generic 
name, dose amount, route of administration, start date, and stop date. 
5.9.2.1. 
Analgesics 
From the Week 24/Baseline visit to the Week 52/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 extension 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 a 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 24/Baseline visit until the patient’s final study visit unless urgently needed for patient 
safety. 
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6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities (see 
Section 1.1).  Study procedures are briefly described within Section 6.5.  Further details of the 
procedures are provided in the Study Reference Manual. 
6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities (see Section 1.1).  The study is divided into 2 periods:  Open-Label Treatment 
period and Safety Follow-Up period.  Unscheduled visits may occur as needed to evaluate 
patients. 
6.2. 
Open-Label Treatment Period (Week 24/Baseline to Week 52) 
As denoted in the Schedule of Activities (see Section 1.1), certain Week 24 visit procedures of 
MVT-601-3001 or MVT-601-3002 will serve as the Week 24/Baseline procedures for patients 
who are interested in participating in this extension study, and these Week 24 procedures will be 
performed under the informed consent for the parent study. 
Patients will be required to sign an informed consent form for the extension study, and will be 
eligible if they meet all of the eligibility criteria. 
Once eligibility is determined, all additional Week24/Baseline visit procedures described in the 
Schedule of Activities (see Section 1.1) that were not performed as part of the Week 24 visit of 
the parent study will be completed.  These include the following: 
• Informed consent; 
• Record concomitant medications; 
• Dispense study treatment; 
• Dispense feminine products; 
• Take study drug dose in clinic; and 
• Record adverse events, if any. 
Patients will commence taking their open-label treatment once daily, beginning on the day of the 
Week 24/Baseline visit and continuing through the Week 52 visit.  Following the 
Week 24/Baseline visit, on-treatment study visits will occur at Weeks 28, 32, 36, 40, 44, 48, 
and 52. 
At each post-Week24/Baseline visit, patients will return their feminine products for alkaline 
hematin testing.  A venous blood sample (for hemoglobin) must be collected each time feminine 
products are collected to be sent to the central laboratory conducting the alkaline hematin 
assessment.  The site must document the start and stop dates of the patient’s menses 
corresponding to the collected feminine products. 
Safety monitoring including physical examination, ECGs, clinical laboratory tests, pregnancy 
tests, and adverse event collection will occur at each visit.  Bone densitometry will occur at the 
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Week 24/Baseline, Week 36, and Week 52/Early Termination visits.  A transvaginal ultrasound 
(with or without a transabdominal ultrasound) will be performed at Week 24/Baseline and 
Week 52/Early Termination.  An endometrial biopsy will have been performed at the parent 
study Week 24 visit for all patients who participated in MVT-601-3001 (see MVT-601-3001 
protocol for details) and in some patients who participated in MVT-601-3002 (see MVT-601-
3002 protocol for details). 
Study drug compliance will be reviewed at each visit. 
Fasting (other than water) for at least 8 hours is required prior to blood sampling on 
Week 24/Baseline and Week 52/Early Termination visits and for 1 hour after administration of 
the study drug in the clinic.  Laboratory requisitions must indicate whether or not the patient was 
not fasted for their chemistry and lipid testing. 
Refer to the Schedule of Activities (see Section 1.1) for information about study procedures 
during the Open-Label Treatment period. 
6.3. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 52 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 52; however, for 
patients whose last dose of study drug is during Week 32 or earlier, the following procedures do 
not need to be performed:  transvaginal ultrasound (with or without a transabdominal ultrasound) 
and bone densitometry.  These procedures may be performed, however, at the investigator’s 
discretion, if they aid in follow-up of ongoing adverse events. 
Patients (including those who complete the Week 52 visit and those who withdraw early from 
this study) will have a Follow-up visit approximately 30 days after the last dose of study drug, or 
prior to the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention or other invasive procedure for 
uterine fibroids, whichever occurs first.  However, for patients who enroll directly into another 
relugolix clinical study upon completion of the Week 52 visit, then the Follow-up visit may be 
waived. 
The Follow-up visit will be used to assess safety after discontinuation of study treatment 
including adverse events, clinical safety laboratories, and return of menstruation.  Refer to the 
Schedule of Activities (see Section 1.1) for individual study visit procedures during the Follow-
up visit. 
6.4. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or follow-up on adverse events, at the patient’s request, or as deemed necessary by the 
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 needed.  See 
the Schedule of Activities (Section 1.1) for tests that may be performed, as indicated by the 
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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. 
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 collected at each visit until the patient completes 
treatment or terminates participation from the study prior to completing treatment.  The site must 
document the start and stop dates of the patient’s menses corresponding to the collected feminine 
products.  Each time the patient submits her feminine products from a menstrual cycle for 
analysis, a venous blood sample will be collected and sent to the laboratory.  Details regarding 
materials, process, and requirements for the menstrual blood loss collection will be provided in 
the Study Reference Manual. 
6.5.1.2. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal ultrasound will be performed for all subjects.  Once the transvaginal ultrasound is 
done, a transabdominal ultrasound, with or without saline or gel contrast, may also be done if the 
uterus cannot be adequately imaged on transvaginal ultrasound; for example, due to enlarged 
size.  Transvaginal ultrasound, with or without transabdominal ultrasound, is performed to 
determine uterine and myoma volumes.  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; this single operator should be the same, if possible, as 
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 x D2 x D3 x π / 6 
Where: 
D1 = the longest diameter of the myoma or uterus (unit of length:  cm) 
D2 = the longest diameter of the myoma or uterus that is perpendicular to D1 (unit of length:  
cm) 
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). 
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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.  
The largest myoma among those measurable at the Screening 1 visit of the parent study (see the 
MVT-601-3001 or MVT-601-3002 protocol) will continue to be measured throughout the 
extension study. 
6.5.1.3. 
Endometrial Biopsy 
Per the parent study MVT-601-3001 protocol, an endometrial biopsy is performed for all 
subjects at the Week 24 visit, whereas per the parent study MVT-601-3002 protocol, an 
endometrial biopsy is performed at the Week 24 visit only if indicated (endometrial thickness at 
any location is ≥ 4 mm or if any other endometrial abnormality is visualized on the Week 24 
ultrasound). 
Patients who have endometrial hyperplasia or endometrial carcinoma, will be withdrawn from 
study drug treatment and followed per instructions in the parent study protocol. 
6.5.1.4. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum estradiol will be collected pre-dose at 
the visits indicated in the study Schedule of Activities (see Section 1.1).  These 
pharmacodynamic samples will be analyzed at a central laboratory. 
6.5.1.5. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire was designed to measure a women’s self-assessment of 
menstrual blood loss and its impact on her social and leisure activities, physical activities, and 
ability to work (see Appendix 1).  The MIQ has undergone psychometric validation.  Patients 
will complete the MIQ at each study visit during the Open-Label Treatment period.  Patients will 
complete the MIQ at each visit at the site before other study procedures, such as blood draws and 
physical examinations, are performed. 
6.5.1.6. 
Uterine Fibroid Symptom – Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life score is used to evaluate the 
symptom severity and the quality of life of patients with uterine fibroids (see Appendix 2).  
Patients will complete the UFS-QoL questionnaire at the site at the Week 24/Baseline visit, 
Week 36, and Week 52/Early Termination visit before other study procedures, such as blood 
draws and physical examinations, are performed. 
6.5.1.7. 
European Quality of Life Five-Dimension Five-Level Scale 
The European Quality of Life Five-Dimension Five-Level Scale is a standardized instrument for 
use as a measure of health outcomes (see Appendix 3).  Mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression are each assessed on 5-point categorical scales ranging 
from “no problem” to “severe problem.” 
Patients will complete the EQ-5D-5L questionnaire at the site at the Week 24/Baseline visit and 
the Week 52/Early Termination visit before other study procedures, such as blood draws and 
physical examinations, are performed. 
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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. 
6.5.2.3. 
Physical and Gynecologic Exams 
A complete physical examination will include head, ears, eyes, nose, mouth, thyroid, skin, heart 
and lung examinations, lymph nodes, gastrointestinal, skeletal, and neurological systems.  All 
subsequent physical examinations should focus on signs and symptoms reported by the patient to 
assess for clinically significant changes from previous assessments. 
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 Section 1.1).  Laboratory 
requisition forms must be completed and samples must be clearly labelled 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 safety 
parameters will be provided to the site by the central laboratory.  The samples collected for 
clinical laboratory tests are listed in Table 6-1. 
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Table 6-1 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
Chloride 
Bicarbonate 
Blood Urea Nitrogen 
Creatinine 
Glucose 
Calcium 
Phosphate 
Magnesium 
Sodium 
Albumin 
Creatinine Kinase 
Hemoglobin A1c 
Creatine Kinase 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Gamma-Glutamyl Transferase 
Alkaline phosphatase 
White Blood Cell (WBC) Count 
WBC Differential 
Red Blood Cell Count 
Hemoglobin 
Hematocrit 
Mean Corpuscular Volume 
Platelet Count 
RBC morphology 
Protein 
Glucose 
Blood 
Urobilinogen 
Bilirubin 
Color and Clarity 
pH 
Leucocyte Esterase 
Ketones 
Nitrite 
Specific Gravity 
Urine Microscopy (reflex 
testing based on abnormal 
urine analysis) 
Lipids 
Pregnancy 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
Pregnancy test (human 
chorionic gonadotropin) 
Hormones 
Estradiol 
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. 
6.5.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at Week 24 visit in the parent study and at the Week 52/Early 
Termination 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 
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abnormal.  The investigator or sub-investigator will judge if any of the findings are clinically 
significant. 
6.5.2.6. 
Bone Mineral Density 
Bone mineral density is determined using DXA scanning and will be assessed at the lumbar 
spine (L1, L2, L3 and L4), total hip, and femoral neck (same leg within each patient).  Training, 
quality review, and readings will be done by a central radiology laboratory as described in the 
central radiology charter for bone mineral density. 
Throughout the study, the same DXA apparatus will used at each site and operated in the same 
scan mode for all scans for an individual patient, and should be the same as used for the patient 
during the parent study (MVT-601-3001 or MVT-601-3002).  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 subject will be monitored by a central radiology 
laboratory over the course of the study. 
Patients who experience a bone mineral density loss from the parent study Baseline of ≥ 7% at 
any of the anatomical sites assessed will be discontinued from the extension study.  Patients 
should be assessed for secondary causes of bone loss if determined necessary by the investigator 
and followed up to resolution if bone mineral density loss is determined by the investigator to be 
related to study drug. 
Patients with a bone mineral density loss of > 3% at lumbar spine or total hip at their 
Week 52/Early Termination visit relative to parent study Baseline measurement will undergo 
another bone densitometry scan at 6 (± 1) months and will be contacted to obtain information 
about medications and conditions (eg, pregnancy) that might affect bone mineral density through 
the time of the follow-up bone densitometry.  The follow-up bone densitometry will be 
submitted for central reading. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, then the follow-up bone densitometry scan at 6 (± 1) months conducted under this 
protocol may be waived. 
6.5.2.7. 
Status of Menstruation Recovery 
If the first menstruation after the end of study treatment administration is observed before the 
Follow-up visit, the date of onset of the first menstruation is recorded in the electronic case 
report form (eCRF).  Patients whose menses has not resumed as of the Follow-Up visit for whom 
there is no explanation for the lack of resumption (eg, medical procedure or medications) will be 
contacted again by telephone 3 (+ 0.5) months after the Follow-Up visit to determine if menses 
has resumed and will be asked about factors that may affect resumption of menses. 
If the patient enrolls directly into another relugolix clinical study upon completion of the 
Week 52 visit, follow-up under this protocol to determine the status of menstruation recovery 
may not be required. 
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7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), ECGs, bone mineral density assessments, and clinical laboratory tests. 
7.1. 
Adverse Event Definitions 
7.1.1. 
Adverse Event 
Adverse event:  An adverse event is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product, whether or not related to the medicinal product. 
Events meeting the definition of an adverse event include: 
• A worsening, excluding minor fluctuations, in the nature, severity, frequency, or 
duration of a pre-existing condition; 
• Development of an intercurrent illness during the study; 
• Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product; 
• Injury or accidents:  If a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately); and 
• An investigational abnormality (eg, laboratory parameter, vital sign, ECG) only if the 
abnormality is considered clinically significant by the investigator based on at least 
one of the following criteria: 
o Induces clinical signs or symptoms; 
o Requires active intervention; 
o Requires interruption or discontinuation of study drug. 
Events that do not meet the definition of an adverse event include: 
• Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an adverse event; 
• Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen; 
• Situations where an untoward medical event has not occurred (eg, planned 
hospitalization for an elective procedure, with elective defined as known or planned 
at the time of signing of the informed consent); 
• Events of heavy menstrual bleeding, as heavy menstrual bleeding is quantified as an 
efficacy endpoint, unless meets seriousness criteria. 
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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 detained at the 
hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting.  Complications that occur 
during hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event should be considered 
serious.  Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from the Week 24/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 (eg, sprained ankle), which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect; 
f. Important medical events that jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above.  Examples of such 
events are invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. 
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7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local 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 or not related to the study drug treatment, must be fully and 
completely documented on the adverse event case report form and in the patient’s source 
documents.  In addition, any adverse event resulting in permanent treatment discontinuation must 
be recorded on the appropriate case report form as well as documented in the patient’s source 
documents.  Adverse event terms should include a diagnosis, as available, in preference to listing 
the individual signs and symptoms.  If the diagnosis is not known, the investigator should record 
each sign and symptom as an individual adverse event. 
Overdose and pregnancy in the patient will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events and serious adverse events will be collected under this extension study protocol 
from the administration of the first dose of extension study drug until the Follow-up visit 
approximately 30 days after the last dose of study drug or the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or 
surgical intervention for uterine fibroids, whichever occurs first, as also specified in the study 
Schedule of Activities (Section 1.1).  Serious adverse events reported to the investigator after the 
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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: 
a. 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). 
b. 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. 
c. Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable and/or 
in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 
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Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
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 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 4. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
•
ALT or AST > 8 x ULN; or
•
ALT or AST > 5 x ULN and persists for more than 2 weeks; or
•
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or 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 
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Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 0 0 3 
Effecti ve:  0 8- A U G - 2 0 1 7 
M y o va nt  Scie nces G m b H  
5 3 
C O N FI D E N TI A L  
Wee k  2 4/ Baseli ne v al ues.  T he i n vesti gat or a n d s p o ns or m ust disc uss a n d a gree wi t h a n y 
decisi o n t o rec h alle n ge.  
Rec halle n ge s h o ul d n ot o cc ur w h e n  t he eti ol o g y of t he li ver test a b n or malities is c o nsi dere d 
p ossi bl y dr u g i n d uce d. 
7. 5. 2.  
Criteri a f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g i n Ass oci ati o n w it h Li ver 
Test A b n or m aliti es  
St u d y dr u g treat me nt s h o ul d be disc o nti n ue d per m a ne ntl y if all of t he f oll o wi n g 4 criteria are 
met (ie,  p ote ntial se ver e dr u g-i n d uce d li ver i nj ur y/H y’s la w cas e):  
1.  A S T or A L T i ncr eases t o ≥ 3 x U L N; A N D
2.
T otal bilir u bi n i ncreases t o >  2 x U L N or I N R >  1. 5; A N D
3.  Al kali ne p h os p hatase v al ue d oes n ot reac h 2 x U L N ; A N D
4.  N o alter nati ve ca use e x plai ns t he c o m bi nati o n of t he a b o ve la b orat or y a b n or malities;
i m p orta nt alter nati ve ca uses i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g:
•
He pat o biliar y tract diseas e ;
•
Viral he patitis (e g, he p atitis A/ B/ C/ D/ E, E pstei n -Barr vir us) ;
•
E x p os ure t o he pat ot o xic a ge nts/ dr u gs or he p at ot o xi ns, i ncl u di n g her b al a n d dietar y
s u p ple me nts, pla nts, a n d m us hr o o ms;
•
Alc o h olic he patitis ;
•
N o nalc o h olic steat o he p atitis;
•
A ut oi m m u ne he patitis.
If a n alter nati ve ca use for he pat ot o xicit y is i de ntifi e d, t he n it s h o ul d be deter mi ne d ( base d o n t he 
se verit y of t he he p at ot o xicit y or e ve nt) w h et her st u d y dr u g  treat me nt s h o ul d be wit h hel d or 
per ma ne ntl y disc o nti n ue d as a p pr o priat e f or t he s afet y of t he p atie nt. 
7. 6.  
Seri o us A d verse E ve nt Re p orti n g  
Usi n g a Safet y Re p ort  F or m, all seri o us a d vers e e v e nts m ust be re p orte d wit hi n 2 4  h o urs of t he 
st u d y site pers o n nel ’s k n o wle d ge of t he e ve nt, re gar dless of t h e i n vesti gat or assess me nt of t he 
relati o ns hi p of t he e ve nt t o st u d y dr u g. 
T he c o ntact i nf or mati o n f or s u b missi o n of seri o us a d verse e ve nts , a d v erse e ve nts of cli nical 
i nterest, a n d e v e nts of o v er d ose is a vaila bl e o n t he seri o us a d vers e ev e nt re p ort f or m  a n d is as 
f oll o ws: 
Se n d c o m plete d S af et y Re p ort  F or ms t o Q ui ntilesI M S S afet y: 
Site L oc ati o n 
E- m ail  
( Pri m ar y re p orti n g met h o d) 
F a x N u m ber  
( Sec o n d ar y re p orti n g met h o d) 
All st u d y  sites 
 
 
Pa ge 1 3 4
M V T- 6 0 1- 3 0 0 3 C S R - A p pe n di x 1 6. 1. 1. Pr ot oc ol a n d Pr ot oc ol A me n d me nts
P P D
P P D


Cli nical St u d y Pr ot oc ol:  M V T - 6 0 1- 3 0 0 3  
 
Effecti ve:  0 8- A U G - 2 0 1 7 
M y o va nt  Scie nces G m b H  
5 4 
C O N FI D E N TI A L  
F or q uesti o ns o n Seri o us A d verse E ve nt /A d vers e E ve nt of Cli nic al I nterest  re p orti n g, 
ple ase c all:  
•  N ort h/ S o ut h A merica :  
 
•  E ur o pe, Asia, Pacific, a n d Africa:  see re gi o n-s pecific p h o ne n u m bers acc o m pa n yi n g 
t he Safet y Re p ort  F or m  
T he i nitial re p ort s h o ul d i ncl u de: 
•  St u d y n u m b er ( M V T - 6 0 1- 3 0 0 3); 
•  Site a d dress  a n d n u m ber; 
•  I n v esti gat or na me; 
•  Patie nt I de ntifi cati o n N u m ber, se x, a n d a ge; 
•  Deta ils of st u d y dr u g a d mi nistrati o n; 
•  T he date of t h e re p ort ; 
•  A descri pti o n of t he seri o us a d verse e ve nt (e ve nt t er m, seri o us ness of t h e e ve nt , date 
of o nset, i nte nsit y); 
•  Ca us al relati o ns hi p t o t he st u d y dr u g. 
If t he patie nt die d, t he re p ort s h o ul d i ncl u de t he ca use of deat h as the e v e nt ter m ( wit h deat h as 
o utc o me) a n d w h et her or n ot t he e ve nt lea di ng t o deat h was relate d t o st u d y dr u g  treatme nt, as 
well as t he a ut o ps y fi n di n gs if a v aila ble.  
D o n ot dela y re p orti n g a s us pecte d seri o us a d vers e e ve nt i n or der t o o btai n a d diti o nal 
i nf or mati o n.  A n y a d diti o nal i nf or mati o n, if c ollect e d, ca n b e re p orte d as a f oll o w - u p t o t he 
i nitial re p ort.  All seri o us a d verse e ve nts will be f oll o we d u ntil res ol uti o n, u ntil t he e ve nt has 
sta bilize d, a n d/ or reac h e d a ne w bas eli ne.  All seri o us a d verse e ve nts c o nti n ui n g at t he 
c o m pleti o n of t he st u d y m ust be assesse d or f oll o we d t o deter mi ne o utc o m e. 
7. 7.  
St u d y Dr u g  O ver d ose  M a n a ge me nt  
T he m e dical m o nit or m ust be c o ntacte d i n t he e ve nt of a n y st u d y dr u g o ver d ose. 
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of st u d y dr u g, t o or b y 
a st u d y p atie nt, at a d ose a b o ve t hat assi g ne d t o t h at i n di vi d ual pati e nt acc or di n g t o t he st u d y 
pr ot oc ol. 
F or t his st u d y, a n y d ose of rel u g oli x > 8 0 m g  wit hi n a 2 4- h o ur wi n d o w is a n o ver d ose a n d a n y 
d ose of estra di ol/ n oret hi n dr o ne acetate > 2 x t he pr ot oc ol d ose is a n o ver d os e (ie, m ore t h a n 
2 ca ps ules ta ke n wit hi n a 2 4- h o ur wi n d o w).  T h ere is n o k n o w n a nti d ote f or a n o ver d os e. 
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or or treati n g p h ysicia n s h o ul d: 
•  C o ntact t he m e dical m o nit or i m me diatel y;  
•  Cl osel y m o nit or t he patie n t f or a d vers e e v e nts  a n d la b orat or y a b n or malities ; 
Pa ge 1 3 5
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• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form according to Section 7.6, whether or not the 
overdose is associated with an adverse event; 
• If possible, obtain a plasma sample for pharmacokinetic analysis within 2 days from 
the date of the last dose of study drug if requested by the medical monitor 
(determined on a case-by-case basis); 
• Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF. 
The medical monitor, in consultation with the investigator, will make decisions regarding patient 
status and potential dose interruptions, based on the clinical evaluation of the patient. 
7.8. 
Pregnancy Reporting 
If any patient becomes pregnant during the study, the site must discontinue the patient from the 
study treatment immediately and have her return for an Early Termination visit. 
If the patient agrees, the investigator should notify the patient’s primary care physician of the 
pregnancy and provide details of the patient’s participation in the study and treatment. 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the pregnancy 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 this 
information, as available. 
The investigator will follow the medical status of the mother, as well as the fetus, and will report 
the outcome to the sponsor. 
7.9. 
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 (identified risks) associated with relugolix in women include nonserious 
events of hot flush, headache, hyperhidrosis, and loss of bone mineral density.  In this protocol, 
relugolix will be evaluated for its benefit on the heavy menstrual bleeding associated with uterine 
fibroids.  Low-dose hormonal add-back therapy with estradiol and norethindrone acetate will be 
evaluated for maintenance of bone mineral density during treatment with relugolix. 
Potential risks that may be associated with relugolix treatment in women, based on nonclinical 
data and data available for similar compounds, include drug interactions, cardiovascular effects 
(corrected QT 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 
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the addition of estradiol/norethindrone acetate.  Summaries of findings from both nonclinical and 
clinical studies conducted with relugolix can be found in the current version of the investigator 
brochure. 
The risk assessment and mitigation strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density was included in 
the parent studies. 
Bone mineral density will be 
monitored at the 
Week 24/Baseline, Week 36, 
and Week 52/Early 
Termination visits with 
specified discontinuation and 
follow-up criteria and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-glycoprotein 
inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF 
> 470 msec in the parent 
studies. 
12-lead ECG at the 
Week 24/Baseline and 
Week 52/Early Termination 
visits, and as clinically 
applicable; withdrawal for 
QTcF > 500 msec. 
Hepatic Enzymes 
Isolated increases in hepatic transaminases 
have been observed in prior clinical 
studies.  There have been no reported cases 
consistent with drug-induced liver injury 
including an increase in bilirubin.  
Abnormal liver test results are considered 
adverse events of clinical interest in this 
study. 
Exclusion criteria for 
AST and ALT > 2 x the 
ULN; total bilirubin 
values > 1.5 x ULN 
Abnormal liver test results 
(AST or ALT > 3 x ULN) 
that develop during the 
Open-Label Treatment 
period will be reported 
within 24 hours of study 
personnel awareness. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Phospholipidosis 
Data from nonclinical studies in rats and 
monkeys showed histopathological 
changes consistent with PLD.  PLD by 
itself is not adverse.  No clinical evidence 
of relugolix-related PLD-associated 
toxicity has been observed nor was there a 
clinically meaningful increase in a 
biomarker of PLD assessed in phase 2 
clinical studies. 
Patients with significant 
underlying medical 
conditions are excluded. 
Routine safety monitoring 
including laboratory 
assessments, ECGs, and 
assessment of adverse 
events, including any 
ophthalmologic adverse 
events, will be monitored 
during this study. 
Metabolic Changes 
Metabolic changes (insulin resistance, 
dyslipidemia, and increased weight) with 
increased risk of diabetes are a potential 
risk of the hypoestrogenic state induced by 
relugolix. 
Exclusion criteria for 
current medical history of 
cardiovascular disease in 
the parent studies. 
Fasting lipids and glucose 
will be monitored during the 
study. 
Reproductive Toxicity 
Premenopausal 
compliance with 
specified acceptable non-
hormonal contraception; 
exclusion of pregnant and 
lactating women. 
Pregnancy testing at each 
study visit; immediate 
withdrawal for pregnancy. 
Risk of Estradiol (1.0 mg)/Norethindrone 
Acetate (0.5 mg) 
Low-dose estradiol and norethindrone 
acetate are approved for the prevention of 
postmenopausal osteoporosis and the 
treatment of moderate to severe vasomotor 
symptoms.  It is contraindicated for 
women with a history of breast cancer or 
estrogen-dependent neoplasia, history of 
(or active) deep vein thrombosis, 
pulmonary embolism, thromboembolic 
disease (myocardial infarction or stroke 
within the past year), liver dysfunction, 
prior hypersensitivity, and pregnancy. 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy excluded from 
the parent studies.  
Physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed at the 
Week 24/Baseline visit. 
Clinical chemistries 
assessing liver tests, fasting 
glucose and lipids, and urine 
pregnancy tests will be 
performed throughout the 
study.  Adverse events will 
be recorded at each visit. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies  (Continued)
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8.
DATA QUALITY ASSURANCE
8.1. 
Clinical Procedures 
Sponsor personnel or designee(s) will visit the study site if necessary prior to initiation of the 
study to review information about the study drug, protocol requirements, eCRFs, monitoring 
requirements, reporting of serious adverse events, and to ensure a full understanding of the Study 
Reference Manual with the site personnel. 
8.2. 
Monitoring 
This study will be monitored by the sponsor (or designee) in accordance with current Good 
Clinical Practice (GCP) regulations.  By signing this protocol, the investigator grants permission 
to Myovant Sciences GmbH (or designee) and appropriate regulatory authorities to conduct on-
site monitoring of all appropriate study documentation.  In order to assure the accuracy of data 
collected in the eCRF, it is mandatory that representatives of the sponsor (or designee) have 
access to original source documents (eg, patient records, patient charts, and laboratory reports).  
During the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.  A study monitor will contact and visit the 
site regularly and will be allowed, on request at a mutually acceptable time, to inspect the various 
records of the study.  It will be the study monitor’s responsibility to inspect the eCRF at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
correctness and accuracy of all eCRF entries, and to meet with the investigator to discuss study 
progress and compliance with the protocol and GCP.  The study monitor should have access to 
laboratory test results and any other source records and data needed to verify the entries on the 
eCRF.  The investigator agrees to cooperate with the study monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved.  For this study, patient data will be 
entered into a sponsor-approved electronic database and combined with data provided from other 
sources in validated datasets then transmitted electronically to the sponsor (or designee). 
Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
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9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study. 
All efficacy and safety measures over the course of both the parent and extension studies will be 
presented by the parent study treatment group using descriptive statistics.  No formal treatment 
comparisons will be performed for this extension study.  Continuous data will be summarized by 
means, standard deviations, medians, maximum, minimum, and number of patients.  Categorical 
data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
This is a single-arm, open-label extension study; patients are not randomized.  All patients who 
have entered the extension study will be treated with open-label relugolix and low-dose 
hormonal add-back therapy for 28 weeks. 
9.2. 
Analysis Populations 
Efficacy data analyses will be performed on the Intent-to-Treat Population, defined as all patients 
who were randomized in a parent study and who have received any amount of study drug. 
Safety data analyses will be performed on the Safety Population, defined as all patients who were 
randomized in a parent study and who have received any amount of study drug. 
The analyses methods for safety and efficacy endpoints are similar to those used for the parent 
studies, unless otherwise specified in the SAP. 
9.3. 
Sample Size Estimation 
Because this is an extension study, the sample size will be determined by the numbers of patients 
who have completed either parent study (MVT-601-3001 or MVT-601-3002) and who are 
eligible and willing to participate in this study.  It is estimated that approximately 600 patients 
(75% of 780 patients who will be randomized in total into the parent studies) will participate in 
this extension study. 
9.4. 
Efficacy Analyses 
Efficacy endpoints will be summarized by the original treatment groups assigned in the parent 
study. 
Descriptive statistics will be provided for efficacy endpoints (listed below) similar to those used 
for the parent studies. 
•
Proportion of women who achieve or maintain a menstrual blood loss volume of < 80
mL AND at least a 50% reduction from parent study Baseline to the last 35 days of
treatment, as measured by the alkaline hematin method.
•
Time to achieve a menstrual blood loss volume of < 80 mL AND at least a 50%
reduction from parent study Baseline menstrual blood loss volume as measured by the
alkaline hematin method;
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•
Change from parent study Baseline to Week 52 in menstrual blood loss;
•
Proportion of women who achieve or maintain amenorrhea over the last 35 days of
treatment;
•
Proportion of women with a hemoglobin below the lower limit of normal at parent
study Baseline who achieve an increase of ≥ 1 g/dL from parent study Baseline at
Week 52;
•
Proportion of women with a hemoglobin below the lower limit of normal at parent
study Baseline who achieve a normal hemoglobin at Week 52;
•
Change from parent study Baseline to Week 52 in hemoglobin;
•
Change from parent study Baseline to Week 52 in the Uterine Fibroid Scale –
Symptom Severity;
•
Change from parent study Baseline to Week 52 in the Uterine Fibroid Scale – Health-
related Quality of Life subscales and total score;
•
Change from parent study Baseline to Week 52 in the MIQ score for physical
activities;
•
Change from parent study Baseline to Week 52 in the MIQ score for social and
leisure activities;
•
Change from parent study Baseline to Week 52 in uterine volume;
•
Change from parent study Baseline to Week 52 in uterine fibroid volume.
The point estimate and 2-sided 95% confidence interval (CI) for the responder rate (defined as 
proportion of women who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from the parent study Baseline in menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method), will be calculated for each 
parent study treatment group. 
Baseline menstrual blood loss is defined as the average menstrual blood loss from the two 
Screening menstrual cycles used to meet the inclusion criteria prior to the date of the first dose of 
study drug in the parent study as assessed by the alkaline hematin method.  The menstrual blood 
loss during the last on-treatment cycle (Week 52) is the total menstrual blood loss during the last 
35 days on treatment as assessed by the alkaline hematin method. 
Patients from Group C, who discontinue the extension study before Week 32 (28 days) will be 
considered non-responders. 
For the endpoints of time to achieving a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from parent study Baseline menstrual blood loss volume, time to event will be 
defined as weeks from randomization in the parent study to first occurrence of the event as 
assessed by the alkaline hematin method.  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 parent study treatment arm. 
Descriptive statistics will be provided for changes in menstrual blood loss, hemoglobin, Uterine 
Fibroid Scale – Symptom Severity, Menorrhagia Impact Questionnaire Score, Numerical Rating 
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Scale score for uterine fibroid-associated pain, uterine volume, and uterine fibroid volume to 
parent study Baseline. 
For binary endpoints, the point estimate and 2-sided 95% CI for the proportion will be provided 
by parent study treatment group. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.5. 
Safety Analyses 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations, clinical laboratory tests, and 12-lead ECGs. 
The treatment-emergent period will be defined as the period of time from the first dose date of 
study drug in the parent study 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 parent study Baseline versus post-baseline results.  All data will be listed and 
summarized by visit.  The change from parent study Baseline to each post-baseline study visit 
will be presented by parent study treatment group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from parent study Baseline to each post-baseline study visit will be presented by 
parent study treatment group for each parameter. 
Clinical laboratory data consist of chemistry, hematology, and hormonal tests.  Only data 
collected by the central laboratory will be used to do the analyses.  ECGs will also be read 
centrally.  The distributions of QTc interval will be summarized at each visit.  All data will be 
listed and summarized by visit.  The change from parent study Baseline to each post-baseline 
study visit will be presented by treatment group for each ECG parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by the parent study treatment arm. 
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Bone mineral density data will be collected and analyzed by the central radiology laboratory 
including bone mineral content (g), bone area (area, cm2), and bone mineral density (g/cm2) each 
for L1, L2, L3, L4, total hip, and femoral neck, and average bone mineral density of L1-L4 
(lumbar spine), Z-score for bone mineral density lumbar spine (L1-L4), total hip, and femoral 
neck. 
For the relugolix add-back treatment Group A, the lower bound of the 95% CI for (arithmetic) 
mean percentage change at Week 52 from parent study Baseline in bone mineral density lumbar 
spine (L1-L4) will be compared with a pre-specified clinically acceptable threshold of -2.2% to 
evaluate magnitude of bone mineral density loss after 52 weeks of treatment.  If the lower bound 
is > -2.2%, the bone mineral density loss for the relugolix add-back treatment will be considered 
insignificant.  As supportive analysis, least square means and 95% CI for % change at Week 52 
from parent study Baseline in bone mineral density will be provided based on mixed effects 
model (assumed missing at random) for each parent study treatment group. 
All data will be listed and summarized by visit.  The change, percent change from parent study 
Baseline to Weeks 36 and 52 and associated 95% CIs will be presented by the parent study 
treatment group for each bone mineral density parameter.  The number and percentage of 
patients meeting a bone mineral density decline of at least 4%, 5%, 6%, or 7% by body area 
(lumbar spine, total hip, or femoral neck) will be estimated with 95% CIs by the parent study 
treatment group. 
Additional analyses will be performed to 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. 
Pharmacodynamic Analyses 
The change from the parent study Baseline to Week 52 in pre-dose concentrations of serum 
estradiol will be summarized.  Percentage of patients with concentrations of serum estradiol 
levels < 10 pg/mL and < 20 pg/mL will be provided. 
9.7. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed: 
• Change from parent study Baseline to Week 52 in the European Quality of Life Five-
Dimension Five-Level scale. 
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10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International 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 
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 
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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 patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the investigator brochure, protocol, eCRFs and other study forms, the investigational drug, and 
any other study information, remain the sole and exclusive property of the sponsor during the 
conduct of the study and thereafter.  This information is not to be disclosed to any third party 
(except employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from the sponsor.  The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain. 
10.1.5. 
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 
brochure, protocol/amendments, IRB or IEC and governmental approval with 
correspondence, informed consent forms, drug records, staff curriculum vitae, 
authorization and training forms, and other appropriate documents and correspondence. 
2. Patient clinical source documents.  The required source data should include the following 
for each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
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• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified.  
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with the sponsor.  The investigator must 
notify the sponsor before destroying any clinical study records. 
Clinical study documentation includes the investigator brochure, signed protocol and 
amendments, signed informed consents, notification of serious adverse events and related 
reports, any dispensing and accountability logs, shipping records of investigational product and 
study-related materials, documentation of financial aspects of the study, insurance statement, and 
signed agreement between the involved parties, dated and documented IRB/IEC approval, 
approval of regulatory authorities as applicable, decoding procedures for blinded studies, 
curriculum vitae and all training records of study site personnel, and all correspondence 
pertaining to the conduct of the study. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the sponsor must be notified in advance. 
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. 
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10.1.8. 
Investigational Product Accountability 
The investigator or investigator’s designee (ie, 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. 
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. 
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When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
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 Publically Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of patients begins.  Results will be posted as required. 
10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  Should this be necessary, the 
sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRBs/IECs.  In terminating the study, the sponsor and the investigator will 
assure that adequate consideration is given to the protection of the study participants’ interests. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
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• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
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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11.
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 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 03 August 2017. 
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 Auguest 2017. 
Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. American 
Journal of Obstetrics and Gynecology 1992;166(2):740-5. 
Cardozo ER. The estimated annual cost of uterine leiomyomata in the United States. American 
Journal of Obstetrics and Gynecology 2012;206(3):0092-0100. 
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://www.effectivehealthcare.ahrq.gov/ehc/products/152/642/DEcIDE31_UterineFibro 
id_03-07-2011.pdf. Accessed: 03 August 2017. 
Hallberg L, Nilsson L. Determination of menstrual blood loss. Scand J Clin Lab Invest. 
1964;16(2):244–248. 
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. 
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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. Clinical Practice. Uterine Fibroids. N Engl J Med. 2015;372(17):1646-55. 
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. 
Menorrhagia Impact Questionnaire 
In addition to the MIQ items listed in the table, patients describe all activities that were limited 
by excessive bleeding (MIQ item 5). 
 
Copyright ©, Ferring B.V., all rights reserved. 
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Appendix 2. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 
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Appendix 3. 
European Quality of Life Five-Dimension Five-Level Scale 
 
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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
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Appendix 4. 
Assessment of Abnormal Liver Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) should be withheld for any liver test abnormality 
listed in Section 7.5.1, pending investigation of alternative causes of liver injury.  Follow-up 
should continue until the liver test abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix 4 Table 1, and per the investigations 
in Appendix 4 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 4 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 4 Table 2 Investigations of Alternative Causes for Abnormal Liver Tests 
Obtain a detailed history and perform a physical examination: 
•
Detailed history of symptoms (eg, right upper quadrant pain, fatigue, nausea, vomiting, and
fever); 
•
Prior and concurrent disease or illnesses;
•
Exposure to environmental (eg, travel, new sexual exposure, exposure to ill family members or
coworkers, etc) and/or industrial chemical agents;
•
Prior and concurrent use of alcohol, recreational drugs, and special diets;
•
Concomitant use of medications (including nonprescription medicines and herbal and dietary
supplements), plants and mushrooms;
•
Physical examination.
Recommended tests: 
Also perform additional tests as clinically indicated or in consultation with a gastroenterologist or 
hepatologist. 
•
Repeat liver tests as per Appendix 4 Table 1a;
•
Obtain gamma-glutamyl transferase, albumin, INR, and glucose in conjunction with repeat
liver tests;
•
CBC with differential to assess for eosinophilia;
•
Serum acetaminophen (paracetamol) concentration;
•
Obtain viral serologies for hepatitis A, B, C, D, and E; consider testing for Epstein Barr virus;
•
Evaluate for alcoholic hepatitis, nonalcoholic steatohepatitis, biliary tract disease, autoimmune
hepatitis, etc;
•
Serology for celiac disease;
•
Appropriate liver imaging;
•
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist or
gastroenterologist).
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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SAP_001.pdf: 
Statistical Analysis Plan  
 
MVT-601-3003 
 
Myovant Sciences GmbH 
1 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN  
 
Study Titles: 
LIBERTY EXTENSION: An International Phase 3 
Open-Label, Single-Arm, Long-Term Efficacy and Safety 
Extension Study to Evaluate Relugolix Co-Administered with 
Low-Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
 
Investigational 
Product: 
 
Relugolix 
Protocol Number: 
MVT-601-3003 
 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
Regulatory 
Identifier(s): 
IND # 131161 
EudraCT # 2017-003310-74 
 
Version/Effective Date: 
31-Jan-2020 
 
 
 
 
 
 
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. 
1


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S T A TI S TI C A L A N A L Y SI S P L A N A P P R O V A L S H E E T 
LI B E R T Y E X T E N SI O N : A n I nt er n ati o n al P h as e 3 O p e n- L a b e l, Si n g l e- Ar m, L o n g- T er m 
Effi c a c y a n d S af et y E xt e n si o n St u d y t o E v a lu at e Re lu g oli x C o- A d m i nist er e d wit h L o w- D o se 
Estr a di o l a n d N or et hi n d r o n e A c et at e i n W o m e n wit h H e a v y M e n str ual Bl e e di n g As so ci at e d wit h 
Ut e ri ne Fi br oi ds 
T hi s st atisti c al a n a lysis pl a n h as b e e n a p pr o v e d b y M y o v a nt S ci e n c es G m b H. T h e f oll o wi n g 
si g n atur es d o c u m e nt t hj s a p pr o v a l. 
 
 
 
 
 
 
 
 
 
 
 
 
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M V T- 6 0 1- 3 0 0 3 
S T A TI S TI C A L A N A L Y SI S P L A N A P P R O V A L S H E E T 
LI B E R T Y E X T E N SI O N: A n I nt er n ati o n al P h as e 3 O p e n- L a b el, Si n gl e- A n n, L o n g- T er m 
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4


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
4 
CONFIDENTIAL 
 
5.1. 
Subject Disposition .....................................................................................................22 
5.2. 
Protocol Deviations ....................................................................................................22 
5.3. 
Demographic and Baseline Characteristics ................................................................22 
5.4. 
Medical History ..........................................................................................................24 
5.5. 
Prior Medications and Concomitant Medications ......................................................24 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................25 
7. 
EFFICACY ANALYSES ...........................................................................................26 
7.1. 
General Considerations ...............................................................................................26 
7.1.1. 
Analyses for Categorical Data ....................................................................................26 
7.1.2. 
Analyses for Continuous Data ....................................................................................26 
7.2. 
Primary Efficacy Endpoint .........................................................................................27 
7.2.1. 
Primary Efficacy Analysis ..........................................................................................27 
7.2.2. 
Definitions Related to Menstrual Blood Loss ............................................................27 
7.2.2.1. 
Menstrual Blood Loss Volume ...................................................................................27 
7.2.2.2. 
Baseline Menstrual Blood Loss Volume ....................................................................28 
7.2.2.3. 
Week 52/EOT Feminine Product Collection Interval ................................................28 
7.2.2.4. 
MBL Volume at Week 52/EOT ..................................................................................29 
7.2.2.5. 
Feminine Product Return Rate at Week 52/EOT .......................................................29 
7.2.3. 
Definition of Responder Status at Week 52/EOT .......................................................29 
7.2.4. 
Missing Data Handling Rules .....................................................................................30 
7.2.5. 
Subgroup Analyses .....................................................................................................32 
7.3. 
Secondary Efficacy Endpoints ....................................................................................33 
7.3.1. 
Percent Change from Baseline to Week 52 in MBL Volume ....................................33 
7.3.2. 
Proportion of Women Who Achieve Amenorrhea Over the Last 35 Days of 
Treatment ....................................................................................................................33 
7.3.2.1. 
Determination of Amenorrhea ....................................................................................33 
7.3.3. 
Change from Baseline in Hemoglobin .......................................................................34 
7.3.4. 
UFS-QoL Score ..........................................................................................................35 
7.3.5. 
Change from Baseline to Week 52 in Uterine Volume and Uterine Fibroid 
Volume .......................................................................................................................37 
7.3.6. 
Menorrhagia Impact Questionnaire ............................................................................37 
7.4. 
Exploratory Efficacy Endpoints .................................................................................37 
7.4.1. 
Exploratory Efficacy Analyses ...................................................................................37 
5


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
5 
CONFIDENTIAL 
 
8. 
PHARMACODYNAMIC ANALYSES .....................................................................38 
9. 
SAFETY ANALYSES ...............................................................................................39 
9.1. 
Adverse Events ...........................................................................................................39 
9.1.1. 
Relationship to Study Drug ........................................................................................40 
9.1.2. 
Severity of Adverse Event ..........................................................................................40 
9.1.3. 
Serious Adverse Event ................................................................................................41 
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug ...............................................41 
9.1.5. 
Adverse Events Leading to Dose Interruption ............................................................41 
9.1.6. 
Adverse Events Resulting to Fatal Outcome ..............................................................41 
9.1.7. 
Adverse Event Categories ...........................................................................................41 
9.1.8. 
Exposure-adjusted Adverse Events ............................................................................42 
9.2. 
Laboratory Data ..........................................................................................................42 
9.3. 
Other Safety Analyses ................................................................................................43 
9.3.1. 
Electrocardiograms .....................................................................................................43 
9.3.2. 
Vital Signs ..................................................................................................................44 
9.3.3. 
Endometrial Biopsy ....................................................................................................44 
9.3.4. 
Bone Mineral Density .................................................................................................46 
10. 
REFERENCES ...........................................................................................................48 
APPENDICES ...............................................................................................................................49 
APPENDIX 1:  LIST OF PRE-DEFINED THRESHOLD IN SELECTED CHEMISTRY 
AND HEMATOLOGY TEST RESULTS ..................................................................50 
 
6


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
6 
CONFIDENTIAL 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints ...................................................................................9 
Table 2: 
Visit Windows for Monthly Assessments ..................................................................18 
Table 3: 
Visit Windows for Bone Mineral Density Assessments .............................................19 
Table 4: 
Visit Windows for Week 12, 24, and 52 Assessments (ECG) ...................................19 
Table 5: 
Visit Windows for Week 12, 24, 36, and 52 Assessments (UFS-QoL) .....................19 
Table 6: 
Visit Windows for Week 24 and 52 Assessments (Transvaginal Ultrasound, 
EQ-5D-5L, Endometrial Biopsies) .............................................................................19 
Table 7: 
Time Window for Feminine Product Collection ........................................................20 
Table 8: 
Categories for Demographic and Baseline Characteristics ........................................23 
Table 9: 
LOCF Approach for Derivation of Responder Status at Week 52/EOT and 
Missing Data Handling Rules – for Primary Analysis ...............................................31 
Table 10: Planned Subgroup Analyses .......................................................................................32 
Table 11: Rules for Determining Amenorrhea by Visit ..............................................................34 
Table 12: Constitution of Adverse Event Categories .................................................................42 
Table 13: Categories of Liver Test Elevations ...........................................................................43 
Table 14: Categories of Potentially Clinically Significant Abnormalities in Vital Signs ..........44 
Table 15:  Categories of Primary Diagnosis in Endometrial Biopsies ........................................45 
Table 16: Planned Subgroup Analyses .......................................................................................47 
 
 
 
7


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
7 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS 
 
Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMD 
bone mineral density 
BMI 
body mass index 
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 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FP 
feminine product 
FPRR 
feminine product return rate 
HRQL 
health-related quality of life 
ICH 
International Council on Harmonisation 
LOCF 
last observation carried forward 
LS 
least squares 
MBL 
menstrual blood loss 
mITT 
modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
msec 
millisecond 
NETA 
norethindrone acetate 
NRS 
Numerical Rating Scale 
PT 
Preferred Term 
QTcF 
corrected QT interval Fridericia 
SAP 
statistical analysis plan 
SD 
standard deviation 
SMQ 
standard MedDRA query 
SOC 
System Organ Class 
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 
8


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12


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
12 
CONFIDENTIAL 
 
2. 
STUDY DESIGN 
2.1. 
Summary of Study Design 
The LIBERTY EXTENSION study is an international phase 3 open-label, single-arm, long-term 
efficacy and safety extension study that will enroll eligible patients who have completed their 
participation in one of the phase 3 randomized, double-blind, placebo-controlled parent studies 
(MVT-601-3001 or MVT-601-3002).  All patients will receive oral relugolix 40 mg once daily 
co-administered with low-dose estradiol 1 mg and norethindrone acetate 0.5 mg for 28 weeks.   
Approximately 600 women with heavy menstrual bleeding associated with uterine fibroids will 
be enrolled.  The objectives of the study are to evaluate long-term efficacy and safety through up 
to 52 weeks of treatment (including treatment during the parent study) with relugolix co-
administered with low-dose estradiol/norethindrone acetate.  Eligible patients will have 
completed participation in one of the parent studies and consented to participate in this extension 
study.   
Screening and baseline procedures will be done at the same visit for this extension study 
(referred to as the “Week 24/Baseline visit” in this study), which coincides with the Week 24 
visit from the parent study and will be defined as the date of completion of the last Week 24 
procedure in the parent study.   
Patients will have received their last dose of study drug in the parent study on the day prior to the 
Week 24/Baseline visit and will receive their first dose of study drug for this extension study in 
the clinic after the patient is determined to be eligible for this extension study and has provided 
informed consent to participate.  Study participants will then take the open-label study treatment 
(relugolix 40 mg co-administered with estradiol 1 mg and norethindrone acetate 0.5 mg) orally 
once daily for 28 weeks.   
At the Week 36 visit and Week 52/Early Termination visit, each patient will have an assessment 
of bone mineral density (BMD) by DXA.  
Patients who complete the study and are eligible may be enrolled in study MVT-601-035 at 
Week 52 visit after all Week 52 procedures for the MVT-601-3003 study have been completed.  
Patients who enroll directly into the MVT-601-035 study upon completion of the Week 52 visit 
will have the Follow-up visit and the follow-up procedures performed under this protocol, 
including the follow-up bone densitometry scan at 6 (± 1) months and status of menstruation 
recovery. 
2.2. 
Sample Size Considerations 
Because this is an extension study, the sample size will be determined by the numbers of patients 
who have completed either parent study (MVT-601-3001 or MVT-601-3002) and who are 
eligible and willing to participate in this study.  No formal statistical testing has been planned. 
13


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
13 
CONFIDENTIAL 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
An interim safety analysis will be performed for the study at the time when at least 100 patients 
in the parent studies Group A (relugolix + E2/NETA treatment group) have completed the Week 
52 study visit.  At this timepoint, all patients enrolled in the extension study, regardless of their 
treatment assignment in the parent studies, will have completed their Week 36 study visit.  The 
analysis cutoff date will be set as a date when at least 100 patients in the parent study Group A 
(relugolix + E2/NETA treatment group) complete the Week 52 study visit.  Data from any 
assessments after this date will be excluded for this interim safety analysis. 
3.2. 
Final Analyses 
The final analysis of all efficacy and safety data from MVT-601-3003 will occur after all patients 
who entered the study have had the opportunity to be followed for 28 weeks of open-label 
treatment with relugolix + E2/NETA and through the 30-day safety follow-up visit.   
3.3. 
Safety Follow-Up Analyses 
Patients who are not proceeding into study MVT-601-035 and who have endometrial hyperplasia 
or endometrial cancer on the endometrial biopsy should be treated as per standard of care and 
additional follow up should be evaluated and managed, as needed, by a gynecologist.  In 
addition, they should undergo a repeat biopsy in 3 to 6 months after the Week 52/Early 
Termination and will be contacted to obtain information on procedures performed or treatments 
received (if any) for the biopsy findings through the time of the repeat biopsy.  The repeat biopsy 
will be submitted to the central laboratory.  
Patients who are not proceeding into study MVT-601-035 and who have a BMD loss of > 3% at 
the lumbar spine (L1–L4) or total hip relative to the Baseline measurement at their Week 
52/Early Termination visit occurring on or after Week 36 will undergo a follow-up DXA scan 6 
months (± 1 month) after discontinuation of study drug and will be contacted to obtain 
information about medications and conditions (eg, pregnancy, hyperparathyroidism, 
hypothyroidism, etc.) that might affect BMD through the time of the repeat DXA scan.  Patients 
who have a BMD loss of > 2% at the lumbar spine (L1-L4) or total hip relative to the Baseline 
measurement at their Early Termination visit occurring prior to Week 36 will also undergo a 
follow-up DXA scan 6 months (± 1 month) after discontinuation of study drug.  All follow-up 
DXA scans will be submitted for central reading.   
Patients whose menses had not resumed as of the safety follow-up visit for unexplained reasons 
will be contacted by telephone to determine if menses have resumed.   
Data collected during the additional safety follow-up period which is available at the time of 
database lock will be summarized and reported in the clinical study report.  Complete data 
collected during the additional safety follow-up period will be summarized and reported in an 
addendum to the clinical study report. 
 
14


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16


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
16 
CONFIDENTIAL 
 
visit date.  The exact date of last dose of parent study drug will be known for all patients entering 
the MVT-601-3003 study.   
4.3.2. 
Definition of Date of First Dose and Date of Last Dose of Extension Study Drug 
The date of first dose of extension study drug is defined as the date when a patient receives the 
first dose of open-label study drug (relugolix or E2/NETA) in the MVT-601-3003 study.  The 
date of last dose of extension study drug is defined as the date a patient receives the last dose of 
open-label study drug in the MVT-601-3003 study.  If the complete date of last dose of extension 
study drug is unknown, the last date the extension study drug was dispensed will be used.  For 
patients missing only day for date of last dose of extension study drug, either first of the month 
of last dose of extension drug or last date extension study drug was dispensed will be used, 
whichever is later.   
4.3.3. 
Study Day 
Study day will be calculated with respect to the date of the first dose of study drug in the parent 
study (Study Day 1).  For assessments conducted on or after the date of the first dose of parent 
study drug, study day will be calculated as: 
(Assessment date – date of first dose of parent study drug) + 1 
For assessments conducted before the date (and time) of the first dose of parent study drug, study 
day will be calculated as: 
(Assessment date – date of first dose of parent study drug) 
4.3.4. 
Extension Study Day 
Extension study day will be calculated with respect to the date of the first dose of open-label 
study drug in the extension study (Extension Study Day 1).  For assessments conducted on or 
after the date of the first dose of extension study drug, extension study day will be calculated as: 
(Assessment date – date of first dose of extension study drug) + 1 
For assessments conducted before the date (and time) of the first dose of extension study drug, 
extension study day will be calculated as: 
(Assessment date – date of first dose of extension study drug) 
For patients who do not receive any amount of extension study drug, extension study day will be 
calculated as above with respect to the date of enrollment in the extension study. 
4.3.5. 
Definition of Treatment Duration 
Overall treatment duration is defined as the duration of time from the date of the first dose of 
parent study drug to the date of the last dose of extension study drug as follows:  
(Date of last dose of extension study drug – Date of first dose of parent study drug) + 1 
For patients missing day and month for date of last dose of extension study drug, the last date 
extension study drug was dispensed will be used to calculate treatment duration.  For patients 
missing only day for date of last dose of extension study drug, the later of first of the month of 
17


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
17 
CONFIDENTIAL 
 
last dose of extension drug or last date extension study drug was dispensed will be used to 
calculate treatment duration.     
4.3.6. 
Definition of Extension Study Treatment Duration 
Treatment duration in the extension study is defined as the duration of time from the date of the 
first dose of extension study drug to the date of the last dose of extension study drug as follows:  
(Date of last dose of extension study drug – Date of first dose of extension study drug) + 1 
For patients missing day and month for date of last dose of extension study drug, the last date 
extension study drug was dispensed will be used to calculate treatment duration.  For patients 
missing only day for date of last dose of extension study drug, the later of first of the month of 
last dose of extension drug or last date extension study drug was dispensed will be used to 
calculate treatment duration.     
4.3.7. 
Definition of Baseline Value and Post-Baseline Value 
Unless otherwise specified, Baseline values are defined as the last measurement before the first 
administration (date and time) of study drug in the parent study.  A post-Baseline value is 
defined as a measurement taken after the first administration 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. 
4.3.8. 
Visit Windows 
Visit windows, which will be used to associate assessments with a scheduled visit, will be used 
only for summarizing data by visit.  The windows for scheduled assessments are shown in 
Table 2, Table 3 (BMD), Table 4 (electrocardiogram [ECG]), Table 6 (UFS-QoL), and Table 6 
(transvaginal ultrasound and EQ-5D-5L) respectively.  For safety assessments, the study day will 
be used to determine the associated visit window.  There will be no separation of data from the 
parent and extension study.  For example, if an assessment in the extension study falls in the 
Week 24 visit window, it will be summarized as Week 24. 
If the results from more than one assessment are within a given visit window, the non-missing 
result from the assessment closest to the target date will be used.  If two assessments are equally 
close to the target day, the earlier assessment will be used.  For summaries of shift from Baseline 
in safety parameters, all values will be considered for these analyses. 
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Statistical Analysis Plan  
 
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CONFIDENTIAL 
 
Table 2: 
Visit Windows for Monthly Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 4a 
1 
29 
43 
Week 8 
44 
57 
71 
Week 12 
72 
85 
99 
Week 16 
100 
113 
127 
Week 20 
128 
141 
155 
Week 24 
156 
169 
183 
Week 28 
184 
197 
211 
Week 32 
212 
225 
239 
Week 36 
240 
253 
267 
Week 40 
268 
281 
295 
Week 44 
296 
309 
323 
Week 48 
324 
337 
351 
Week 52 
352 
365 
Date of last dose + 6b 
Safety Follow-Upc 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a Start day of Week 4 for study day 1 includes only post-Baseline assessments that occurred after the first dose. 
b End day of Week 52 is date of last dose + 1 for patients entering the MVT-601-035 study. 
c The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids. 
 
 
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Statistical Analysis Plan  
 
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CONFIDENTIAL 
 
Table 3: 
Visit Windows for Bone Mineral Density Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 36 
197 
253 
308 
Week 52 
309 
365 
421 
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 extension study drug + 30 days will also be excluded from analysis. 
Table 4: 
Visit Windows for Week 12, 24, and 52 Assessments (ECG) 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 52 
309 
365 
421 
 
Table 5: 
Visit Windows for Week 12, 24, 36, and 52 Assessments (UFS-QoL) 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Week 36 
197 
253 
308 
Week 52 
309 
365 
421 
Safety Follow-upa 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical intervention 
for uterine fibroids. 
 
Table 6: 
Visit Windows for Week 24 and 52 Assessments (Transvaginal Ultrasound, 
EQ-5D-5L, Endometrial Biopsies)   
Visit 
Start Day 
Target Day 
End Day 
Week 24 
128 
169 
196 
Week 52 
309 
365 
421 
Safety Follow-upa 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids. 
20


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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
23 
CONFIDENTIAL 
 
Table 8: 
Categories for Demographic and Baseline Characteristics  
Variable 
Category 
Age (years) 
< 40, ≥ 40  
Geographic region 
North America, Rest of World 
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 
BMI (kg/m2) at Baseline 
< 18.5, 18.5 to <25, 25 to <30, 30 to < 35,  
35 to < 40, ≥ 40 
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 Baseline (cm3) 
< 25, ≥ 25 
Volume of uterus at Baseline (cm3) 
< 300, ≥ 300 
Menstrual blood loss volume at Baseline (mL) 
< 225, ≥ 225 
Menstrual blood loss volume at Baseline (mL) 
< 160, ≥ 160 
Hemoglobin at Baseline (g/dL) 
Min to < 8, ≥ 8 to <10.5, ≥ 10.5 to <12, ≥ 12 
UFS-QoL 
Bleeding and Pelvic Discomfort Scale 
 
0 to < 25, 25 to <50, 50 to <75, 75 to 100 
Maximum NRS score for uterine fibroid-
associated pain at Baseline 
< 4, ≥ 4 
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 
Abbreviations:  BMI = body mass index; NRS = Numerical Rating Scale; UFS-QoL = Uterine Fibroid Symptom 
and Health-Related Quality of Life. 
 
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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
24 
CONFIDENTIAL 
 
5.4. 
Medical History 
Medical history collected at the time of entry into the parent study will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) and will be summarized by system 
organ class (SOC) and preferred term (PT) for the Extension Safety population.  Additionally, 
summaries of uterine fibroid–specific medical and surgical treatment history collected at the time 
of entry into the parent study will be provided.  A patient with multiple occurrences of medical 
history within a PT will be counted only once in that PT. 
5.5. 
Prior Medications and Concomitant Medications 
Prior medications and concomitant medications taken during the parent and extension study 
treatment period will be summarized for all patients in the Extension Safety population by parent 
study treatment group.  Medications are considered concomitant if exposure occurs during the 
parent or extension treatment period.  Medications are considered prior if exposure started prior 
to the date of first dose of parent study drug.   
The number and percentage of patients who took at least one dose of a prior medication for 
treatment of uterine fibroids will be summarized by parent study 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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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
25 
CONFIDENTIAL 
 
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 the parent study.  Extent of exposure to relugolix and E2/NETA during the 
extension study will be summarized for patients in the Extension Safety population.  Overall 
exposure to relugolix (with or without E2/NETA), overall exposure to E2/NETA, and overall 
exposure to any study drug (relugolix [with or without E2/NETA] and placebo) throughout the 
parent study and extension study will be summarized by parent study treatment group.  
Compliance with open-label study drug during the extension study for the Extension Safety 
population will be summarized by parent study treatment group.  Overall compliance with study 
drug throughout the parent study and extension study will be summarized by parent study 
treatment group.  Exposure to and compliance with relugolix and E2/NETA will be summarized 
separately and will be based on the drug accountability case report forms. 
Study drug exposure summaries will include the total dosage of relugolix and E2/NETA taken in 
milligrams and treatment duration.  Total dosage of relugolix and E2/NETA taken during the 
extension study and overall, throughout the parent and extension studies, will be summarized by 
parent study treatment group.  Treatment duration during the extension study and overall with 
any study drug (relugolix, E2/NETA, or placebo) will be summarized by parent study treatment 
group. 
Study drug compliance will be summarized for the extension study treatment period and for the 
overall parent and extension study treatment period, and will be calculated as follows: 
(total tablets taken / total tablets expected to be taken) × 100 
The total tablets taken will be calculated as:   
(total tablets dispensed - total tablets returned) 
The total tablets expected to be taken is calculated as the total number of tablets a patient is 
expected to take each day times the length of time (in days) that the patient was in the 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 extension study visits after week 24 and did not return dispensed 
extension study drug, extension study drug compliance will not be calculated and will be 
categorized as “not able to calculate” in summaries of extension study drug compliance. 
Summary statistics of study drug compliance (eg, mean, median, etc.) will be presented, along 
with a categorical summary (eg, < 80%, 80% to 100%, > 100%). 
 
 
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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
26 
CONFIDENTIAL 
 
7. 
EFFICACY ANALYSES 
7.1. 
General Considerations 
Efficacy analyses will be conducted on the Extension Study population according to the parent 
study randomized treatment assignment.  Stratified analyses will incorporate the randomization 
stratification factors.  If the group of patients at any factor level from a randomization 
stratification factor (eg, patients with Baseline MBL volume ≥ 225 mL) comprises < 10% of the 
entire mITT population, this stratification factor (eg, Baseline MBL volume) will not be used for 
stratified analyses.  In addition, if there are < 15 patients in 1 of the 4 strata (derived from the 2 
stratification factors each with 2 levels), only stratification factor of Baseline MBL volume (< 
225 versus ≥225 mL) 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.     
No formal treatment comparisons will be performed for this extension study.  As there is no 
inferential statistics for this analysis, there is no need for multiplicity adjustment.  
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 
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 will also be calculated for each visit, including only the patients who are 
in the analysis who have data for that visit by treatment group. 
For endpoints evaluating the change (absolute or percent change) from Baseline to Week 52, 
mean change as well as least squares (LS) means change and 95% CI will be summarized. LS 
means and 95% CI will be derived separately for each treatment group using a mixed model 
repeated measures approach with randomization stratification factors 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 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 4.3.8.  In addition, summary statistics (mean change or mean % change) will be 
graphically presented as appropriate.   
27


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32


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
32 
CONFIDENTIAL 
 
efficacy or for 
surgical 
intervention for 
uterine fibroids 
Completed study 
or discontinued 
early for other 
reasons 
 
100%  
FP 
Compliance 
N/A 
N/A 
Responder based 
on the observed 
MBL volume 
<100% 
FP 
Compliance 
 
MBL volume 
≥ 80 mL or 
<50% reduction 
from Baseline 
N/A 
Non-responder 
based on the 
observed MBL 
volume 
MBL volume 
< 80 mL and 
≥ 50% reduction 
from Baseline 
N/A 
Based on LOCF 
MBL volume 
No FP 
Collection  
N/A 
 
 
Reported “Amenorrhea”a  
Responder  
Reported “Spotting or 
negligible bleeding” 
confirmed by Diaryb 
Responder  
Reported “Amenorrhea” 
or “Spotting or negligible 
bleeding” which was not 
confirmed, or other reason 
for no FP collection 
Based on LOCF 
MBL volume 
Abbreviations:  FP, feminine product; EOT, end of treatment; MBL, menstrual blood loss; N/A, not available. 
a Amenorrhea confirmed if Week 52/EOT visit interval is ≥ 35 days, if amenorrhea reported at prior visit, or if paper 
diary confirms no bleeding/spotting with use of feminine product for a total of 35 days.  
b Defined as those patients who meet the following criteria:  Diary entry rate > 70% and no more than 3 consecutive 
days and no more than 5 total days of bleeding/spotting and use of feminine product reported on the Diary over the 
Week 52/EOT visit window (see Table 7).  
 
7.2.5. 
Subgroup Analyses 
Subgroup analyses of the primary efficacy endpoint will be performed to assess whether 
response rate is consistent across clinically important subgroups.  The response rate and 95% CI 
may be displayed in a separate forest plot for each subgroup.  Subgroups will include, but will 
not be limited to, the subgroups outlined in Table 10. 
Table 10: 
Planned Subgroup Analyses  
Subgroup Name  
Subgroup Level 
Geographic region  
North America vs Rest of World 
33


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36


Statistical Analysis Plan  
 
MVT-601-3003 
Myovant Sciences GmbH 
36 
CONFIDENTIAL 
 
 
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 ONLY: 
Transformed Score = [(Actual raw score – lowest possible raw score)/(Possible raw score 
range)] * 100 
On the basis of transformed score for BPD Scale, change from Baseline in the transformed score 
for BPD Scale at Week 52 will be defined as a secondary endpoint.  The proportion of patients 
who are responders (defined as meeting a meaningful change threshold from Baseline in the 
BPD Scale) at Week 52 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 
Baseline to Week 52 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.  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. 
 
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. 
a HRQL Total includes following scales: concern, activities, energy/mood, control, self-conscious, and sexual 
function. 
37


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Statistical Analysis Plan  
 
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CONFIDENTIAL 
 
8. 
PHARMACODYNAMIC ANALYSES 
Serum pharmacodynamic data for the extension study consists of serum E2 trough 
concentrations.  This data will be listed and summarized using descriptive statistics (including 
raw and change from Baseline) by parent study treatment group, and visit.  The number and 
percentage of patients with individual E2 concentration values < 10 pg/mL, 10 to < 20 pg/mL, 20 
to < 50 pg/mL, 50 to < 70 pg/mL and ≥ 70 pg/mL will be summarized by parent study treatment 
group and visit.  E2 concentration values below the limit of quantification will be set to half of  
the lower limit of quantification.  Boxplots of E2 concentration values over time, including visits 
in both the parent study and extension study, will be plotted.   
 
39


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42


Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
 
Table 12: 
Constitution of Adverse Event Categories 
Category 
Search Criteria 
Bone health 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 (broad) 
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 = Standardised MedDRA Query.   
9.1.8. 
Exposure-adjusted Adverse Events 
Adverse events by time to onset and an exposure-adjusted adverse event analysis will be 
provided.  The exposure-adjusted adverse event rate will be summarized by system organ class 
and preferred term for each parent study treatment group, where the exposure-adjusted adverse 
event rate is calculated as number of patients with a particular adverse event by total exposure-
time among patients at risk of an initial occurrence of the event.  Exposure-time is derived as 
exposure to any study drug throughout the parent and extension study. 
9.2. 
Laboratory Data 
Laboratory parameters, including chemistry and hematology panels, specified as per protocol for 
the parent and extension studies, and collected from the central laboratory will be tabulated and 
presented in by-patient listings.  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 gradable parameter to summarize Baseline toxicity grade versus worst 
post-Baseline toxicity grade throughout the parent and extension studies.  For laboratory 
parameters that are not gradable by the CTCAE, a shift table based upon the normal range (low, 
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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
 
normal, and high) will be provided for each parameter to summarize the Baseline versus worst 
post-Baseline results throughout the parent and extension studies. 
Boxplots of laboratory values over time, including visits in both the parent study and extension 
study, will be plotted for key laboratory parameters.  These laboratory parameters include, but 
are not limited to, hematology (hemoglobin, platelets, leukocytes, neutrophils), creatinine, 
glomerular filtration rate, and hepatic function panel (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin). 
The change from Baseline to each post-Baseline study visit will be presented by parent study 
treatment group for each laboratory test in both tables and figures. 
The number and proportion of patients with liver test elevations will be presented by parent 
study treatment group.  Liver test elevations are assessed by using post-Baseline results for ALT, 
AST, ALP, and total bilirubin based on the definitions presented in Table 13. 
Table 13: 
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 1) by parent study treatment group. 
9.3. 
Other Safety Analyses 
9.3.1. 
Electrocardiograms 
ECG interval results and changes from Baseline will be summarized descriptively for each 
scheduled visit, including visits in both the parent study and extension study, in both tables and 
figures using data provided by and read by central reading. 
A categorical analysis of corrected QT interval using Fridericia’s calculation (QTcF) intervals 
will also be performed for each scheduled visit and for the maximum post-Baseline value.  The 
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Statistical Analysis Plan  
 
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Myovant Sciences GmbH 
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CONFIDENTIAL 
 
number and percentage of patients in each QTcF interval category (< 450 msec, 450 to 480 msec, 
481 to 500 msec, and > 500 msec) will be summarized.  Categories of changes from Baseline 
(≥ 30 msec and ≥ 60 msec) will be summarized as well. 
ECG intervals will be presented in by-patient listing.  Overall ECG assessments performed by 
local reading will also be listed. 
9.3.2. 
Vital Signs 
Blood pressure (systolic and diastolic), heart rate, and BMI will be summarized at Baseline and 
each subsequent scheduled assessment, including visits in both the parent study and extension 
study, by parent study treatment group.  Change from 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 14, 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 14: 
Categories of Potentially Clinically Significant Abnormalities in Vital Signs 
Parameter 
Category 
Systolic blood pressure 
≥ 140 mmHg 
≥ 180 mmHg  
≤ 90 mmHg 
Increase of ≥ 20 mmHg from Baseline 
Decrease of ≥ 20 mmHg from Baseline 
Diastolic blood pressure  
≥ 90 mmHg 
≥ 105 mmHg 
≤ 50 mmHg 
Increase of ≥ 15 mmHg from Baseline 
Decrease of ≥ 15 mmHg from Baseline 
Heart rate 
≥ 120 bpm 
< 45 bpm 
Increase of ≥ 15 bpm from Baseline 
Decrease of ≥ 15 bpm from Baseline 
Abbreviations:  bpm = beats per minute; mmHg = millimeters of mercury. 
 
9.3.3. 
Endometrial Biopsy 
The protocol-specified endometrial biopsy procedure is performed at the Week 52 or Early 
Termination Visit in the extension study.  Consensus readings were performed on all endometrial 
biopsies.  Endometrial biopsies will be summarized according to primary diagnosis categories 
45


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BMD percentage changes from Baseline will also be summarized by intrinsic factors (eg, age, 
race, body mass index) and extrinsic factors (eg, geographic region).  Subgroups will include, but 
will not be limited to, the subgroups outlined in Table 16.  
Table 16: 
Planned Subgroup Analyses  
Subgroup Name 
Subgroup Level 
Geographic region 
North America, Rest of World 
Age category (years) 
< 40, ≥ 40  
Race 
Black or African American, Not Black or African American 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino  
BMI (kg/m2) at Baseline 
<30, ≥ 30  
Abbreviations:  BMI = body mass index. 
Patients not enrolling in the MVT-601-035 study who had evidence of BMD loss of > 3% at the 
lumbar spine (L1 to L4) or total hip at their Week 52/EOT visit relative to the pre-treatment 
baseline measurement and patients who has evidence of BMD loss of > 2% at the lumbar spine 
(L1 to L4) or total hip at their EOT occurring prior to Week 36, underwent further testing and 
follow-up to evaluate recovery per the protocol.  All available 6-month and 12-month post-
treatment follow-up BMD data will be summarized to display the number and percent of patients 
who completed post-treatment follow-up, who met the threshold for recovery, and who did not 
meet the threshold for recovery. 
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10. 
REFERENCES 
2015 International Society for Clinical Densitometry (ISCD) Official Positions – Adult 
(https://www.iscd.org/official-positions/2015-iscd-official-positions-adult/; accessed 
30 Apr 2019). 
Leslie WD, Lix LM, Tsang JF, Caetano PA.  Single-site vs Multisite Bone Density Measurement 
for Fracture Prediction.  Arch Intern Med 2007; 167 (15): 1641-7 
 
 
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APPENDICES 
 
 
 
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APPENDIX 1:  LIST OF PRE-DEFINED THRESHOLD IN SELECTED 
CHEMISTRY AND HEMATOLOGY TEST RESULTS 
Chemistry Laboratory 
Liver Function 
 
  ALT > ULN and < 3× ULN 
  Total BILI > ULN 
  ALT ≥ 3× ULN and < 5× ULN 
  Total BILI >2× ULN 
  ALT ≥ 5× ULN and < 10× ULN 
 
  ALT ≥ 10× ULN and < 20× ULN 
  ALT or AST ≥ 3× ULN and Total BILI > 2× ULN 
  ALT ≥ 20× ULN 
  ALT or AST ≥ 3× ULN and Total BILI > 2× ULN 
and ALP < 2× ULN 
 
   
  AST > ULN and < 3× ULN 
  GGT > ULN and < 3× ULN 
  AST ≥ 3× ULN and < 5× ULN 
  GGT ≥ 3× ULN and < 5× ULN 
  AST ≥ 5× ULN and < 10× ULN 
  GGT ≥ 5× ULN and < 10× ULN 
  AST ≥ 10× ULN and < 20× ULN 
  GGT ≥ 10× ULN and < 20× ULN 
  AST ≥ 20× ULN 
  GGT ≥ 20× ULN 
 
   
  ALT or AST > ULN and < 3× ULN 
 
  ALT or AST ≥ 3× ULN and < 5× ULN 
 
  ALT or AST ≥ 5× ULN and < 10× ULN 
 
  ALT or AST ≥ 10× ULN and < 20× ULN 
 
  ALT or AST ≥ 20× ULN 
 
 
 
Renal Function 
 
  CR > 1.5 mg/dL and > BL 
  GFR < 15 mL/min per 1.73 m2 
  CR > 50% increase from BL 
  GFR ≥ 15 - < 30 mL/min/1.73 m2 
 
  GFR ≥ 30 - < 60 mL/min min/1.73 m2 
 
  GFR ≥ 60 - < 90 mL/min min/1.73 m2 
 
  GFR ≥ 90 mL/min min/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 at Week 24 
   Gluc ≥ 200 mg/dL and ≥ 126 BL 
          ≥ 100 - < 126 mg/dL at Week 24 
   Gluc ≥ 500 mg/dL  
          ≥ 126 mg/dL at Week 24 
   Gluc ≥ 500 mg/dL and ≥ 126 BL 
 
 
      ≥ 100 - < 126 mg/dL at BL 
Total CHOL > 200 mg/dL and > BL 
          < 100 mg/dL at Week 24 
Total CHOL increase > 30 mg/dL from BL 
          ≥ 100 - < 126 mg/dL at Week 24 
 
          ≥ 126 mg/dL at Week 24 
HDL < LLN and < BL 
 
LDL > ULN and > BL 
     ≥ 126 mg/dL at BL 
TRIG > ULN and > BL 
         < 100 mg/dL at Week 24 
 
         ≥ 100 - < 126 mg/dL at Week 24 
 
         ≥ 126 mg/dL at Week 24 
 
 
 
Electrolytes and other Chemistry Parameters 
 
ALB < LLN and < BL 
CK > 2× ULN and > BL 
ALB > ULN and > BL 
CK > 5× ULN and > BL 
 
CK > 10× ULN and > BL 
ALP > 2× ULN and > BL 
 
ALP > 5× ULN and > BL 
MG < LLN and < BL 
ALP > 10× ULN and > BL 
MG > ULN and > BL 
 
 
CA < LLN and < BL 
PHOS < LLN and < BL 
CA > ULN and > BL 
PHOS > ULN and > BL 
 
 
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K < LLN and < BL 
NA < LLN and < BL 
K > ULN and > BL 
NA > ULN and > BL 
 
 
Hematology Laboratory 
HCT < LLN and < BL 
NEUT < LLN and < BL 
HCT decrease ≥ 10 from BL 
NEUT > ULN and > BL 
 
 
HGB ≤= 10.5 g/dL and < BL 
BASO < LLN and < BL 
HGB decrease > 1 g/dL from BL 
BASO > ULN and > BL 
 
 
MCV < LLN and < BL 
EOS < LLN and < BL 
MCV > ULN and > BL 
EOS > ULN and > BL 
 
EOS > 5% and > BL 
WBC < LLN and < BL 
 
WBC > ULN and > BL 
PLT < LLN and < BL 
 
PLT < 100 × 109/L and < BL 
LYM < LLN and < BL 
PLT > ULN and > BL 
LYM > ULN and > BL 
 
 
HbA1c ≥ 6.5 and > BL 
MONO < LLN and < BL 
HbA1c increase > 1.0 from BL 
MONO > ULN and > BL 
 
Abbreviations:  ALB = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase ; BL = baseline; BILI = bilirubin; CA = calcium; CHOL = cholesterol; CR = creatinine; EOS = eosinophils; 
GGT = gamma-glutamyl transferase;  HCT = hematocrit; HDL = high-density lipoprotein; HbA1c = hemoglobin A1C; HGB 
= hemoglobin; K = potassium; LDL = low-density lipoprotein; LLN = lower limit of normal; LYM = lymphocytes; MG = 
magnesium; MCV = mean corpuscular volume; MONO = monocytes; NA = sodium; PHOS = phosphorus; PLT = platelets; 
ULN = upper limit of normal; WBC = while blood cells. 
 
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