LIBERTY 1: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered With and Without Low-Dose Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids
Phase: PHASE3
Conditions: Heavy Menstrual Bleeding, Uterine Fibroid
Sponsor: Myovant Sciences GmbH

 
 Study Title:  
LIBERTY 1: An International Phase 3 Randomized, 
Double- Blind, Placebo-Controlled Efficacy and Safety 
Study to Evaluate Relugolix Co-Administered with and 
without Low-Dose Estradiol and Norethindrone Acetate in 
Women with Heavy Menstrual Bleeding Associated with 
Uterine Fibroids 
 
 
NCT Number:  
03049735 
 
Document Date: 
Protocol Original: 10-NOV-2016 
Protocol Amendment 1: 08-FEB-2017 
Protocol Amendment 2: 18-SEP-2017 
  
 
 
 
 
 

CLINICAL STUDY PROTOCOL 
 
Study Title: 
LIBERTY 1:  An International Phase 3 Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate Relugolix Co-Administered with and without Low-
Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3001 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
Regulatory Identifier(s): 
EudraCT # 2016-003727-27 
IND # 131161 
Version and 
Effective Date: 
Original:  10-NOV-2016 
Amendment 1:  08-FEB-2017 
Amendment 2:   18-SEP-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The information contained in this document, particularly unpublished data, is the property or 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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MVT-601-3001 CSR - Appendix 16.1.1. Protocol and Protocol Amendments
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MVT-601-3001 CSR - Appendix 16.1.1. Protocol and Protocol Amendments
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PPD

Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
AMENDMENT 2:  SUMMARY OF CHANGES 
Protocol MVT-601-3001 entitled “LIBERTY 1:  An International Phase 3 Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered 
with and without Low-Dose Estradiol and Norethindrone Acetate in Women with Heavy 
Menstrual Bleeding Associated with Uterine Fibroids” has been amended as described in the 
table below.  The main purpose of the amendment was to provide clarification regarding roll-
over of patients into the extension study MVT-601-3003 and follow-up assessments for patients 
who do not enroll in the extension study.  Modifications were also made to the secondary 
efficacy endpoints related to disease related symptoms and impact of disease on activities, 
function and quality of life.  This includes the addition of a new patient global assessments for 
function and symptoms.  The amendment also includes modifications or clarifications to study 
eligibility as well as study procedures or tests.  A detailed list of changes is described below.  
Note that corrections of typos, minor clarifications and minor wording changes to improve 
readability and understanding are not included in this table.  
 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Synopsis: 
Location 
Multinational, including North 
and South America, Europe, and 
Australia 
Multinational, including North 
and South America, South 
Africa, and Europe and 
Australia 
To update regions 
where study is 
conducted. 
Title Page: 
Sponsor 
Myovant Sciences GmbH 
c/o Vischer AG 
Aeschenvorstadt 4 
CH-4010 Basel 
Switzerland 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
Sponsor address 
updated. 
Synopsis: 
Secondary 
Efficacy 
Objectives 
Section 3 Study 
Objective and 
Endpoints 
• To determine the benefit of 24 
weeks of relugolix 40 mg once 
daily co-administered with 
either 12 or 24 weeks of low 
dose estradiol and norethindrone 
acetate compared with placebo 
for 24 weeks on the following: 
… 
 
None. 
 
 
 
 
None. 
 
• 
To determine the benefit of 24 
weeks of relugolix 40 mg once 
daily co-administered with 
either 12 or 24 weeks of low 
dose estradiol and 
norethindrone acetate 
compared with placebo for 24 
weeks on the following: 
… 
o Impact of uterine fibroids on 
symptoms, activities, and 
health-related quality of life as 
measured by components of 
the Uterine Fibroid Symptom 
and Health-Related Quality of 
Life (UFS-QOL); 
o Patient global assessment for 
function and symptoms as 
measured by the Patient 
Global Assessment (PGA) for 
To add a new 
secondary efficacy 
objective related to 
the impact of uterine 
fibroids on 
symptoms, 
activities, and QOL 
and to add a patient 
global assessment 
for function and 
symptoms. 
Clarified the 
instrument to be 
used for assessing 
impact of heavy 
menstrual bleeding 
on social, leisure 
and physical 
activities.  
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
 
 
o Impact of heavy menstrual 
bleeding on social, leisure, and 
physical activities; 
function and symptoms; 
o Impact of heavy menstrual 
bleeding on social, leisure, and 
physical activities as 
measured by the 
Menorrhagia Impact 
Questionnaire (MIQ); 
o Pain associated with uterine 
fibroids; 
 
Synopsis: Safety 
Objectives  
Section 3 Study 
Objective and 
Endpoints 
 
None. 
 
 
 
 
None. 
• To determine the percent 
change from Baseline to Week 
12 in bone mineral density at 
the lumbar spine (L1-L4) in 
Group A compared with 
Group B in women with heavy 
menstrual bleeding associated 
with uterine fibroids; 
• To determine the incidence of 
vasomotor symptoms with 
relugolix 40 mg once daily co-
administered with either 12 or 
24 weeks of low-dose estradiol 
and norethindrone acetate in 
women with heavy menstrual 
bleeding associated with 
uterine fibroids. 
Objectives related to 
BMD analysis at 12 
weeks and analysis 
of vasomotor 
symptoms are added 
Synopsis: Study 
Design 
Section 4.1 
Overall Study 
Design 
Section 5.1 
Treatments 
Administered 
During the randomized treatment 
period, study participants will 
take blinded study treatment 
orally once daily for 24 weeks.   
During the Randomized 
Treatment Period, study 
participants will take the blinded 
study treatment (1 tablet and 1 
capsule) orally once daily for 24 
weeks.  The last dose of study 
drug for the Randomized 
Treatment Period will be taken 
on the immediate day prior to 
the Week 24 visit. 
 
To allow transition 
into the extension 
study (MVT-601-
3003). Week 24 visit 
will be the first day 
of MVT-601-3003. 
Patients who qualify 
for and provide 
informed consent to 
enroll in MVT-601-
3003 will take the 
first dose of open 
label study drug at 
Week 24.  
Synopsis: Study 
Design 
 
All patients completing the Week 
24 visit, including women 
randomized to placebo, will be 
offered the opportunity to enroll 
in an open-label extension study 
in which all eligible patients will 
receive relugolix co-administered 
with low-dose estradiol and 
norethindrone acetate.  Patients 
During the Randomized 
Treatment Period, study 
participants will take the blinded 
study treatment (1 tablet and 1 
capsule) orally once daily for 24 
weeks.  The last dose of study 
drug for the Randomized 
Treatment Period will be taken 
on the day immediately before to 
Added additional 
text to provide 
details on the 
transition of patients 
into the extension 
study (MVT601-
3003).  The Week 
24 visit will be the 
first day of the 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
who do not enroll into the 
extension study will have a 
follow-up visit to assess safety 
approximately 30 days after the 
end of treatment (ie, after the 
patient’s last dose of study 
medication). 
the Week 24 visit. 
Eligible patients, including 
women randomized to placebo, 
will be offered the opportunity to 
enroll in a 28-week open-label 
extension study where patients 
will receive relugolix co-
administered with low-dose 
estradiol and norethindrone 
acetate.  Patients who do not 
enroll into the extension study 
will have a Follow-Up visit 
approximately 30 days after the 
patient’s last dose of study drug.  
Patients who are not proceeding 
to the extension study and who 
have endometrial hyperplasia or 
endometrial cancer on the 
endometrial biopsy or bone 
mineral density loss of > 2% at 
the lumbar spine (L1-L4) or total 
hip at their Week 24/Early 
Termination visit relative to the 
baseline measurement will 
undergo further testing and 
follow-up to evaluate recovery 
(see Section 6.6).  Patients whose 
menses has not resumed as of the 
Follow-Up visit for unexplained 
reasons (eg, not explained by 
concomitant medications or 
medical procedures) will be 
contacted by telephone to 
determine if menses has resumed 
(see Section 6.6).  Patients with 
reductions in visual acuity will be 
referred for ophthalmology 
consultation (see Section 6.8.2.8). 
extension study.  
Also added 
additional follow-up 
activities for patients 
not enrolling into 
the extension study. 
 
 
 
Synopsis: 
Inclusion 
Criteria  
Section 4.3.1 
Inclusion 
Criteria 
Section 4.7 
Contraception/ 
Pregnancy 
Avoidance 
 
8. Agrees to use two forms of 
nonhormonal contraception (dual 
contraception, as described in 
Section 4.7) consistently during 
the screening period, and the 
randomized treatment period.  
However, the patient is not 
required to use dual contraception 
if she:  
… 
 
 
 
 
8. Agrees to use two forms of 
nonhormonal contraception 
during the study and for 30 
days following the last dose of 
study drug.  Specifically agrees 
to use nonhormonal 
contraception, (dual 
contraception as described in 
Section 4.7 consistently during 
the Screening period, and the 
Randomized Treatment Period 
and either nonhormonal or oral 
contraceptives after return of 
menses following treatment 
To specify use of 
contraceptives for 
30 days following 
treatment.  
Also removed the 
requirement for dual 
nonhormonal 
contraception as 
spermicide is not 
available in all 
countries.   
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
 
 
 
 
 
 
c. Is not sexually active with 
men; periodic sexual 
relationship(s) with men requires 
the use of dual non-hormonal 
contraception as noted above; 
discontinuation.  However, the 
patient is not required to use dual 
specified non-hormonal 
contraception if she:  
… 
c. Is not sexually active with 
men; periodic sexual 
relationship(s) with men requires 
the use of dual non-hormonal 
contraception as described in 
Section 4.7; 
Synopsis: 
Inclusion 
Criteria   
Section 4.3.1 
Inclusion 
Criteria 
9. Has an adequate endometrial 
(aspiration) biopsy performed 
during the screening period, with 
results showing no clinically 
significant endometrial pathology 
(hyperplasia, polyp, or 
endometrial cancer).  Note:  
polyps < 2.0 cm by ultrasound 
are not excluded; 
9. Has an adequate endometrial 
(aspiration) biopsy performed 
during the screening period, with 
results showing no clinically 
significant endometrial pathology 
(hyperplasia, polyp, or 
endometrial cancer).  Note: 
polyps < 2.0 cm by ultrasound 
are not excluded; Patients for 
whom polyps are detected on 
biopsy but are either not 
evident on ultrasound or <2 cm 
are eligible; 
To provide clarity. 
Synopsis: 
Exclusion 
Criteria  
Section 4.3.2 
Exclusion 
Criteria 
4. Has a weight that exceeds the 
weight limit of the DXA scanner; 
4. 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 or 
spinal hardware in the lumbar 
spine); 
Adds exclusion for 
any other condition 
that would interfere 
with obtaining an 
interpretable DXA 
scan. 
Synopsis: 
Exclusion 
Criteria  
Section 4.3.2 
Exclusion 
Criteria 
 
6. …  A history of successfully 
treated hyperparathyroidism, 
hyperprolactinemia, or 
hyperthyroidism is allowed if the 
patient’s bone mineral density is 
within normal limits; 
6. …  A history of successfully 
treated hyperparathyroidism, 
hyperprolactinemia, or 
hyperthyroidism is allowed if 
the patient’s bone mineral 
density is within normal limits; 
Patients whose 
hyperparathyroidism or 
hyperthyroidism has been 
successfully treated or whose 
hyperprolactinemia has been 
successfully treated and/or who 
meet bone mineral density 
eligibility criteria for the study 
are allowed; 
To provide clarity. 
Synopsis: 
13. Has any of the following 
13. Has any of the following 
Added to exclude 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Exclusion 
Criteria  
Section 4.3.2 
Exclusion 
Criteria 
clinical laboratory abnormalities 
at any screening visit: … 
… 
d.  None. 
 
e.  None. 
clinical laboratory abnormalities 
at any screening visit: 
… 
d.  Hypocalcemia (< lower limit 
of normal [LLN]) or 
hypercalcemia (> ULN); 
e.  Hypophosphatemia (< LLN) 
or hyperphosphatemia (> ULN) 
patients with 
conditions that 
would result in 
abnormal calcium 
and phosphorus 
levels. 
Synopsis: 
Exclusion 
Criteria 
Section 4.3.2 
Exclusion 
Criteria 
14. Has clinically significant 
cardiovascular disease including: 
… 
e.  QT interval by the Fridericia 
correction formula (QTcF) of 
> 470 msec; 
 
g.  Uncontrolled hypertension, as 
indicated by systolic blood 
pressure > 160 mmHg on 2 
repeat measures at least 15 
minutes apart or diastolic blood 
pressure > 100 mmHg at any 
screening visit or the Baseline 
Day 1 visit; 
14. Has clinically significant 
cardiovascular disease including: 
… 
e.  QT interval by the Fridericia 
correction formula (QTcF) of 
> 470 msec on the Screening 
visit or Baseline Day 1 ECG; 
g.  Uncontrolled hypertension, as 
indicated by systolic blood 
pressure > 160 mmHg on 2 
repeat measures at least 15 
minutes apart or diastolic blood 
pressure > 100 mmHg on 2 
repeat measures at least 15 
minutes apart at any screening 
visit or the Baseline Day 1 visit; 
To provide 
clarification on 
visits for the 
exclusion criteria. 
To clarify that both 
systolic and diastolic 
blood pressure 
criteria must be 
demonstrated on 2 
repeat measures.  
Synopsis: 
Exclusion 
Criteria 
Section 4.3.2 
Exclusion 
Criteria 
16. Has a history of clinically 
significant condition(s) including, 
but not limited to the following: 
… 
a.  Untreated thyroid dysfunction 
or palpable thyroid abnormality 
(patients with adequately treated 
hypothyroidism who are stable on 
medication are not excluded); 
 
None. 
16. Has a history of clinically 
significant condition(s) including, 
but not limited to the following: 
… 
a.  Untreated thyroid dysfunction 
or palpable thyroid 
abnormality (patients with 
adequately treated 
hypothyroidism who are stable on 
medication are not excluded); 
d.  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; 
Deleted as 
redundant. 
Untreated palpable 
abnormality would 
generally fall under 
untreated thyroid 
dysfunction. 
 
 
 
To add an exclusion 
criterion for 
systemic 
autoimmune disease. 
Synopsis: 
Exclusion 
17. Is currently pregnant or 
lactating, or intends to become 
17. Is currently pregnant or 
lactating, or intends to become 
To clarify the 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Criteria 
Section 4.3.2 
Exclusion 
Criteria 
pregnant or to donate ova during 
the study period or within 2 
months after the last dose of 
study drug; 
pregnant during the study 
period through 1 month after 
the last dose of study drug or 
intends to donate ova during the 
study period or within 2 months 
after the last dose of study drug; 
pregnancy window. 
Synopsis: 
Exclusion 
Criteria 
Section 4.3.2 
Exclusion 
Criteria 
23. Is inappropriate for 
participation in this study for 
other reasons, as determined by 
the investigator or sub-
investigator or medical monitor. 
23. Is inappropriate for 
participation in this study for 
other reasons because of 
conditions that may interfere 
with interpretation of study 
results or prevent the patient 
from complying with study 
requirements, including 
contraception requirements, as 
determined by the investigator, 
sub-investigator, or medical 
monitor; 
To explain 
circumstances and 
provide examples 
when a potential 
patient would be 
inappropriate for 
participation in the 
study.  
Synopsis: 
Exclusion 
Criteria 
Section 4.3.2 
Exclusion 
Criteria 
None. 
24. Has received a blood 
transfusion within 8 weeks prior 
to Screening Visit 1 or during the 
screening period. 
Added new 
exclusion criteria to 
avoid confounding 
the assessment of 
hemoglobin.  
Synopsis: 
Secondary 
Efficacy 
Endpoints 
Section 3 Study 
Objective and 
Endpoints 
Section 9.3.2 
Statistical 
Considerations 
and Data 
Analyses 
 
The following secondary 
endpoints will be assessed 
comparing each relugolix 
treatment group to placebo 
inferentially and relugolix Group 
A to Group B descriptively: 
… 
• Proportion of women who 
achieve amenorrhea over the 
last 35days of treatment as 
measured by the alkaline 
hematin method; 
• Time to amenorrhea as 
measured by the by the alkaline 
hematin method; 
None. 
 
 
None. 
 
 
The following secondary 
endpoints will be assessed 
comparing each relugolix 
treatment group to placebo 
inferentially and relugolix Group 
A to Group B descriptively: 
… 
• Proportion of women who 
achieve amenorrhea over the 
last 35 days of treatment as 
measured by the alkaline 
hematin method; 
• None. 
 
• Change from Baseline to 
Week 24 in impact of uterine 
fibroids based on the UFS-
QOL activities domain; 
• Change from Baseline to 
Week 24 in the interference of 
uterine fibroids with physical 
activities based on UFS-QOL 
Question 11; 
• Change from Baseline to 
Time to amenorrhea 
Endpoint removed 
due to redundancy. 
Presenting the 
amenorrhea rate 
using a proportion 
versus a cumulative 
Kaplan-Meier 
probability is 
preferred since it is 
more consistent with 
method used for the 
primary responder 
endpoint analysis. 
 
Added secondary 
endpoints related to 
UFS-QOL and PGA 
for function and 
symptoms to address 
the added secondary 
objectives. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
None. 
 
 
 
None. 
 
 
None. 
 
 
None. 
 
 
 
None. 
 
None. 
Week 24 in the interference of 
uterine fibroids with social 
activities based on UFS-QOL 
Question 20; 
• Change from Baseline to 
Week 24 in embarrassment 
caused by uterine fibroids 
based on UFS-QOL Question 
29; 
• Change from Baseline to 
Week 24 in uterine fibroid-
related symptoms based on the 
Uterine Fibroid Scale – 
Symptom Severity; 
• Change from Baseline to 
Week 24 in uterine fibroid-
related quality of life based on 
the Uterine Fibroid Scale –  
Health-related Quality of Life; 
• Change in PGA for uterine 
fibroid related function from 
Baseline to Week 24; 
• Change in PGA for uterine 
fibroid symptoms from 
Baseline to Week 24; 
Synopsis: Safety 
Endpoints  
Section 3 Study 
Objective and 
Endpoints 
 
None. 
 
 
 
• Percent change from Baseline to 
Weeks 12 and 24 in bone 
mineral density at the spine 
(average of L1-L4), total hip, 
and femoral neck as assessed by 
DXA; 
• Percent change from Baseline 
to Week 12 in bone mineral 
density at the lumbar spine (L1-
L4) in Group A compared with 
Group B as assessed by DXA; 
• Percent change from Baseline 
to Weeks 12 and 24 in bone 
mineral density at the lumbar 
spine (average of L1-L4), total 
hip, and femoral neck as 
assessed by DXA; 
Endpoint for 
assessment of bone 
mineral density at 
Week 12 is pre-
specified as a 
separate endpoint 
with comparison 
between Group A 
and Group B. This 
endpoint will 
support inclusion of 
add-back therapy in 
the treatment 
regimen. 
Synopsis: 
Exploratory 
Endpoints  
Section 3 Study 
Objective and 
Endpoints 
Section 9.6 
Exploratory 
Analyses 
• Change from Baseline to Week 
24 in the Uterine Fibroid Scale 
– Quality of Life Symptom 
Severity and Health-related 
Quality of Life subscales 
comparing each relugolix 
treatment group to placebo 
inferentially and the two 
relugolix groups descriptively; 
None. 
Exploratory 
endpoints related to 
UFS-QOL are 
removed, and 
secondary endpoints 
related to  
assessments of 
certain components 
UFS-QOL are 
added. 
Section 1.1 
Visit window timing (days) 
Visit window timing (days) 
Visit window 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Schedule of 
Activities 
Table 1-1 
Week 24 (or Early Termination 
of Study Drug) 
± 10 
Week 24 (or Early Termination 
of Study Drug): 
± 10 -10/+20 
expanded to allow 
transition of eligible 
patients into open 
label extension 
study MVT-601-
3003 without 
interruption.  
 
None. 
PGA for function 
PGA for symptoms 
Added new 
assessments in line 
with new secondary 
efficacy endpoints.  
 
Treatment Compliance  
Treatment Compliance and 
Study Drug Accountability 
Updated to clarify 
the assessment. 
 
Week 4 through Week 24 
None. 
 
 
Week 24 (or Early Termination 
of Study Drug) 
None. 
 
Follow-up 
None. 
 
Week 4 through Week 24 
Treatment compliance and drug 
accountability  
 
Week 24 (or Early Termination 
of Study Drug) 
Urinalysis 
 
Follow-up 
Temperature collection, 
pregnancy test, status of 
menstruation recovery 
Added additional 
assessments for 
treatment 
compliance and 
urinalysis at week 
24. 
Added additional 
assessments for 
follow up visit for 
patients who do not 
roll-over to the 
extension study. 
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnotes 
 
d.  The Baseline Day 1 visit 
should occur within 7 days of the 
onset of menses.  Collect clinical 
laboratory, PK sample, pre-dose 
pharmacodynamic sample, 
pregnancy and urinalysis test 
samples prior to first dose of 
study drug.  The patient must 
complete MIQ, UFS-QoL, and 
EQ-5D questionnaires prior other 
study procedures and prior to 
first dose of study drug. 
d.  The Baseline Day 1 visit 
should occur within 7 days of the 
onset of menses.  The following 
procedures must be completed 
prior to randomization: urine 
pregnancy, vital signs, waist 
circumference, weight, 
temperature, complete physical 
examination, visual acuity 
assessment,12-lead ECG, and 
review of eligibility criteria.  
Collect clinical laboratory 
sample, PK sample, pre-dose 
pharmacodynamic sample, 
pregnancy and urinalysis prior to 
first dose of study drug.  The 
patient must Whenever 
possible, complete MIQ, UFS-
QOL, PGA for symptoms and 
PGA for function, and EQ-5D-
5L questionnaires prior other 
To clarify order of 
assessments during 
baseline Day 1 visit. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
study procedures and prior to 
the first dose of study drug.  
 
e.  For an Unscheduled visit, 
these procedures will be 
performed as needed, based on 
the reason(s) for the Unscheduled 
visit. 
e.  For an Unscheduled visit, 
these procedures will be 
performed as needed, based on 
the reason(s) for the Unscheduled 
visit. The last dose of study 
drug in the Randomized 
Treatment Period will be taken 
on the day immediately before 
the Week 24 visit. Note: Week 
24 visit data is defined as the 
last day on which a Week 24 
visit procedure is conducted. 
To provide clarity 
on definition of 
Week 24 visit and 
when the last dose is 
taken. 
 
h.  Visual acuity must be assessed 
with the study eye chart.  The 
patient should wear any 
prescription glasses or contacts 
during the assessment. 
h.  Presenting visual acuity must 
be assessed with the supplied 
study eye chart.  If the patient 
uses corrective lenses, she 
should wear anyher usual 
prescription glasses or contact 
lenses during the assessment, 
and the same prescription 
lenses should be worn at 
subsequent visual testing, as 
possible. Perform the visual 
acuity testing using the entire 
eye chart.  Do not stop at a 
visual acuity of 100 – continue 
as far as the patient can go per 
the testing instructions.   See 
Study Reference Manual for 
additional instructions on 
visual acuity testing and see 
Section 6.8.2.8 for overall 
guidance including follow-up. 
To provide guidance 
on visual acuity 
examination and 
follow-up. 
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnote i 
Section 6.2.1 
Screening 1 
Visit 
Section 6.8.2.3 
Physical and 
Gynecologic 
Exams 
Papanicolaou test must be 
conducted for women without a 
test result within 6 months prior 
to the Screening 1 visit. 
Papanicolaou test must be 
conducted for women without a 
test result within 6 months 2 
years prior to the Screening 1 
visit. 
Window for 
Papanicolaou test 
expanded to 
approach the 
guidelines for 
cervical cancer 
screening.   
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnote j 
 
…Samples should be obtained in 
the fasted state (no food or drink 
other than water after midnight) 
for the Baseline and Week 24 
visit clinical laboratory tests. 
…Samples should be obtained in 
the fasted state (no food or drink 
other than water after midnight) 
for the Baseline and Week 24 visit 
clinical laboratory tests. In 
addition to clinical chemistries 
and a complete blood count, 
include thyroid-stimulating 
hormone at Screening 1.  
Screening laboratory tests may 
be repeated during the 
screening period once, if 
necessary, at the investigator’s 
discretion.  Additional re-testing 
requires the approval of the 
medical monitor.  If the 
hemoglobin is < 10 g/dL and 
mean corpuscular volume is 
below the lower limit of normal, 
a ferritin and iron level will be 
reported through the central 
lab. 
To provide 
clarification on 
laboratory tests: to 
indicate thyroid-
stimulating hormone 
testing at Screening 
1, repeats of 
screening tests, and 
testing for iron and 
ferritin in patients 
with microcytic 
anemia. 
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnote k 
…In addition to clinical 
chemistries and a complete blood 
count, include a lipid profile, 
levels of parathyroid hormone, 
thyroid-stimulating hormone, 
prolactin, Vitamin D, iron, 
ferritin, and hemoglobin A1c.   
…In addition to clinical 
chemistries and a complete blood 
count, include a lipid profile, 
levels of parathyroid hormone, 
thyroid-stimulating hormone, 
prolactin, Vitamin D, iron, 
ferritin, and hemoglobin A1c.  
Parathyroid 
hormone testing is 
removed (patients 
with abnormal 
calcium and 
phosphorus will be 
excluded). 
Thyroid stimulating 
hormone level will 
be obtained at 
Screening 1.  
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnotes m, n 
…Administer study drug after PK 
and pharmacodynamics sample 
collections are complete… 
…Administer study drug after PK 
and pharmacodynamics sample 
collections are complete (Study 
drug is not administered at 
Week 24 Visit; for patients 
proceeding into the extension 
study, refer to protocol for 
study MVT-601-3003). 
Added note at end of 
footnotes for PK and 
PK samples 
clarifying that no 
study drug is 
administered at the 
Week 24 visit  
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnote o 
Section 6.8.1.11 
Pharmacogenom
ics Sample 
Pharmacogenomics sample:  a 
separate pharmacogenomics 
consent is required before this 
sample may be collected. 
Pharmacogenomics sample 
(unless precluded by local law 
or regulations):  a separate 
pharmacogenomics consent is 
required before this sample may 
be collected. 
 
Added note that 
pharmacogenomics 
sample will not be 
obtained if 
precluded by local 
laws or regulations 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Collection   
Section 1.1 
Schedule of 
Activities 
Table 1-1 
footnotes 
 
None. 
w.  Patients not proceeding to the 
extension study who have 
endometrial hyperplasia or 
endometrial cancer on the 
endometrial biopsy at the 
Week 24/Early Termination visit 
will be followed and will undergo 
a repeat biopsy in 3 to 6 months 
after the Week 24/Early 
Termination visit (see Section 
6.7).  The repeat biopsy will be 
submitted to the central 
laboratory. 
Added new footnote 
to provide guidance 
on scheduling DXA 
assessments and 
follow-up for 
patients not entering 
the extension study. 
 
None. 
x.  Schedule DXA as early as 
possible within the Week 
24/Early Termination visit 
window.  Patients not proceeding 
to the extension study who have 
had a bone mineral density loss 
of > 2% at the lumbar spine (L1-
L4) or total hip at their Week 
24/Early Termination visit 
relative to baseline will undergo 
another DXA scan at 6 (± 1) 
months after the Week 24/Early 
Termination visit scan to evaluate 
recovery and will be contacted 
about medications and conditions 
(eg, pregnancy) that might affect 
bone mineral density through the 
time of the repeat DXA scan.  
The follow-up DXA scan will be 
submitted for central reading. 
Added new footnote 
for follow-up 
procedures for 
abnormal 
endometrial biopsy 
for patients not 
proceeding into the 
extension. 
 
None. 
y.  Patient will enter responses in 
a paper questionnaire at the site.  
Added new footnote 
that PGAs for 
functions and 
symptoms are 
completed as a 
paper questionnaire. 
 
None. 
z. The patient should be asked to 
bring all study drug to the clinic 
at each visit.  Please refer to 
section 5.8. 
Clarification. 
Section 2.2.4.4 
Clinical Studies 
in Women with 
Uterine Fibroids 
or 
The serious identified risk 
associated with relugolix 
treatment is loss of bone mineral 
density in women. Nonserious 
adverse events related to 
Adverse drug reactions 
associated with relugolix in 
women with uterine fibroids or 
endometriosis include hot flush, 
headache, hyperhidrosis and bone 
Updated for 
consistency with the 
Investigator 
Brochure. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Endometriosis 
and Men with 
Prostate Cancer 
 
relugolix class effects include hot 
flush and headache in both sexes; 
reproductive system events 
(abnormal uterine bleeding, 
genital hemorrhage, menorrhagia 
or heavy menstrual bleeding, 
menstruation irregular, and 
oligomenorrhea), arthralgia, and 
hyperhidrosis in women with 
uterine fibroids or endometriosis; 
and vision blurred, hepatic 
enzyme increased, libido 
decreased, and anxiety in men. 
density decreased. Adverse drug 
reactions associated with 
relugolix in men with prostate 
cancer include hot flush, fatigue, 
arthralgia, nausea, weight 
increased, gynecomastia and 
night sweats. 
Section 4.1 
Overall Study 
Design 
Figure 4-1 
Open-Label Extension Study 
(Eligible Patients) 
24 Weeks 
Open-Label Extension Study 
(Eligible Patients) 
28 Weeks 
Study schematic 
updated to indicate 
the open-label 
extension is 28 
weeks instead of 24 
weeks 
Section 4.1 
Overall Study 
Design 
Figure 4-2 
Figure legend 
Bottom scenario: 
… 
• Patients whose first screening 
cycle MBL is < 80 mL and 
whose second screening cycle 
menstrual blood loss is > 160 
mL will follow the bottom 
scenario visit schedule 
Additional Scenarios (not 
depicted): 
… 
• …  If the second screening 
menstrual blood loss is ≥ 160 
mL, the patient should follow 
the top scenario visit schedule. 
Bottom scenario: 
… 
None. 
 
 
 
Additional Scenarios (not 
depicted): 
… 
• …  If the second screening 
menstrual blood loss is ≥ 160 
mL, the patient should follow 
the top scenario visit schedule, 
and the patient does not need 
to collect menstrual blood loss 
for another cycle. 
Clarification 
Schematic of 
Screening Visit 
Scenarios is updated 
to indicate that for 
patient with MBL ≥ 
160 mL do not need 
to collect menstrual 
blood loss for 
another cycle.  
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Section 4.6 
Removal of 
Patients from 
Therapy 
 
• Patients who are, in the 
opinion of the investigator or 
the medical monitor, grossly 
non-compliant with the 
protocol’s requirements.   
• Patients who are, in the 
opinion of the investigator or 
the medical monitor, grossly 
non-compliant 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; missing 
multiple study visits; and 
persistent (> 2 consecutive 
months) with < 50% of the 
required number of days of 
eDiary completion;  
• Patients whose treatment 
assignment has been 
unblinded by the 
investigative site will be 
permanently discontinued 
from treatment; 
To provide 
definition of gross 
non-compliance. 
Add criteria for 
withdrawal from 
treatment for patient 
whose treatment 
assignment has been 
unblinded to 
harmonize with 
Section 5.7. 
Section 4.7 
Contraception/ 
Pregnancy 
Avoidance  
 
In this study, medications and 
devices containing hormones are 
excluded, and patients must agree 
to use two forms of non-
hormonal contraception (dual 
contraception), unless any of the 
following apply: … 
 
 
 
 
The only acceptable methods of 
dual contraception are: 
• Condom with spermicide 
(cream, spray, foam, gel, 
suppository or polymer film); 
 
In this study, medications and 
devices containing hormones for 
contraception are excluded, and 
patients must agree to use two 
forms ofnon-hormonal 
contraception (dual 
contraception) throughout the 
study, including through 30 
days following the last dose of 
study drug, unless any of the 
following apply: … 
 
The only acceptable methods of 
dual 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); 
 
As the common 
spermicide, 
nonoxynol-9 (N-9), 
is no longer 
approved in several 
countries 
participating in the 
study and other 
effective 
spermicides are not 
readily available in 
those countries, the 
protocol-specified 
contraceptive 
methods were 
reviewed and the 
use of a condom 
(male or female) 
with or without 
spermicide 
permitted. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Section 5.1 
Treatments 
Administered 
 
Each patient will be instructed to 
take one tablet and one capsule 
per day.   
Each patient will be instructed to 
take one tablet and one capsule 
per day.  The last dose of study 
drug will be taken on the day 
immediately before the Week 
24 visit.  Note: Week 24 visit 
data is defined as the last day 
on which a Week 24 visit 
procedure is conducted. 
Added text to clarify 
last dose due to 
transition into 
extension study (see 
above). 
Section 5.4 
Directions for 
Administration 
 
The study treatment should be 
taken in the fasted state (other 
than water) in the morning, at 
least 1 hour before breakfast. 
 
… 
Patients should take any oral iron 
supplementation with meals. 
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. 
… 
None. 
Definition of fasted 
state for drug 
administration is 
clarified to include 
tea or coffee. 
Restriction to take 
iron with meals is 
removed. 
Section 5.5 Dose 
Reduction/Dose 
Administration 
Section 7.1.1 
Adverse Event 
…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). 
…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). 
Text removed as it is 
the investigator’s 
responsibility to 
determine 
appropriate 
management of 
study drug in a 
setting of an adverse 
event 
Section 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 
35°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 in an 
appropriate, limited-access, 
secure location within a 
temperature range of 20°C to 
35°C 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.   
Modified to be 
consistent with 
study drug labeling. 
Section 5.7 
Blinding  
 
Investigators will have direct 
access to a given patient’s 
individual study treatment, 
however, the investigator should 
make every effort to first contact 
the medical monitor or 
appropriate study personnel to 
discuss options before 
unblinding the patient’s treatment 
assignment.   
Investigators will haveThe 
decision to unblind a patient’s 
treatment assignment in an 
emergency situation resides 
with the investigator who has 
direct access to unblind a 
patient’s individual study 
treatment; however, the 
investigator should make every 
effortattempt to contact the 
medical monitor or appropriate 
study personnel to discuss 
To provide 
clarification that the 
decision to break the 
treatment code in 
emergency situation 
resides with the 
investigator. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
options before unblinding the 
patient’s treatment assignment 
unless the urgency of the 
medical situation precludes 
this. 
Section 5.8 
Study Drug 
Accountability 
and Treatment 
Compliance 
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. 
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 (see 
Section 4.6). 
Revised to align 
with criteria for 
removal from 
therapy. 
Section 5.10.1 
Prohibited 
Medications 
Table 5-3  
Anti-convulsant drugs (specified) 
Examples 
phenobarbital, carbamazepine, 
phenytoin, valproic acid, and 
primidone 
Anti-convulsant drugs (specified) 
Examples 
phenobarbital, carbamazepine, 
phenytoin, valproic acid, and 
primidone 
Note: All other anticonvulsants 
are allowed  
Added clarification 
that other 
anticonvulsants not 
listed are allowed. 
 
Progestins  
 
Examples 
dienogest 
norethindrone 
medroxyprogesterone 
 
Progestins and progestin 
implants. 
Examples 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone   
etonogestrel  
To include 
additional examples 
of prohibited 
medications. 
 
Estrogen 
Examples 
estradiol valerate 
conjugated estrogens 
 
Estrogen 
Examples 
estradiol valerate 
conjugated estrogens 
ethinyl estradiol 
To include 
additional examples 
of prohibited 
medications. 
 
Oral Contraceptives 
 
Examples  
combined or progestin only 
Hormonal oral contraceptive 
patches and vaginal rings 
Examples  
combined or progestin only 
Nuva Ring 
To include 
additional examples 
of prohibited 
medications. 
Section 5.10.1 
Prohibited 
Medications 
Bone Agents 
Window/Comments 
No prior use if used for reduced 
Bone Agents 
Window/Comments 
No prior use if used for reduced 
Provide a specific 
clarification that 
Calcium and vitamin 
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Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Table 5-3 
bone mineral density 
bone mineral density 
Note:  Calcium and Vitamin D2 
and Vitamin D3 (ergocalciferol 
and cholecalciferol) are allowed 
without restriction. 
D are allowed. 
Section 5.10.1 
Prohibited 
Medications 
Table 5-3 
P-glycoprotein Inducers 
Examples  
carbamazepine 
rifampin 
St. John’s wort 
P-glycoprotein Inducers 
Examples  
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavir 
To include 
additional examples 
of prohibited 
medications. 
 
Clarify when short 
term use of these 
Pgp inducers can be 
allowed in study. 
Section 5.10.1 
Prohibited 
Medications 
Table 5-3 
Moderate and Strong P 
glycoprotein Inhibitors 
Examples 
None. 
 
 
 
 
 
 
 
 
 
 
 
Footnotes 
None. 
 
Moderate and Strong P 
glycoprotein Inhibitors 
Examples  
amiodarone, atazanavirf, 
azithromycina, 
captoprilb, carvedilolg, 
clarithromycina, cobicistatf, 
conivaptan, cyclosporinc, 
diltiazem, dronedarone, 
erythromycina, felodipined, 
itraconazolee, ketoconazolee, 
lopinavir/ritonavirf, quercetin, 
quinidine,,ranolazine, 
ticagrelortg, verapamil 
 
Footnotes 
a. Roxithromycin is allowed 
b. All other angiotensin 
converting enzyme inhibitors 
are allowed 
c. Tacrolimus is allowed 
d. Amlodipine and nifedipine 
are allowed 
e. Fluconazole is allowed 
f. Integrase inhibitors are 
allowed 
g. Metoprolol and atenolol are 
permitted 
To include 
additional examples 
of prohibited 
medications. 
Clarify when short 
term use of these 
Pgp inhibitors can 
be allowed in study. 
Section 6.2.1 
Screening Visit 1  
The order of procedures should 
be as follows. … 
The order of procedures should 
be as follows. … 
Added new text to 
provide clarification 
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Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
 
None. 
 
None. 
• Complete physical 
examination and visual acuity 
assessment 
• Clinical laboratory tests, 
including TSH, urinalysis 
for the order of 
procedures.  
Section 5.10.2.2 
Iron Therapy 
Section 6.2.1 
Screening Visit 1 
Section 6.2.2 
Screening Visit 2 
Section 6.8.2.4 
Clinical 
Laboratory 
Samples 
None. 
 
 
 
 
 
 
If the hemoglobin is < 10 g/dL 
and mean corpuscular volume is 
below the lower limit of normal, 
a ferritin and iron level will be 
obtained as an unscheduled test 
If the hemoglobin is < 10 g/dL 
and mean corpuscular volume 
is below the lower limit of 
normal, a ferritin and iron level 
will be reported through the 
central lab.  
 
If the hemoglobin is < 10 g/dL 
and mean corpuscular volume is 
below the lower limit of normal, 
a ferritin and iron level will be 
reported through the central 
lab obtained as an unscheduled 
test. 
Added new text to 
provide guidance on 
laboratory diagnosis 
and management of 
iron deficiency 
anemia.  
For Section 6.2.2 
Clarified that iron 
and ferritin are be 
reflex labs that will 
be reported trough 
central laboratory. 
Section 6.2.6 
Retesting 
 
None. 
Screening laboratory tests may be 
repeated once during the 
Screening period, if necessary, at 
the investigator’s discretion.  For 
laboratory-based entry criteria, 
the most recent value will be used 
to determine eligibility.  
Additional laboratory retesting 
requires the approval of the 
medical monitor.  Retesting of 
other procedures (except once, as 
required, due to technical or 
logistical issues such as an 
inadequate sample) also require 
approval of the medical monitor. 
New section added 
to allow single 
repeat of screening 
laboratory tests. 
Section 6.6 
Additional 
Safety Follow-
Up Procedures 
 
None. 
For patients not continuing into 
the extension study (MVT 601-
3003), additional safety 
procedures are required in some 
circumstances as described below.  
These procedures will be 
performed during unscheduled 
visits. 
• Patients whose menses has not 
resumed as of the Follow-Up 
visit for whom there is no 
explanation for the lack of 
resumption (eg, medical 
procedure or medications) will 
be contacted by telephone 3 
(+0.5) months after the Follow-
Up visit to determine if menses 
New section added 
to provide guidance 
for additional safety 
follow up 
procedures for 
patients who do not 
proceed into 
extension study. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
has resumed and questioned 
about factors that may affect 
resumption of menses. 
• Patients with endometrial 
biopsy findings of endometrial 
hyperplasia or endometrial 
cancer on the endometrial 
biopsy at the Week 24/Early 
Termination visit will undergo 
a repeat biopsy in 3 to 6 months 
after the Week 24/Early 
Termination and will be 
contacted to obtain information 
on procedures performed or 
treatments received (if any) for 
the biopsy findings during 
through the time of the repeat 
biopsy.  The repeat biopsy will 
be submitted to the central 
laboratory.  In addition, patients 
with endometrial hyperplasia 
with atypia will be evaluated 
and managed, as needed, by a 
gynecologist. 
• Patients who have had a bone 
mineral density loss of > 2% at 
the lumbar spine (average of 
L1-L4) or total hip at their 
Week 24/Early Termination 
visit relative to baseline 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 bone mineral density 
through the time of the repeat 
DXA scanning.  The follow-up 
DXA scan will be submitted for 
central reading. 
Section 6.8.1.2 
Transvaginal 
and 
Transabdominal 
Ultrasound 
 
None. 
Saline or gel contrast is not 
required, but may be performed 
to demonstrate fibroids that meet 
the criterion for inclusion if these 
are not adequately visualized 
with transvaginal ultrasound 
alone or when endometrium 
cannot be evaluated or when 
Added clarification 
regarding use of 
saline or gel contrast 
for ultrasound. 
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Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
there are ambiguous and 
potentially exclusionary findings 
on the transvaginal or 
transabdominal ultrasound (eg, 
suspected intrauterine masses, 
equivocal endometrial findings, 
etc.).  If transabdominal 
ultrasound or ultrasound with 
saline or gel contrast is 
performed at Screening, it should 
also be performed at Week 24 
Section 6.8.1.5 
Patient Diary 
 
The eDiary data will be reviewed 
by the investigator to identify any 
potential adverse events. 
 
The eDiary data will be reviewed 
by the study staff.  investigator 
to identify any potential 
adverse events  
To ensure 
consistency with 
section 7.2 of the 
protocol stating that 
eDiary entries will 
be reviewed by 
study site personnel. 
Section 6.8.1.9 
Patient Global 
Assessment for 
Symptoms and 
Patient Global 
Assessment for 
Function 
 
None. 
These simple questions are used 
by the patient to qualitatively 
describe severity of symptoms or 
effects on function (PGA) (see 
Appendix 6) on a schedule 
described in the Schedule of 
Activities (Section 1.1).  With the 
exception of Baseline Day 1 (see 
Section 1.1), patients will answer 
these questions before other types 
of study procedures.   The PGA 
for function and PGA for 
symptoms will be completed on a 
paper questionnaire at the study 
site on a schedule described in 
the Schedule of Activities 
(Section 1.1).  With the exception 
of Baseline Day 1, patients will 
answer these questions before 
other types of study procedures.   
The PGA for function and PGA 
for symptoms will be completed 
on a paper questionnaire at the 
study site. 
New section added 
to describe 
assessments for the 
newly add PGA 
secondary 
objectives. 
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Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Section 6.8.1.10 
Status of 
Menstruation 
Recovery 
After the Follow-up visit, 
additional follow-up for the status 
of menstruation recovery will not 
be continued. 
None. 
Menstruation 
recovery follow up 
outlined in Section 
6.6. 
Section 6.8.2.3 
Physical and 
Gynecologic 
Exams 
Visual acuity will be checked at 
the beginning and end of the 
study by a standard visual eye 
chart.  The patient should wear 
any prescribed glasses or contacts 
during the visual acuity 
assessment.   
None. 
Visual acuity 
assessment 
instructions moved 
to a new section. 
Section 6.8.2.4 
Clinical 
Laboratory 
Samples  
Table 6-1 
Chemistry 
Creatinine Kinase 
 
Hormones 
Intact Parathyroid Hormone 
Chemistry 
Creatinine Kinase 
 
Hormones 
Intact Parathyroid Hormone 
Parathyroid 
hormone testing is 
removed (patients 
with abnormal 
calcium and 
phosphorus will be 
excluded). 
“Creatinine kinase” 
Typographical error 
removed. 
Section 6.8.2.6 
Endometrial 
Biopsy 
 
An endometrial biopsy is to be 
performed during the pelvic 
examination at the Screening 3 
visit.  A pipelle should be used to 
obtain the specimen.  A second 
biopsy is to be performed at the 
Week 24 visit.  The biopsies will 
be read centrally. 
 
An endometrial biopsy will be 
obtained using an endometrial 
suction curette (eg, Pipelle) and 
submitted to the central 
laboratory for reading.  If the 
biopsy is inadequate for diagnosis 
at either Screening or at 
Week 24, it should be repeated 
and sample submitted to the 
central laboratory.  If the second 
specimen is also inadequate for 
diagnosis at Screening, the 
patient is not eligible for the 
study.   
To provide 
clarification and 
details for 
endometrial biopsy. 
Section 6.8.2.7 
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. 
 
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). The scans 
will be read by the central 
radiology laboratory in 
accordance with the imaging 
charter. 
Added clarification 
of central reading. 
Section 6.8.2.7 
Bone Mineral 
Density 
The following will be assessed at 
each time point indicated for 
bone densitometry in the study 
Schedule of Activities (Section 
None. 
Deleted details on 
analysis of bone 
mineral density.  
This info will be 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
 
1.1):  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, average bone 
mineral density of L1-L4, and 
T-score for average of L1-L4, 
total hip, and femoral neck. 
provided in the SAP. 
Section 6.8.2.7 
Bone Mineral 
Density 
 
Investigators will be notified if a 
patient experiences a bone 
mineral density loss from 
baseline of 7% or more at any of 
the sties assessed during the 
study.  In this case, repeat scan 
may be required for confirmation 
of the results, and it is at the 
investigator’s discretion to 
consider the patient’s status and 
determine future management.  
Detailed instructions for bone 
mineral density monitoring will 
be provided in the Study 
Reference Manual. 
 
Investigators will be notified if a 
patient experiences a bone 
mineral density loss from 
baseline of 7% or more at any of 
the anatomical sites assessed 
during the study.  In this case, 
repeat scan may be required 
for confirmation of the results, 
and it is at the investigator’s 
discretion to consider the 
patient’s status and determine 
future management.  Detailed 
instructions for bone mineral 
density monitoring DXA 
scanning will be provided in the 
Study Reference Manual.   
Please see Section 6.6 for 
follow-up of patients who are 
not continuing into the 
extension study (MVT-601-
3003) and whose bone mineral 
density has decreased by > 2% 
at the lumbar spine (L1-L4) or 
total hip at the Week 24/Early 
Termination visit relative to 
Baseline. 
Further specified 
follow-up measures 
for observed bone 
mineral density loss.  
Section 6.8.2.8 
Visual Acuity  
None. 
Presenting visual acuity must be 
assessed with the supplied study 
eye chart.  If the patient uses 
corrective lenses, she should 
wear her usual prescription 
glasses or contact lenses during 
the assessment, and the same 
prescription lenses should be 
worn at subsequent visual testing, 
as possible. Perform the visual 
acuity testing using the entire eye 
chart. Do not stop at a visual 
acuity of 100 – continue as far as 
the patient can go per the testing 
instructions (see Study Reference 
Manual for additional details).  
New section created 
to provide additional 
details and to align 
with other studies 
with relugolix. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Patients whose presenting visual 
acuity score is 90 or lower at the 
Baseline visit should be 
encouraged to obtain a diagnostic 
evaluation from an eye care 
provider, ie, an ophthalmologist 
or an optometrist.  Any findings 
(ie, diagnoses) from the eye 
examination should be recorded 
as medical history.   
Patients whose presenting visual 
acuity score at Week 24 /Early 
termination has decreased by 10 
or more points from Baseline 
should be referred to an 
ophthalmologist for a diagnostic 
evaluation.  A copy of the 
ophthalmology consultation must 
be submitted to the sponsor. 
Section 7.1.1 
Adverse Event 
 
Events that do not meet the 
definition of an adverse event 
include: 
… 
• None. 
 
Events that do not meet the 
definition of an adverse event 
include: 
… 
• Events of heavy menstrual 
bleeding, as heavy menstrual 
bleeding is quantified as an 
efficacy endpoint, unless the 
event meets seriousness criteria. 
As heavy menstrual 
bleeding is being 
assessed as an 
efficacy endpoint, 
added it to list of 
events that do not 
meet definition of 
adverse event.  Also 
clarified that would 
be reportable as an 
adverse event if met 
the criteria for 
seriousness. 
Section 7.6 
Serious Adverse 
Event Reporting 
 
Table providing details to send 
completed Safety Report Forms 
to PRA Safety & Risk 
Management 
Table updated to send completed 
Safety Report Forms to 
QuintilesIMS 
Updated Contact 
info for reporting 
Serious Adverse 
events. Updates to e-
mail and phone 
number are also 
included in this 
section. 
Section 7.10 
Benefit/Risk 
Assessment 
Table 7-2 
Impact on Eligibility 
Exclusion criteria for a history of 
osteoporosis, osteopenia, 
metabolic bone disease, … 
Impact on Eligibility 
Exclusion criteria for a history of 
osteoporosis, osteopenia , 
metabolic bone disease, … 
Osteopenia is not an 
exclusion criterion 
in this study. 
Section 7.10 
Benefit/Risk 
Assessment 
Table 7-2 
Hepatic Enzymes 
Hepatic Enzyme Increase 
Updated naming of 
this potential risk, 
matching IB 
nomenclature 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Section 9.2 
Statistical 
Considerations 
and Data 
Analyses 
 
The Per-Protocol Population will 
consist of those members of the 
ITT Population who have no 
major protocol violations. 
The Per-Protocol Population will 
consist of those members of the 
ITT Population who have no 
relevant major protocol 
violations, defined as a subset of 
all major protocol violations 
(details will be provided in the 
statistical analysis plan).  
Clarification. 
Section 9.3.2 
Statistical 
Considerations 
and Data 
Analyses 
 
For the secondary endpoints of 
time to achieving a menstrual 
blood loss volume of < 80 mL 
AND at least a 50% reduction 
from baseline menstrual blood 
loss volume and time to 
amenorrhea, time to event will be 
defined as weeks from 
randomization to first occurrence 
of the event as assessed by the 
alkaline hematin method.  
Patients for whom the first time 
at which menstrual blood loss of 
<80 mL AND at least a 50% 
reduction from baseline is 
achieved is during a cycle when 
no feminine products were 
returned due to amenorrhea 
absence of a menstrual period, 
the most recent menstruation stop 
date will be used.   
… 
Descriptive statistics will be 
provided for changes in 
menstrual blood loss, 
hemoglobin, Numerical Rating 
Scale score for uterine fibroid-
associated pain, uterine volume, 
and uterine fibroid volume 
baseline.   
For the secondary endpoints of 
time to achieving a menstrual 
blood loss volume of < 80 mL 
AND at least a 50% reduction 
from baseline menstrual blood 
loss volume and time to 
amenorrhea, time to event will 
be defined as weeks from 
randomization to first occurrence 
of the event as assessed by the 
alkaline hematin method.  
Patients for whom the first time 
at which menstrual blood loss 
of <80 mL AND at least a 50% 
reduction from baseline is 
achieved is during a cycle when 
no feminine products were 
returned due to amenorrhea 
absence of a menstrual period, 
the most recent menstruation 
stop date will be used.   
… 
Descriptive statistics will be 
provided for changes in 
menstrual blood loss, 
hemoglobin, UFS-QOL score, 
PGA for function and 
symptoms, MIQ Score, 
Numerical Rating Scale score for 
uterine fibroid-associated pain, 
uterine volume, and uterine 
fibroid volume baseline.   
Changes made to 
ensure consistency 
with changes in 
secondary efficacy 
endpoints.  
Section 9.4 
Safety Analyses 
 
None. 
To support the inclusion of add-
back therapy in the treatment 
regimen, the safety endpoint of 
mean percent change from 
Baseline in bone mineral density 
lumbar spine at Week 12 will be 
analyzed using pooled data from 
the two replicate studies (MVT-
601-3001 and MVT-601-3002) 
with a formal comparison of 
To provide 
clarification on 
analysis plans for 
bone mineral density 
which includes 
pooling of data 
across the two 
replicate studies. 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
Section(s) 
Protocol Amendment 1 
Amendment 2 
Rationale 
Group A versus Group B (see 
details in the joint statistical 
analysis plan).  
Appendix 6 
Patient Global 
Assessments 
None. 
Patient Global Assessment (for 
function)  
 
How much were your usual 
activities limited by uterine 
fibroids symptoms such as heavy 
bleeding over the last 4 weeks? 
1. No limitation at all 
2. Mild limitation 
3. Moderate limitation 
4. Quite a bit of limitation 
5. Extreme limitation 
 
Patient Global Assessment (for 
symptoms)  
 
How severe were your uterine 
fibroids symptoms such as heavy 
bleeding over the last 4 weeks? 
1. Not severe 
2. Mildly severe 
3. Moderately severe 
4. Very severe 
5. Extremely severe 
To support 
secondary 
objectives. 
 
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Page 26

 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
LIBERTY 1:  An International Phase 3 Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate Relugolix Co-Administered with and without Low-
Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3001 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
Regulatory Identifier(s): 
EudraCT # 2016-003727-27 
IND # 131161 
Version and 
Effective Date: 
Original:  10-NOV-2016 
Amendment 1:  08-FEB-2017 
Amendment 2:  18-SEP-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. 
 
1 
 
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PPD

Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
 
Date 
 
Site 
 
 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
TABLE OF CONTENTS 
Clinical Study Protocol ............................................................................................................................... 1 
Sponsor Signature Page .............................................................................................................................. 2 
Investigator Statement ................................................................................................................................ 3 
Table of Contents ........................................................................................................................................ 4 
List of Tables ............................................................................................................................................... 8 
List of Figures .............................................................................................................................................. 8 
List of Abbreviations .................................................................................................................................. 9 
1. 
Protocol Synopsis ......................................................................................................................... 11 
1.1. 
Schedule of Activities ................................................................................................................ 22 
2. 
Introduction .................................................................................................................................. 27 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding ..................................................................... 27 
2.2. 
Relugolix ................................................................................................................................... 28 
2.2.1. 
Indication .......................................................................................................................... 28 
2.2.2. 
Pharmacology ................................................................................................................... 28 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 29 
2.2.4. 
Previous Human Experience ............................................................................................. 30 
3. 
Study Objectives and Endpoints ................................................................................................. 34 
4. 
Investigational Plan ..................................................................................................................... 37 
4.1. 
Overall Study Design................................................................................................................. 37 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 40 
4.3. 
Selection of Study Population ................................................................................................... 42 
4.3.1. 
Inclusion Criteria .............................................................................................................. 42 
4.3.2. 
Exclusion Criteria ............................................................................................................. 44 
4.4. 
Screening ................................................................................................................................... 47 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID Number ............................. 47 
4.6. 
Removal of Patients from Therapy ............................................................................................ 48 
4.7. 
Contraception/Pregnancy Avoidance ........................................................................................ 49 
5. 
Treatments .................................................................................................................................... 50 
5.1. 
Treatments Administered .......................................................................................................... 50 
5.2. 
Identity of Investigational Product ............................................................................................ 50 
5.2.1. 
Product Characteristics ..................................................................................................... 51 
5.3. 
Randomization and Stratification .............................................................................................. 51 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
5.4. 
Directions for Administration .................................................................................................... 51 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 52 
5.6. 
Storage, Packaging, and Labeling ............................................................................................. 52 
5.7. 
Blinding ..................................................................................................................................... 53 
5.8. 
Study Drug Accountability and Treatment Compliance ........................................................... 53 
5.9. 
Treatment after the End of Study .............................................................................................. 53 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 53 
5.10.1. 
Prohibited Medications ..................................................................................................... 53 
5.10.2. 
Permitted Medications ...................................................................................................... 56 
5.10.3. 
Prohibited Non-Drug Therapies ........................................................................................ 57 
6. 
Study Assessments and Procedures ............................................................................................ 57 
6.1. 
Schedule of Observations and Procedures ................................................................................. 57 
6.2. 
Screening Period ........................................................................................................................ 57 
6.2.1. 
Screening 1 Visit ............................................................................................................... 58 
6.2.2. 
Screening 2 Visit ............................................................................................................... 59 
6.2.3. 
Screening 3 Visit ............................................................................................................... 59 
6.2.4. 
Screening 4 Visit ............................................................................................................... 60 
6.2.5. 
Menstrual Blood Loss Repeat Collection ......................................................................... 60 
6.2.6. 
Re-Screening ..................................................................................................................... 60 
6.2.7. 
Retesting ........................................................................................................................... 60 
6.3. 
Randomized Treatment Period (Baseline to Week 24) ............................................................. 60 
6.4. 
Continuation into Extension Study ............................................................................................ 61 
6.5. 
Early Termination Visit and Follow-up Visit ............................................................................ 61 
6.6. 
Additional Safety Follow-Up Procedures .................................................................................. 62 
6.7. 
Unscheduled Visits .................................................................................................................... 62 
6.8. 
Study Procedures ....................................................................................................................... 63 
6.8.1. 
Efficacy-Related Procedures ............................................................................................. 63 
6.8.2. 
Safety-Related Procedures ................................................................................................ 66 
6.8.3. 
Biological Sample Retention and Destruction .................................................................. 70 
7. 
Safety Considerations .................................................................................................................. 70 
7.1. 
Adverse Event Definitions......................................................................................................... 70 
7.1.1. 
Adverse Event ................................................................................................................... 70 
7.1.2. 
Serious Adverse Event ...................................................................................................... 71 
7.2. 
Adverse Event Reporting........................................................................................................... 72 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 73 
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Clinical Study Protocol:  MVT-601-3001 
 
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7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 73 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 74 
7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 74 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 75 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 75 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 76 
7.7. 
Study Drug Overdose Management .......................................................................................... 77 
7.8. 
Pregnancy Reporting ................................................................................................................. 77 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, Electrocardiograms, and Bone 
Mineral Density Measures ........................................................................................................ 78 
7.10. 
Benefit/Risk Assessment ........................................................................................................... 78 
8. 
Data Quality Assurance ............................................................................................................... 80 
8.1. 
Clinical Procedures .................................................................................................................... 80 
8.2. 
Monitoring ................................................................................................................................. 80 
9. 
Statistical Considerations and Data Analyses ........................................................................... 81 
9.1. 
Randomization Methods ............................................................................................................ 81 
9.2. 
Analysis Populations ................................................................................................................. 81 
9.3. 
Efficacy Analyses ...................................................................................................................... 82 
9.3.1. 
Primary Endpoint Analysis ............................................................................................... 82 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 83 
9.4. 
Safety Analyses ......................................................................................................................... 84 
9.5. 
Pharmacokinetic and Pharmacodynamic Analyses ................................................................... 85 
9.6. 
Exploratory Analyses ................................................................................................................ 86 
9.7. 
Interim Analyses ........................................................................................................................ 86 
10. 
Responsibilities ............................................................................................................................. 86 
10.1. 
Investigator Responsibilities...................................................................................................... 86 
10.1.1. 
Good Clinical Practice ...................................................................................................... 86 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 86 
10.1.3. 
Informed Consent ............................................................................................................. 87 
10.1.4. 
Confidentiality .................................................................................................................. 87 
10.1.5. 
Study Committees and Communication ........................................................................... 87 
10.1.6. 
Study Files and Retention of Records ............................................................................... 88 
10.1.7. 
Electronic Case Report Forms .......................................................................................... 89 
10.1.8. 
Investigational Product Accountability ............................................................................. 89 
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10.1.9. 
Inspections ........................................................................................................................ 90 
10.1.10. 
Protocol Compliance ......................................................................................................... 90 
10.2. 
Sponsor Responsibilities............................................................................................................ 90 
10.2.1. 
Protocol Modifications ..................................................................................................... 90 
10.2.2. 
Study Report ..................................................................................................................... 90 
10.2.3. 
Posting of Information on Publically Available Clinical Trial Registers ......................... 90 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 91 
10.3.1. 
Access to Information Monitoring .................................................................................... 91 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 91 
10.3.3. 
Study Discontinuation ....................................................................................................... 91 
10.3.4. 
Publications ....................................................................................................................... 91 
References .................................................................................................................................................. 92 
Appendices ................................................................................................................................................. 94 
Appendix 1. 
Breast Imaging Reporting and Data System (BI-RADS) ............................................. 94 
Appendix 2. 
Daily eDiary ................................................................................................................. 95 
Appendix 3. 
Menorrhagia Impact Questionnaire ............................................................................ 100 
Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire .................................... 101 
Appendix 5. 
European Quality of Life Five-Dimension Five-Level Scale ..................................... 104 
Appendix 6. 
Patient Global Assessments ........................................................................................ 106 
Appendix 7. 
Assessment of Abnormal Liver Function Tests ......................................................... 107 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-3001............................................................. 22 
Table 5-1 
Description of MVT-601-3001 Study Drugs .................................................................... 50 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization ............................................ 51 
Table 5-3 
Prohibited Medications and Windows of Exclusion Prior to Screening ........................... 54 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 68 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 74 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies ....................................................... 78 
 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .................... 107 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............................ 108 
 
LIST OF FIGURES 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001) ......................... 31 
Figure 4-1 
MVT-601-3001 Study Schematic ..................................................................................... 38 
Figure 4-2 
Schematic of MVT-601-3001 Screening Visit Scenarios ................................................. 39 
 
 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
LIST OF ABBREVIATIONS 
Term 
Explanation 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
di-22:6-BMP 
di-22:6-bis(monoacylglycerol)phosphate 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EQ-5D-5L 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HDL 
high-density lipoprotein 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
Intent-to-Treat (Population) 
IVRS/IWRS 
Interactive Voice/Web Recognition Service 
LFT 
liver function tests 
LH 
luteinizing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIQ 
Menorrhagia Impact Questionnaire 
mmHg 
millimeters of mercury 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
PBAC 
Pictorial Blood Loss Assessment Chart 
PD 
PGA 
Pharmacodynamics 
Patient Global Assessment 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Term 
Explanation 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
SD 
standard deviation 
UFS-QOL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
VAS 
visual analogue score 
WBC 
white blood cells 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
1. 
PROTOCOL SYNOPSIS 
Study Title 
LIBERTY 1:  An International Phase 3 Randomized, Double-Blind, Placebo-
Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered 
with and without Low-Dose Estradiol and Norethindrone Acetate in Women 
with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number 
MVT-601-3001 
Location 
Multinational, including North and South America, South Africa, and Europe 
Study Centers 
Approximately 120 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 50 years diagnosed with heavy menstrual bleeding 
associated with uterine fibroids 
Number of Patients 
Planned 
Approximately 390 (~ 130 relugolix co-administered with low-dose estradiol 
and norethindrone acetate, ~ 130 relugolix monotherapy followed by relugolix 
co-administered with low-dose estradiol and norethindrone acetate, and 
~ 130 placebo) 
Study Objectives 
Primary Efficacy Objective 
• 
To determine the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding associated with uterine 
fibroids. 
 
Secondary Efficacy Objectives 
• 
To determine the benefit of relugolix 40 mg once daily for 12 weeks 
followed by 12 weeks of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate compared with placebo for 
24 weeks on heavy menstrual bleeding associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo for 24 weeks on the 
following: 
o Achievement of amenorrhea; 
o Change in hemoglobin; 
o Impact of uterine fibroids on symptoms, activities, and health-related 
quality of life as measured by components of the Uterine Fibroid 
Symptom and Health-Related Quality of Life (UFS-QOL); 
o Patient global assessment for function and symptoms as measured by 
the Patient Global Assessment (PGA) for function and symptoms; 
o Impact of heavy menstrual bleeding on social, leisure, and physical 
activities as measured by the Menorrhagia Impact Questionnaire 
(MIQ); 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
 
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Safety Objectives 
• 
To determine the safety of 24 weeks of relugolix 40 mg once daily 
co-administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate in women with heavy menstrual bleeding associated 
with uterine fibroids compared with placebo for 24 weeks; 
• 
To determine the percent change from Baseline to Week 12 in bone 
mineral density at the lumbar spine (L1-L4) in Group A compared with 
Group B in women with heavy menstrual bleeding associated with uterine 
fibroids; 
• 
To determine the change in bone mineral density of women with heavy 
menstrual bleeding associated with uterine fibroids treated with 24 weeks 
of relugolix 40 mg once daily co-administered with either 12 or 24 weeks 
of low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks; 
• 
To determine the incidence of vasomotor symptoms with relugolix 40 mg 
once daily co-administered with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate in women with heavy menstrual 
bleeding associated with uterine fibroids. 
 
Pharmacokinetic and Pharmacodynamic Objectives 
• 
To evaluate the pharmacokinetic (PK) and pharmacodynamic effects of 
24 weeks of relugolix 40 mg once daily when co-administered with either 
12 or 24 weeks of low-dose estradiol and norethindrone acetate. 
 
Exploratory Objectives 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo on patient-reported quality 
of life outcome measures (EQ-5D-5L). 
Study Design 
This study is an international phase 3, randomized, double-blind, placebo-controlled efficacy and safety 
study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-dose estradiol 
and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
compared with 24 weeks of placebo.  Approximately 390 women with heavy menstrual bleeding 
associated with uterine fibroids will be enrolled and randomized 1:1:1 to the relugolix plus low-dose 
hormonal add-back therapy group (Group A; N ≈ 130), the relugolix monotherapy followed by co-
administration with low-dose hormonal add-back therapy group (Group B; N ≈ 130), or placebo group 
(Group C; N ≈ 130).  Stratification variables will include:  geographic region (North America versus 
Rest of World) and mean screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the 
alkaline hematin method. 
The study consists of a screening period (up to ~13 weeks), a randomized treatment period (24 weeks), 
and a follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) may be arranged for 
patients with study-related safety concerns and as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by centrally-reviewed 
transvaginal ultrasound (with or without a transabdominal ultrasound).  Heavy menstrual bleeding will 
be defined as menstrual blood loss of ≥ 80 mL per cycle for 2 cycles or ≥ 160 mL during 1 cycle during 
the screening period.  Women with iron-deficient microcytic anemia and hemoglobin ≥ 8 g/dL and ≤ 10 
g/dL during Screening must be treated with oral or parenteral iron replacement therapy.  Between the 
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Baseline Day 1 and Week 24 visits, patients will attend visits monthly (ie, every 4 weeks).  At the 
Screening, Week 12, and Week 24 visits, patients will have an assessment of bone mineral density with 
dual-energy x-ray absorptiometry (DXA).  An endometrial biopsy will also be performed at Screening.  
Another transvaginal ultrasound (with or without a transabdominal ultrasound) will be performed at 
Week 24, followed by a repeat endometrial biopsy.  Patients will have paired baseline and end-of-
treatment endometrial biopsies, independent of ultrasound results.  Feminine products will be 
standardized and will be collected and assessed for blood loss by the alkaline hematin method.  
Complete blood counts and chemistries will be collected monthly and uterine fibroid volumes will be 
assessed at the Screening and Week 24 visits.  Patients will complete daily electronic diaries (eDiary) 
including compliance with study treatment, menstrual bleeding, use of feminine products for menstrual 
bleeding, uterine fibroid-associated pain by the Numerical Rating Scale, and use of pain medication to 
treat pain caused by uterine fibroids.  Quality of life questionnaires will be completed according to the 
Schedule of Activities. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, endometrial 
biopsies, and assessments of bone mineral density.  Height will be measured at the Screening 1 visit 
and weight will be measured at specified intervals. 
Samples will be collected for PK assessment of relugolix, estradiol, and norethindrone and for the 
pharmacodynamic assessment of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
estradiol, and progesterone. 
During the Randomized Treatment Period, study participants will take the blinded study treatment (1 
tablet and 1 capsule) orally once daily for 24 weeks.  The last dose of study drug for the Randomized 
Treatment Period will be taken on the day immediately before to the Week 24 visit. 
Eligible patients, including women randomized to placebo, will be offered the opportunity to enroll in a 
28-week open-label extension study where patients will receive relugolix co-administered with low-
dose estradiol and norethindrone acetate.  Patients who do not enroll into the extension study will have a 
Follow-Up visit approximately 30 days after the patient’s last dose of study drug.  Patients who are not 
proceeding to the extension study and who have endometrial hyperplasia or endometrial cancer on the 
endometrial biopsy or bone mineral density loss of > 2% at the lumbar spine (L1-L4) or total hip at their 
Week 24/Early Termination visit relative to the baseline measurement will undergo further testing and 
follow-up to evaluate recovery (see Section 6.6).  Patients whose menses has not resumed as of the 
Follow-Up visit for unexplained reasons (eg, not explained by concomitant medications or medical 
procedures) will be contacted by telephone to determine if menses has resumed (see Section 6.6).  
Patients with reductions in visual acuity will be referred for ophthalmology consultation (see Section 
6.8.2.8). 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization unless otherwise 
specified): 
1.
Has voluntarily signed and dated the informed consent form prior to initiation of any screening or
study-specific procedures;
2.
Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating the
informed consent form;
3.
Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days
from the start of one menstrual period until the start of the next, by patient history for at least
3 months prior to the Screening 1 visit;
4.
Has a diagnosis of uterine fibroids that is confirmed by a transvaginal ultrasound performed during
the screening period; at least one uterine fibroid must be verified by a central reader to meet at
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least one of the following criteria: 
a. Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter ≥ 2 cm 
(longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3 
Note 1:  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.   
Note 2:  Saline or gel contrast is not required, but may be performed to demonstrate fibroids 
that meet the criterion for inclusion if these are not adequately visualized with transvaginal 
ultrasound alone;  
5. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a menstrual blood 
loss of ≥ 160 mL during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the 
alkaline hematin method during the screening period; 
6. Patient is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids 
within the 6 months following enrollment; 
7. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 visits; 
8. Agrees to use contraception during the study and for 30 days following the last dose of study drug. 
Specifically agrees to use non-hormonal contraception, as described in Section 4.7 consistently 
during the Screening period and the Randomized Treatment Period and either nonhormonal or oral 
contraceptives after return of menses following treatment discontinuation.  However, the patient is 
not required to use specified non-hormonal contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the screening period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at 
least 4 months prior to the first screening visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram and no evidence of “post-Essure 
syndrome” in the investigator’s opinion); 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
non-hormonal contraception as described in Section 4.7;  
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; periodic abstinence 
is not acceptable; 
9. Has an adequate endometrial (aspiration) biopsy performed during the screening period, with 
results showing no clinically significant endometrial pathology (hyperplasia, polyp, or endometrial 
cancer).  Note:  Patients for whom polyps are detected on biopsy but are either not evident on 
ultrasound or < 2 cm are eligible; 
10. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram (Breast 
Imaging Reporting and Data System category 1 or 2 or equivalent) during the screening period or 
within 6 months prior to the screening period. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating 
pathology other than uterine fibroids that could be responsible for or contributing to the patient’s 
heavy menstrual bleeding, such as uterine or cervical polyps ≥ 2.0 cm, large simple ovarian cyst 
> 4.0 cm, endometrioma(s) > 4.0 cm, or any other clinically significant gynecological disorder 
determined by the investigator to require further evaluation and/or treatment during the study. 
Note:  Saline or gel contrast is not routinely required.  Use of such contrast is required only when 
the endometrium cannot be evaluated or when there are ambiguous and potentially exclusionary 
findings on the transvaginal or transabdominal ultrasound (eg, suspected intrauterine masses, 
equivocal endometrial findings, etc.); 
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2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator; 
3. 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, as well as endometrial ablation for abnormal uterine bleeding 
within 6 months prior to the Screening 1 visit; 
4. 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 
or spinal hardware in the lumbar spine); 
5. Has a baseline bone mineral density z-score < -2.0 at spine, total hip, or femoral neck; 
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic 
(from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures are 
allowed).  Patients whose hyperparathyroidism or hyperthyroidism has been successfully treated or 
whose hyperprolactinemia has been successfully treated and/or who meet bone mineral density 
eligibility criteria for the study are allowed; 
7. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, 
denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral 
density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of more than 
5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, ophthalmic, 
intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
10. 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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A (HAV 
IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical glandular 
cells, atypical endocervical cells, atypical squamous cells favoring high grade.  Of note, patients 
with atypical squamous cells of undetermined significance and low-grade cervical neoplasia may 
be included in the study if high risk human papilloma virus testing is negative or if DNA testing 
for human papilloma virus 16 and 18 is negative;  
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with screening hemoglobin results < 8 g/dL may be 
prescribed iron supplements and have their hemoglobin levels retested prior to the Baseline 
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Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of normal 
(ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical laboratory testing at either the 
Screening 1 or Screening 2 visit (or > 2.0 x ULN if secondary to Gilbert syndrome or pattern 
consistent with Gilbert syndrome); 
c. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification of Diet in Renal 
Disease method; 
d. Hypocalcemia (< lower limit of normal [LLN]) or hypercalcemia (> ULN); 
e. Hypophosphatemia (< LLN) or hyperphosphatemia (> ULN); 
14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina or significant coronary artery disease (ie, ≥ 50% stenosis); 
c. History of congestive heart failure; 
d. History of clinically significant ventricular arrhythmias such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes, or Mobitz II second degree or third degree heart 
block without a permanent pacemaker in place or untreated supraventricular tachycardia (heart 
rate ≥ 120 beats per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec on the Screening visit 
or Baseline Day 1 ECG; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury (mmHg) on 
2 repeat measures at least 15 minutes apart, or treated ongoing symptomatic orthostatic 
hypotension with > 20 mmHg decrease in systolic blood pressure one minute or more after 
assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 100 mmHg on 2 repeat measures at least 15 minutes apart at any screening 
visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening or Baseline 
Day 1 ECG electrocardiogram unless judged by the investigator to be due to physical fitness; 
15. Has been a participant in an investigational drug or device study within the 1 month prior to 
Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the following: 
a. Untreated thyroid dysfunction (patients with adequately treated hypothyroidism who are stable 
on medication are not excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than curatively 
treated nonmelanoma skin cancer or surgically cured Stage 0 in situ melanoma; 
c. Any current psychiatric disorder that would, in the opinion of the investigator or medical 
monitor, impair the ability of the patient to participate in the study or would impair 
interpretation of their data.  Patients with major depression, post-traumatic stress disorder, 
bipolar disorder, schizophrenia or other psychotic disorders, based on Diagnostic and 
Statistical Manual of Mental Disorders-5 criteria who have been unstable or not well 
controlled based on the investigator’s or mental health professional’s judgement or whose 
history or stability cannot be ascertained, or whose psychiatric drug regimen has changed 
during the 3 months prior to Screening or is expected to change during the study should not be 
enrolled; 
d. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren syndrome, 
rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, psoriatic arthritis, vasculitic 
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syndromes, etc).  Psoriasis not requiring or anticipated to require systemic therapy is 
permitted; 
17. Is currently pregnant or lactating, or intends to become pregnant during the study period through 1 
month after the last dose of study drug or intends to donate ova during the study period or within 2 
months after the last dose of study drug; 
18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable exclusionary 
window periods for these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse disorder 
according to Diagnostic and Statistical Manual of Mental Disorders V (all patients must be 
questioned about their drug and alcohol use and this should be documented in the electronic case 
report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in the conduct of this study (eg, spouse, parent, child, or sibling); 
23. 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, 
including contraception requirements, as determined by the investigator, sub-investigator, or 
medical monitor; 
24. Has received a blood transfusion within 8 weeks prior to Screening Visit 1 or during the screening 
period. 
Dose and Route of 
Administration 
Test Product (Group A and Group B) 
• 
Group A:  Relugolix 40 mg tablet will be co-administered orally once 
daily with 1.0 mg estradiol/0.5 mg norethindrone acetate in a co-
formulated tablet.  The low-dose hormonal add-back therapy will be over-
encapsulated. 
• 
Group B:  Relugolix 40 mg tablet co-administered orally once daily with a 
placebo capsule designed to match the over-encapsulated active low-dose 
hormonal add-back therapy in size, shape, and color for 12 weeks, 
followed by relugolix 40 mg tablet co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The active low-dose 
hormonal add-back therapy will be over-encapsulated. 
Reference Product (Group C) 
• 
Group C:  Placebo relugolix manufactured to match relugolix in size, 
shape, and color will be co-administered orally once daily with a placebo 
capsule designed to match the over-encapsulated active low-dose 
hormonal add-back therapy in size, shape, and color. 
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Duration of 
Treatment 
Study treatment will be administered for 24 weeks (randomized treatment 
period).  For women who do not to enroll in an open-label extension study, 
there is a 30-day follow-up period after the end of treatment (ie, after the 
patient’s last dose of study medication). 
Criteria for 
Evaluation 
Inferential efficacy assessments will be made between the following groups 
and placebo after 24 weeks of study treatment: 
• 
Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-
administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• 
Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each 
relugolix group and placebo for safety outcomes and between each of the two 
relugolix groups for both efficacy and safety.  
 
Primary Efficacy Endpoint 
• 
Proportion of women in the relugolix Group A versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
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Secondary Efficacy Endpoints 
• 
Proportion of women in the relugolix Group B versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix 
treatment group to placebo inferentially and relugolix Group A to Group B 
descriptively: 
• 
Time to achieving a menstrual blood loss volume of < 80 mL AND at 
least a 50% reduction from baseline menstrual blood loss volume as 
measured by the alkaline hematin method; 
• 
Change from Baseline to Week 24 in menstrual blood loss; 
• 
Proportion of women who achieve amenorrhea over the last 35 days of 
treatment; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at Baseline who achieve an increase of ≥ 1 g/dL from Baseline at 
Week 24; 
• 
Change from Baseline to Week 24 in impact of uterine fibroids based on 
the UFS-QOL activities domain; 
• 
Change from Baseline to Week 24 in the interference of uterine fibroids 
with physical activities based on UFS-QOL Question 11; 
• 
Change from Baseline to Week 24 in the interference of uterine fibroids 
with social activities based on UFS-QOL Question 20; 
• 
Change from Baseline to Week 24 in embarrassment caused by uterine 
fibroids based on UFS-QOL Question 29; 
• 
Change from Baseline to Week 24 in uterine fibroid-related symptoms 
based on the Uterine Fibroid Scale – Symptom Severity; 
• 
Change from Baseline to Week 24 in uterine fibroid-related quality of life 
based on the Uterine Fibroid Scale –  Health-related Quality of Life; 
• 
Change in PGA for uterine fibroid related function from Baseline to Week 
24; 
• 
Change in PGA for uterine fibroid symptoms from Baseline to Week 24; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for physical activities; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for social and leisure activities; 
• 
Proportion of women who achieve a mean Numerical Rating Scale score 
for uterine fibroid-associated pain over the last 35 days of treatment that is 
at least a 30% reduction from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days prior to randomization; 
• 
Change from Baseline to Week 24 in uterine volume; and 
• 
Change from Baseline to Week 24 in uterine fibroid volume. 
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Safety Endpoints 
• 
Treatment-emergent adverse events, change in vital signs (including 
weight), clinical laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Week 12 in bone mineral density at the 
lumbar spine (L1-L4) in Group A compared with Group B as assessed by 
DXA; 
• 
Percent change from Baseline to Week 24 in bone mineral density at the 
lumbar spine (L1-L4), total hip, and femoral neck as assessed by DXA; 
• 
Incidence of vasomotor symptoms. 
 
Pharmacokinetic and Pharmacodynamic Endpoints 
• 
Pre-dose trough concentrations (Cτ) of relugolix, estradiol, and 
norethindrone from Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-dose concentrations of LH, 
FSH, estradiol, and progesterone. 
 
Exploratory Endpoint 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-
Dimension Five-Level scale comparing each relugolix treatment group to 
placebo inferentially and the two relugolix groups descriptively. 
Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) Population defined as all 
randomized patients, unless otherwise specified in the statistical analysis plan.  Randomization will be 
1:1:1 with the stratification variables of geographic region and mean screening menstrual blood loss 
volume (mL per alkaline hematin method) as follows: 
• 
Geographic Region:  North America versus Rest of World; 
• 
Mean screening menstrual blood loss volume:  < 225 mL versus ≥ 225 mL. 
The randomization stratification factors will be incorporated into inferential testing of all efficacy 
endpoints, unless otherwise specified. 
The primary hypothesis tested in this study is whether relugolix co-administered with 1.0 mg estradiol 
and 0.5 mg norethindrone acetate is superior to placebo in the percentage of women who achieve both a 
menstrual blood loss volume of < 80 mL AND at least a 50% reduction in menstrual blood loss volume 
over the last 35 days on treatment as compared with Baseline. 
The point estimate and 2-sided 95% confidence interval of the difference in the proportion will be 
calculated between the relugolix Group A and placebo Group C.  The between-treatment comparisons 
will be performed using the Cochran-Mantel-Haenszel method. 
The comparisons of the relugolix arms versus placebo will be performed for the secondary efficacy and 
safety endpoints using appropriate statistical methods.  Comparisons between the two relugolix arms 
will be descriptive.  A closed testing procedure will be used to control the overall type I error rate of 
5% across primary and secondary endpoint testing.  Details of this procedure will be provided in the 
statistical analysis plan. 
Sample Size 
Assuming a placebo control response rate of 25%, the assessment of the superiority of relugolix 40 mg 
co-administered with low-dose hormonal add-back therapy (Group A) versus placebo (Group C) in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size of 260 (130 
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patients in each of the relugolix and placebo arms) will provide > 99% power to detect a difference of 
greater than 30 percentage points using a 2-sided test at significance level of 0.05.  The total sample 
size for the study will be approximately 390 patients (130 patients in each of the 3 arms). 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs, physical examinations, 
clinical laboratory tests, 12-lead electrocardiograms, endometrial biopsies, and assessments of bone 
mineral density.  Safety analyses will be based on all randomized patients who receive any amount of 
study drug (safety population).  Drug exposure will be summarized by descriptive statistics.  Severity 
of all treatment-emergent adverse events will be evaluated by the investigator based on the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and will be coded to 
preferred term, higher level term, and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of patients with adverse events will be presented by 
MedDRA system organ class and preferred term, relationship to study drug, and severity.  Descriptive 
statistics will be used rather than inferential statistics.  Laboratory values also will be classified by 
toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory shift tables of the 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), total hip, and femoral neck at the Baseline, Week 12, and Week 
24 visits and the absolute, percent, and standardized changes from baseline will be summarized.  
Vasomotor adverse events will be separately summarized. 
A chartered independent Data and Safety Monitoring Board will monitor all available safety data, 
including bone density assessments, on an ongoing basis during this study. 
Pharmacokinetics and Pharmacodynamics 
The PK concentration data (relugolix, estradiol, and norethindrone pre-dose) and pharmacodynamics 
concentration data (LH, FSH, estradiol, and progesterone pre-dose) will be listed and summarized by 
treatment arm and visit.  In addition, the PK data from this study will be combined with PK data from 
other studies to define a population PK model, which will be reported separately.  Exposure-response 
analyses of the primary efficacy endpoint and safety will be conducted to assess the effect of relugolix 
exposure on outcomes. 
 
 
 
 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3001 
 
SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-upf 
(~30 days 
after last 
dose of study 
drug) 
Day of Study Drug 
Treatment 
 
 
 
 
1 
29 
57 
85 
113 
141 
169 
 
197 
Visit Window Timing (days)
 
Within 5 
(+2) days 
after com-
pletion of 
Screening 
1 menses 
Within 
≤ 15 days 
after 
Screening 
2 visit 
Within 5 
(+2) days 
after com-
pletion of 
2nd 
Screening 
menses 
Within 
7 days of 
the start of 
menses 
± 7 
± 7 
± 7 
± 7 
± 7 
-10/+20 
 
 
-3 to + 10 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe  
X 
Waist Circumference 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
 
 
X 
Xe  
X 
Temperature 
X 
 
 
 
X 
 
 
 
 
 
X 
Xe 
X 
Adverse Event Collectiong 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Acuityh 
 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-upf 
(~30 days 
after last 
dose of study 
drug) 
Complete Physical excluding 
GYN Examination 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
GYN Examination with Pap 
Test, if applicable 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-Directed 
Physical Exam 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
Xe 
X 
12-Lead Electrocardiogram 
 
 
X 
 
X 
 
 
X 
 
 
X 
Xe 
X 
Clinical Laboratory Testsj 
X 
X 
 
 
Xk 
X 
X 
X 
X 
X 
Xl 
Xe 
X 
PK Samplem 
 
 
 
 
X 
X 
 
X 
 
 
X 
Xe 
 
PD Samplen  
 
 
 
 
X 
X 
 
X 
 
 
X 
Xe 
X 
Daily Study Drug 
Administration 
 
 
 
 
X  
(Day 1 through day immediately prior to Week 24/Early Termination visit)  
 
Xe 
 
Administer Dose of Study 
Drug in Clinic  
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
PGx Sampleo 
 
 
 
 
X 
 
 
 
 
 
 
Xe 
 
Pregnancy Test (Urine) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
X 
Urinalysis 
X 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
Mammogramp 
schedule 
X  
 
 
 
 
 
 
 
 
 
 
Transvaginal Ultrasound 
(with or without 
Transabdominal Ultrasound)q 
X 
 
 
 
 
 
 
 
 
 
Xs 
Xe 
 
Endometrial Biopsyr 
X 
 
 
 
 
 
 
 
 
 
Xs, w 
Xe 
 
Bone Densitometryt 
schedule 
X 
 
 
 
 
X 
 
 
Xs, x 
Xe 
 
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Clinical Study Protocol:  MVT-601-3001 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-
UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-upf 
(~30 days 
after last 
dose of study 
drug) 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Feminine Products 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
Dispense Study Treatment 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
Patient paper diary/ eDiaryu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Feminine Product Collection 
and Venous Blood Samplev 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Xe 
 
MIQ 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
UFS-QOL 
 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
 
EQ-5D-5L 
 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
PGA for functiony 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
PGA for symptomsy 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Treatment Compliance and 
Study Drug Accountabilityz 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Xe 
 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Notes: 
Abbreviations:  DXA, dual-energy x-ray absorptiometry; ECG, electrocardiogram; EQ-5D-5L, European Quality of Life Five-Dimension Five-Level Scale; 
GYN, gynecology; MBL, menstrual blood loss; MIQ, Menorrhagia Impact Questionnaire; Pap, Papanicolaou; PD, pharmacodynamics; PGA, Patient Global 
Assessment; PGx, pharmacogenomics; PK, pharmacokinetics; UFS-QOL, Uterine Fibroid Symptom and Health-Related Quality of Life.  
For patients who are re-screening, please see Section 6.2.6 for abbreviated screening procedures. 
 
a. 
The screening period should be initiated after the informed consent form is signed and any exclusionary windows for prohibited medications has been confirmed. 
b. 
Visit to occur within 5 (+2) days of the completion of menses.  Visit 4 should be skipped if the menstrual blood loss is > 160 mL in the first screening cycle. 
c. 
Visit to occur within ≤ 15 days after Screening 2 visit; eDiary dispensation must occur at least 7 days prior to Baseline Day 1.  The alkaline hematin menstrual 
blood loss collection may be repeated once at the discretion of the investigator if one menstrual cycle does not meet menstrual blood loss criteria thought to be due 
to inadequate collection for a highly motivated patient.  
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d. 
The Baseline Day 1 visit should occur within 7 days of the onset of menses.  The following procedures must be completed prior to randomization: urine pregnancy, 
vital signs, waist circumference, weight, temperature, complete physical examination, visual acuity assessment,12-lead ECG, and review of eligibility criteria.  
Collect clinical laboratory sample, PK sample, pharmacodynamic sample, and urinalysis prior to first dose of study drug.  Whenever possible, complete MIQ, UFS-
QOL, PGA for symptoms and PGA for function, and EQ-5D-5L prior to the first dose of study drug.  
e. 
For an Unscheduled visit, these procedures will be performed as needed, based on the reason(s) for the Unscheduled visit. The last dose of study drug in the 
Randomized Treatment Period will be taken on the day immediately before the Week 24 visit. Note: Week 24 visit is defined as the last day on which a Week 24 
visit procedure is conducted. 
f. 
Follow-up visit:  For women who do not continue into the open-label extension study (MVT-601-3003) and/or terminate early from the study, a follow-up visit to 
assess safety will be scheduled 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 for uterine fibroids, whichever occurs first (ie, ~Week 28 for patients who 
complete the study or ~30 days after an Early Termination visit). 
g. 
Collect serious adverse event information from the time of signed informed consent 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.  Collect nonserious adverse event information from the Baseline Day 1 visit (or from the time of signed informed consent if event was 
related to a screening study procedure) through approximately 30 days after the last dose of 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. 
h. 
Presenting visual acuity must be assessed with the supplied study eye chart.  If the patient uses corrective lenses, she should wear her usual prescription glasses or 
contact lenses during the assessment, and the same prescription lenses should be worn at subsequent visual testing, as possible. Perform the visual acuity testing 
using the entire eye chart.  Do not stop at a visual acuity of 100; continue as far as the patient can go per the testing instructions.   See Study Reference Manual for 
additional instructions on visual acuity testing and see Section 6.8.2.8 for overall guidance including follow-up.   
i. 
Papanicolaou test must be conducted for women without a test result within 2 years prior to the Screening 1 visit.  The specimen should be submitted to the central 
laboratory during screening.  Another test should be performed for inadequate or false-positive results and be submitted to the central laboratory.  
j. 
Clinical laboratory tests at each visit include clinical chemistries and a complete blood count.  Samples should be obtained in the fasted state (no food or drink other 
than water after midnight) for the Baseline and Week 24 visit clinical laboratory tests. In addition to clinical chemistries and a complete blood count, include 
thyroid-stimulating hormone at Screening 1.  Screening laboratory tests may be repeated during the screening period once, if necessary, at the investigator’s 
discretion.  Additional re-testing requires the approval of the medical monitor.  If the hemoglobin is < 10 g/dL and mean corpuscular volume is below the lower 
limit of normal, a ferritin and iron level will be reported through the central lab. 
k. 
At the Baseline Day 1 visit, obtain clinical laboratory tests after an overnight fast (other than water) of at least 8 hours.  In addition to clinical chemistries and a 
complete blood count, include a lipid profile, prolactin, Vitamin D, and hemoglobin A1c.  An additional sample will be collected at this visit in all patients and 
stored for possible future testing for presence of hepatitis A, B, and C if required per request from medical monitor to assess etiology of liver test abnormalities. 
l. 
At the Week 24 visit or Early Termination visit, obtain clinical laboratory tests after an overnight fast (other than water) of at least 8 hours.  In addition to clinical 
chemistries and a complete blood count, include a lipid profile, thyroid-stimulating hormone, prolactin, and hemoglobin A1c. 
m. Pharmacokinetics samples:  Samples should be obtained in the fasted state since study drug is administered on an empty stomach (see Section 5.4).  Collect pre-
dose samples for PK analysis of relugolix, estradiol (PK lab), and norethindrone.  Instruct the patient not to take her study treatment at home on these visit days and 
to record the time of her previous dose (ie, the dose taken the day before the visit).  Administer study drug after PK and pharmacodynamics sample collections are 
complete (Study drug is not administered at Week 24 Visit; for patients proceeding into the extension study, refer to protocol for study MVT-601-3003). 
n. 
Pharmacodynamic samples:  Samples should be obtained in the fasted state since study drug is administered on an empty stomach (see Section 5.4).  Collect pre-
dose samples for analysis of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations.  Administer study drug after PK and 
pharmacodynamic sample collections are complete (with the exception of Early Termination and Follow Up visits). Study drug is not administered at the Week 24 
Visit for patients proceeding into the extension study (refer to protocol for study MVT-601-3003). 
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o.
Pharmacogenomics sample (unless precluded by local law or regulations):  a separate pharmacogenomics consent is required before this sample may be collected.
If possible, the pharmacogenomic sample should be collected from consented patients at the Baseline Day 1 visit, but it may be collected at any time during the
study through Week 24 (inclusive)
p.
Patients ≥ 39 years of age at the time of the anticipated Baseline Day 1 visit must have a normal mammogram (Breast Imaging Reporting and Data System category
1 or 2 or equivalent) during the screening period or within 6 months prior to the screening period; if not, schedule at the Screening 1 visit.
q.
Transvaginal ultrasound with or without transabdominal ultrasound must be performed to confirm the presence of uterine fibroids and the absence of any other
pathology that might be responsible for the increase in menstrual bleeding, such as uterine or cervical polyps ≥ 2.0 cm, large simple ovarian cyst > 4.0 cm,
endometrioma(s) > 4.0 cm.  Results must be submitted to and uterine fibroid criteria confirmed by a central reader prior to randomization into the study.  Note:
Transvaginal ultrasound is required.  See inclusion criterion #5 and exclusion criterion #1 for guidance as to when to perform a transabdominal ultrasound and
saline or gel contrast.  If transabdominal ultrasound or ultrasound with saline or gel contrast is performed at Screening, it should also be performed at Week 24.
r.
Obtain sample with an endometrial suction curette (eg, Pipelle).   Endometrial biopsy is performed at Screening 1 visit and Week 24 Visit and submitted to the
central laboratory.  See the Laboratory Manual for guidance on handling and shipping the biopsy sample to the central laboratory for analysis.
s.
Procedure not required at the Early Termination Visit in patients whose last dose of study drug was during Week 6 or earlier.  The procedure may be done if it will
aid in the evaluation of an ongoing adverse event.
t.
Bone densitometry (L1-L4, total hip, femoral neck) will be assessed during the screening period and the central results will be available prior to randomization.
Schedule the test at or shortly after the Screening 1 visit.  Bone densitometry should be completed prior to the Screening 3 visit and as early as possible to ensure
results are available prior to randomization.
u.
Patient paper diary:  Patients enter diary information on menstruation status and feminine product use starting with Screening 1 visit and ending when they receive
their eDiary at the Screening 3 visit.  Patient eDiary:  Ensure that eDiary data collection begins at least 7 days prior to Day 1.  Patients enter eDiary information on a
daily basis for their compliance with study treatment starting at Baseline/Day 1, menstrual bleeding and use of feminine products for menstrual bleeding, uterine
fibroid-associated pain by the Numerical Rating Scale, and use of pain medications (analgesics) starting at Screening 3 visit through Week 24 or Early Termination.
v.
Hemoglobin:  a venous blood sample must be collected each time feminine products are collected to be sent to the central laboratory conducting the alkaline
hematin assessment.
w.
Patients not proceeding to the extension study who have endometrial hyperplasia or endometrial cancer on the endometrial biopsy at the Week 24/Early
Termination visit will be followed and will undergo a repeat biopsy in 3 to 6 months after the Week 24/Early Termination visit (see Section 6.7).  The repeat biopsy
will be submitted to the central laboratory.
x.
Schedule DXA as early as possible within the Week 24/Early Termination visit window.  Patients not proceeding to the extension study who have had a bone
mineral density loss of > 2% at the lumbar spine (L1-L4) or total hip at their Week 24/Early Termination visit relative to baseline will undergo another DXA scan at
6 (± 1) months after the Week 24/Early Termination visit scan to evaluate recovery and will be contacted about medications and conditions (eg, pregnancy) that
might affect bone mineral density through the time of the repeat DXA scan.  The follow-up DXA scan will be submitted for central reading.
y.
Patient will enter responses in a paper questionnaire at the site.
z.
The patient should be asked to bring all study drug to the clinic at each visit.  Please refer to Section 5.8.
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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. 
Combined hormonal contraceptives and progestational agents are commonly prescribed to 
regulate abnormal uterine bleeding, but appear to have limited efficacy in the treatment of 
uterine fibroids [Carr, 1993].  Although no randomized studies evaluating the use of 
levonorgestrel-releasing intrauterine system devices for the treatment of heavy menstrual 
bleeding related to uterine fibroids have been conducted, observational studies have reported a 
reduction in uterine volume and bleeding and this system is approved for use by the United 
States (US) Food and Drug Administration (FDA). 
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 
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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, non-steroidal anti-inflammatory medications, and danazol. 
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 250,000 hysterectomies are performed in the US for uterine fibroids.  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 United States 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 
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 (also known as TAK-385) is an orally-active, potent, highly-selective high-affinity 
small molecule GnRH receptor antagonist with a novel structure.  Relugolix was discovered and 
initially studied by Takeda Pharmaceutical Company, Limited, before development rights 
outside of Japan and certain East Asian countries were licensed to Myovant Sciences GmbH. 
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Relugolix antagonizes 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 
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. 
2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level (NOEL) for liver findings in the 39-week 
monkey toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (AUC) in women receiving 
40 mg once daily (0.101 μg⋅hr/mL), the dose of relugolix to be administered in this study.  Both 
the liver and PLD findings demonstrated evidence of reversibility following a 13-week recovery 
period in monkeys.  No evidence of PLD has been observed in clinical studies.  The relugolix 
toxicology program supports the conduct of clinical studies up to the NOAEL (15 mg/kg/day) 
exposure (5.2 μg⋅hr/mL) for liver toxicity in monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
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2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies (including 1 in women with 
uterine fibroids and 1 in women with endometriosis) have been completed.  In addition, 6 
clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 2 studies in 
men with prostate cancer (US and Europe), and 2 phase 3 studies in women with uterine fibroids 
in Japan.  More than 1380 patients and healthy volunteers have received at least 1 dose of 
relugolix, including 158 women receiving relugolix 40 mg once daily (the proposed phase 3 
dose) for at least 28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg 
once daily for at least 24 weeks and for as long as 48 weeks.  Eighty-eight women have been 
treated with relugolix 40 mg once daily for 24 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of estradiol in female subjects and testosterone in male subjects.  After oral 
administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The pharmacokinetics (PK) and pharmacodynamics of relugolix have 
been evaluated, and appear to be similar in American and Japanese volunteers, despite the lower 
mean body mass index observed in Japanese volunteers. 
A phase 1 study (TAK-385_101) in healthy US premenopausal women demonstrated the 
tolerability of single doses of relugolix 1 to 80 mg, and once-daily dosing of relugolix at 10, 20, 
and 40 mg for 2 weeks.  Plasma concentrations of relugolix increased in a slightly greater than 
dose-proportional manner.  Suppression of serum estradiol was similar after single doses of 40 or 
80 mg once daily relugolix.  The serum concentrations of LH, FSH, estradiol, and progesterone 
rapidly decreased and remained at low levels with multiple doses of relugolix with the majority 
of women having estradiol levels < 10 pg/mL in the 40-mg dose group.  Based on these hormone 
reductions, oral relugolix 40 mg once daily was chosen as the high dose for further study in 
phase 2. 
A 6-week phase 1 study (MVT-601-1001) in healthy US premenopausal women was conducted 
to evaluate the safety, PK, and pharmacodynamics profile of oral relugolix 40 mg once daily and 
relugolix 40 mg once daily in combination with estradiol/norethindrone acetate (1 mg/0.5 mg 
once daily).  Median pre-dose trough concentrations of estradiol in the relugolix alone arm were 
~6 pg/mL; with the addition of 1 mg estradiol once daily, these were increased to ~26 pg/mL, 
and median peak concentrations were ~45 pg/mL.  This trough and peak concentration range is 
consistent with the estradiol range associated with reduced loss of bone mineral density 
[Barbieri, 1992].  Relugolix PK and norethindrone acetate PK were similar to historic data.  The 
estrogenic metabolite of norethindrone, ethinyl estradiol, was below the limit of quantitation in 
almost all PK samples collected.  The adverse event profile was similar to prior phase 1 studies, 
with a marked reduction in hot flushes noted in the relugolix plus hormonal add-back therapy in 
comparison with the relugolix alone arm. 
Relugolix is to be administered in the fasted state, as food decreases the extent of relugolix 
absorption (AUC) by approximately 19%.  The exposure of relugolix is increased by inhibitors 
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of P-glycoprotein (P-gp) up to 6-fold, but relugolix does not significantly impact the exposure of 
cytochrome P450 1A2, 2C9, 2D6, or 3A4 substrates.  In a dedicated study, relugolix did not 
prolong the corrected (QTc) interval. 
2.2.4.2. 
Clinical Studies in Women with Uterine Fibroids or Endometriosis and Men with 
Prostate Cancer 
A phase 2 study (TAK-385/CCT-001) evaluated the efficacy, safety, PK, and pharmacodynamics 
of relugolix 10, 20, and 40 mg once daily for 12 weeks in 216 Japanese women with uterine 
fibroids and heavy menstrual bleeding.  Heavy menstrual bleeding was defined for enrollment 
into the study as a score on the Pictorial Blood Loss Assessment Chart (PBAC) of at least 120; 
uterine fibroids were confirmed by ultrasound, magnetic resonance imaging, computed 
tomography, or laparoscopy.  For the primary endpoint (proportion of patients with a total PBAC 
score of < 10 from Week 6 to 12), statistically significant dose-dependent differences were 
observed in all relugolix treatment groups compared to placebo (Figure 2-1).  The proportion 
was higher in the relugolix 40 mg group (83.6%) compared with 0% in the placebo group 
(p < 0.0001).  In the relugolix 20 mg group, 43.6% of women responded and in the 10 mg group 
20.8% responded, demonstrating a dose-response relationship.  Of the women in the relugolix 
40 mg group, 72.7% achieved amenorrhea from Week 6 to Week 12.  Similarly, improvement 
with increasing dose was also observed in the secondary endpoints including change in myoma 
and uterine volumes and blood concentration of hemoglobin. 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001) 
 
Notes:  Data shown is Pictorial Blood Loss Assessment Chart (PBAC) method of assessing blood loss during Week 
6 to Week 12.  Primary endpoint is proportion of patients with PBAC score < 10. 
Statistically significant difference with p < 0.001 observed for each relugolix treatment arm versus placebo. 
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In the phase 2 uterine fibroid study, the most common treatment-emergent adverse events 
(occurring > 10% in any treatment group and more than placebo) were hot flush, metrorrhagia, 
menorrhagia, headache, genital hemorrhage, menstruation irregular and nasopharyngitis.  With 
the exception of the incidence of nasopharyngitis in all treatment groups, these common adverse 
events were thought to be caused by the pharmacological effect of relugolix.  The adverse events 
associated with menstruation were primarily reported in the first 28 days.  Most of the adverse 
events were mild or moderate, and no serious treatment-emergent adverse event considered 
related to study drug was observed.  Adverse events resulted in study drug discontinuation in 2 
patients (hemoglobin decreased in a placebo patient and tinnitus, libido decreased, menopausal 
depression and hyperhidrosis in one patient treated with relugolix 20 mg once daily).  Bone 
mineral density decreases appeared to correlate with increasing doses of relugolix.  Women 
treated with placebo for 12 weeks had a mild loss of bone mineral density (mean ± standard 
deviation [SD]) of -0.24 ± 2.218% compared with -0.75 ± 2.350%, -2.01 ± 2.334%, and -2.28 ± 
2.194% in the relugolix 10, 20, and 40 mg once daily groups, respectively.  One patient had a 
positive pregnancy test after receiving approximately 46 days of relugolix 10 mg once daily (a 
dose that does not fully suppress estradiol).  Study drug was discontinued.  An ultrasound 
determined that the patient was 7 weeks pregnant.  The patient subsequently had an uneventful 
pregnancy and delivered a healthy infant at 39 weeks. 
In a phase 2 study of women with endometriosis (TAK-385/CCT-101), 487 women were 
randomized to relugolix doses of 10, 20, or 40 mg or placebo, administered orally once daily 
over a 12-week period, or to leuprolide acetate (every 4-week injection) administered for 
12 weeks.  The study demonstrated dose-dependent decreases in pelvic pain as assessed by a 
100 mm visual analogue score (VAS).  The pain scores for pelvic pain were well-balanced across 
the groups at baseline and the means ranged from 14.6 to 15.6 mm.  The changes from baseline 
in the VAS score (mean ± SD) were -10.418 ± 11.0171 mm in the relugolix 40 mg group vs. -
3.753 ± 10.5018 mm in the placebo group (p < 0.0001).  All doses were better than placebo, with 
the greatest benefit observed at the highest dose evaluated, 40 mg once daily.  The decrease in 
mean VAS pain score for the leuprolide group (-10.460 ± 10.3013 mm) was similar to that of the 
relugolix 40 mg group.  The effects of relugolix on pain were maintained following an additional 
12 weeks of treatment in the extension study (total of 24 weeks).  Estradiol levels were 
suppressed for the duration of the study. 
In the 12-week phase 2 endometriosis study (CCT-101) and the companion 12-week extension 
study (OCT-101; total of 24 weeks of treatment), the safety profile of the relugolix 40 mg once 
daily dose was comparable to that of leuprolide treatment.  The most commonly reported 
treatment-emergent adverse events in the relugolix groups than in the placebo group included hot 
flush, metrorrhagia, and menstruation irregular, and were considered to be due to the 
pharmacological effects of relugolix.  The events of menstrual bleeding were primarily reported 
in the first 28 days.  Bone mineral density changes from baseline (mean ± standard deviation 
[SD]) observed after 24 weeks of treatment were -0.23 ± 1.986% in the placebo group, -1.61 ± 
2.338%, -2.58 ± 2.936%, and -4.90 ± 2.912% in the relugolix 10, 20, and 40 mg groups 
respectively, and -4.43 ± 2.157% in the leuprolide group.  Bone mineral density changes from 
baseline in the relugolix 40 mg group at 12 and 24 weeks were comparable to those in the 
leuprolide group for the same durations.  Two patients had liver test abnormalities considered 
study drug-related by the investigator and that resulted in discontinuation of study drug. 
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Two phase 3 studies evaluating relugolix in women with uterine fibroids are ongoing in Japan.  
One study is assessing the effect of relugolix in women with moderate to severe pain associated 
with uterine fibroids, and the other is evaluating women with heavy menstrual bleeding 
associated with uterine fibroids.  Data from these ongoing studies are not available. 
Two phase 2 clinical studies of relugolix (C27002 and C27003) in men with advanced prostate 
cancer requiring androgen deprivation therapy were initiated in North America in 2014.  Study 
C27002, which remains ongoing, enrolled patients with advanced prostate cancer.  In this open-
label, parallel group study, men were randomized to receive oral relugolix at a dose of 80 mg or 
120 mg once daily after a single oral loading dose of 320 mg (N = 50 in each arm) or to the 
GnRH agonist therapy, leuprolide acetate, 22.5 mg administered subcutaneously every 12 weeks, 
(N = 25) for up to 48 weeks.  Study C27003, in which the last clinical study visits have been 
completed, enrolled men in North America or the United Kingdom requiring six months of 
androgen deprivation therapy as neoadjuvant and adjuvant therapy to external beam radiation 
therapy.  Patients were randomized to relugolix 120 mg once daily (after a single oral loading 
dose of 320 mg) (N = 65) or to degarelix 80 mg subcutaneously every four weeks (N = 38) for 
24 weeks (after a single loading dose of 240 mg).  Results from the C27002 final analysis 
demonstrated that both doses of oral relugolix, 80 mg and 120 mg once daily, rapidly reduced 
testosterone levels below the castration threshold (≤ 50 ng/dL) and maintained these levels 
through at least 24 weeks.  These 24-week data were comparable to testosterone levels achieved 
by leuprolide 22.5 mg administered by injection every 3 months.  Study C27003 also 
demonstrated rapid and sustained suppression of testosterone levels by relugolix for the 24-week 
treatment duration. 
In an interim analysis of the phase 2 prostate cancer study C27002, the most common treatment-
emergent adverse events occurring in at least 10% of men with advanced prostate cancer in the 
relugolix 80 mg or 120 mg once daily arms or leuprolide arm included hot flush, alanine 
aminotransferase increase, fatigue, aspartate aminotransferase, diabetes mellitus, hyperhidrosis, 
muscle spasm, injection site reaction, and frequent daytime urination.  The common adverse 
events observed with relugolix in men with prostate cancer were generally consistent with its 
mechanism of action and those observed with leuprolide.  A biomarker for PLD, di-22:6-
bis(monoacylglycerol)phosphate (di-22:6-BMP), was monitored in this study due to findings of 
PLD in nonclinical toxicity studies.  There were no systematic increases in post-baseline serum 
or urinary di-22:6-BMP levels and no changes exceeding 2-fold observed in any patients. 
No clinical evidence of relugolix-related PLD-associated toxicity has been observed regarding 
the heart, liver, central nervous system, or muscle in any clinical study. 
Relugolix has been generally well tolerated.  Adverse drug reactions associated with relugolix in 
women with uterine fibroids or endometriosis include hot flush, headache, hyperhidrosis and 
bone density decreased. Adverse drug reactions associated with relugolix in men with prostate 
cancer include hot flush, fatigue, arthralgia, nausea, weight increased, gynecomastia and night 
sweats.  
More detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Investigator Brochure, along with a full discussion of the safety profile of relugolix. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Inferential efficacy assessments will be made between the following groups and placebo 
Group C after 24 weeks of study treatment: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with 
1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each relugolix group (Group A 
and Group B) and placebo (Group C) for safety outcomes and between each of the two relugolix 
groups for both efficacy and safety. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on heavy 
menstrual bleeding associated with uterine 
fibroids. 
• 
Proportion of women in the relugolix 
Group A versus the placebo Group C who 
achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
baseline menstrual blood loss volume over 
the last 35days of treatment, as measured by 
the alkaline hematin method. 
Secondary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily for 12 weeks followed by 12 
weeks of relugolix 40 mg once daily co-
administered with low-dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding 
associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on the following: 
o Achievement of amenorrhea; 
o Change in hemoglobin; 
o Impact of uterine fibroids on symptoms, 
activities and health-related quality of life 
as measured by components of the 
Uterine Fibroid Symptom and Health-
Related Quality of Life (UFS-QOL); 
o Patient global assessment for function 
and symptoms as measured by the Patient 
Global Assessment (PGA) for function 
• 
Proportion of women in the relugolix Group 
B versus the placebo Group C who achieve a 
menstrual blood loss volume of < 80 mL 
AND at least a 50% reduction from baseline 
menstrual blood loss volume over the last 
35 days of treatment, as measured by the 
alkaline hematin method. 
The following secondary endpoints will be 
assessed comparing each relugolix treatment 
group to placebo inferentially and relugolix 
Group A to Group B descriptively: 
• 
Time to achieving a menstrual blood loss 
volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss 
volume as measured by the alkaline hematin 
method; 
• 
Change from Baseline to Week 24 in 
menstrual blood loss; 
• 
Proportion of women who achieve 
amenorrhea over the last 35 days of 
treatment; 
• 
Proportion of women with a hemoglobin 
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Objective(s) 
Endpoint(s) 
and symptoms; 
o Impact of heavy menstrual bleeding on 
social, leisure, and physical activities as 
measured by the Menorrhagia Impact 
Questionnaire; 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
below the lower limit of normal at Baseline 
who achieve an increase of ≥ 1 g/dL from 
Baseline at Week 24; 
• 
Change from Baseline to Week 24 in impact 
of uterine fibroids based on the UFS-QOL 
activities domain; 
• 
Change from Baseline to Week 24 in the 
interference of uterine fibroids with physical 
activities based on UFS-QOL Question 11; 
• 
Change from Baseline to Week 24 in the 
interference of uterine fibroids with social 
activities based on UFS-QOL Question 20; 
• 
Change from Baseline to Week 24 in 
embarrassment caused by uterine fibroids 
based on UFS-QOL Question 29; 
• 
Change from Baseline to Week 24 in uterine 
fibroid-related symptoms based on the 
Uterine Fibroid Scale – Symptom Severity; 
• 
Change from Baseline to Week 24 in uterine 
fibroid-related quality of life based on the 
Uterine Fibroid Scale –  Health-related 
Quality of Life; 
• 
Change in PGA for uterine fibroid related 
function from Baseline to Week 24; 
• 
Change in PGA for uterine fibroid symptoms 
from Baseline to Week 24; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
physical activities; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• 
Proportion of women who achieve a mean 
Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days 
of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• 
Change from Baseline to Week 24 in uterine 
volume; and 
• 
Change from Baseline to Week 24 in uterine 
fibroid volume. 
Safety 
• 
To determine the safety of 24 weeks of 
• 
Treatment-emergent adverse events, change 
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Objective(s) 
Endpoint(s) 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate in women 
with heavy menstrual bleeding associated with 
uterine fibroids compared with placebo for 
24 weeks; 
• 
To determine the percent change from 
Baseline to Week 12 in bone mineral density 
at the lumbar spine (L1-L4) in Group A 
compared with Group B in women with heavy 
menstrual bleeding associated with uterine 
fibroids; 
• 
To determine the change in bone mineral 
density of women with heavy menstrual 
bleeding associated with uterine fibroids 
treated with 24 weeks of relugolix 40 mg once 
daily co-administered with either 12 or 24 
weeks of low-dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks; 
• 
To determine the incidence of vasomotor 
symptoms with relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of 
low-dose estradiol and norethindrone acetate 
in women with heavy menstrual bleeding 
associated with uterine fibroids. 
in vital signs (including weight), clinical 
laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Week 12 in 
bone mineral density at the lumbar spine (L1-
L4) in Group A compared with Group B as 
assessed by DXA; 
• 
Percent change from Baseline to Week 24 in 
bone mineral density at the lumbar spine (L1-
L4), total hip, and femoral neck as assessed 
by DXA; 
• 
Incidence of vasomotor symptoms. 
Pharmacokinetic and Pharmacodynamic 
• 
To evaluate the pharmacokinetic (PK) and 
pharmacodynamic effects of 24 weeks of 
relugolix 40 mg once daily when co-
administered with either 12 or 24 weeks of 
low-dose estradiol and norethindrone acetate. 
• 
Pre-dose trough concentrations (Cτ) of 
relugolix, estradiol, and norethindrone from 
Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-
dose concentrations of LH, FSH, estradiol, 
and progesterone. 
Exploratory 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo on patient-reported quality of 
life outcome measures (EQ-5D-5L). 
• 
Change from Baseline to Week 24 in the 
European Quality of Life Five-Dimension 
Five-Level scale comparing each relugolix 
treatment group to placebo inferentially and 
the two relugolix groups descriptively. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This study is an international phase 3, randomized, double-blind, placebo-controlled efficacy and 
safety study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate compared with 24 weeks of placebo.  Approximately 390 
women with heavy menstrual bleeding associated with uterine fibroids will be enrolled and 
randomized 1:1:1 to the relugolix plus low-dose hormonal add-back therapy group (Group A; N 
≈ 130), the relugolix monotherapy followed by co-administration with low-dose hormonal add-
back therapy group (Group B; N ≈ 130), or placebo group (Group C; N ≈ 130).  Stratification 
variables will include:  geographic region (North America versus Rest of World) and mean 
screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the alkaline hematin 
method. 
The study consists of a screening period (up to ~13 weeks), a randomized treatment period 
(24 weeks), and a follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) 
may be arranged for patients with study-related safety concerns and as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by centrally-
reviewed transvaginal ultrasound (with or without a transabdominal ultrasound).  Heavy 
menstrual bleeding will be defined as menstrual blood loss of ≥ 80 mL per cycle for 2 cycles or ≥ 
160 mL during 1 cycle during the screening period.  Women with iron-deficient microcytic 
anemia and hemoglobin ≥ 8 g/dL and ≤ 10 g/dL during Screening must be treated with oral or 
parenteral iron replacement therapy.  Between the Baseline Day 1 and Week 24 visits, patients 
will attend visits monthly (ie, every 4 weeks).  At the Screening, Week 12, and Week 24 visits, 
patients will have an assessment of bone mineral density with dual-energy x-ray absorptiometry 
(DXA).  An endometrial biopsy will also be performed at Screening.  Another transvaginal 
ultrasound (with or without a transabdominal ultrasound) will be performed at Week 24, 
followed by a repeat endometrial biopsy.  Patients will have paired baseline and end-of-treatment 
endometrial biopsies, independent of ultrasound results.  Feminine products will be standardized 
and will be collected and assessed for blood loss by the alkaline hematin method.  Complete 
blood counts and chemistries will be collected monthly and uterine fibroid volumes will be 
assessed at the Screening and Week 24 visits.  Patients will complete daily electronic diaries 
(eDiary) including compliance with study treatment, menstrual bleeding, use of feminine 
products for menstrual bleeding, uterine fibroid-associated pain by the Numerical Rating Scale, 
and use of pain medication to treat pain caused by uterine fibroids.  Quality of life questionnaires 
will be completed according to the Schedule of Activities. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, 
endometrial biopsies, and assessments of bone mineral density.  Height will be measured at the 
Screening 1 visit and weight will be measured at specified intervals. 
Samples will be collected for PK assessment of relugolix, estradiol, and norethindrone and for 
the pharmacodynamic assessment of luteinizing hormone (LH), follicle-stimulating hormone 
(FSH), estradiol, and progesterone. 
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During the Randomized Treatment Period, study participants will take the blinded study 
treatment (1 tablet and 1 capsule) orally once daily for 24 weeks.  The last dose of study drug for 
the Randomized Treatment Period will be taken on the immediate day prior to the Week 24 visit. 
Eligible patients, including women randomized to placebo, will be offered the opportunity to 
enroll in a 28-week open-label extension study where patients will receive relugolix co-
administered with low-dose estradiol and norethindrone acetate.  Patients who do not enroll into 
the extension study will have a Follow-Up visit approximately 30 days after the patient’s last 
dose of study drug.  Patients who are not proceeding to the extension study and who have 
endometrial hyperplasia or endometrial cancer on the endometrial biopsy or bone mineral density 
loss of > 2% at the lumbar spine (L1-L4) or total hip at their Week 24/Early Termination visit 
relative to the baseline measurement will undergo further testing and follow-up to evaluate 
recovery (see Section 6.6).  Patients whose menses has not resumed as of the Follow-Up visit for 
unexplained reasons (eg, not explained by concomitant medications or medical procedures) will 
be contacted by telephone to determine if menses has resumed (see Section 6.6).  Patients with 
reductions in visual acuity will be referred for ophthalmology consultation (see Section 6.8.2.8). 
A schematic of the overall study design is provided as Figure 4-1.  Details of the screening 
period visits are provided in Figure 4-2. 
Figure 4-1 
MVT-601-3001 Study Schematic 
  
 
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Figure 4-2 
Schematic of MVT-601-3001 Screening Visit Scenarios  
 
Figure 4-2 
Screening visit 1 may be conducted at any time during the pre-screening cycle. 
Top scenario: 
• 
Eligibility is based on 2 consecutive screening cycles, each with ≥ 80 mL of menstrual blood loss 
assessed by the alkaline hematin method where the first screening cycle menstrual blood loss is 
also < 160 mL. 
Bottom scenario: 
• 
Eligibility is based on first screening cycle with ≥ 160 mL menstrual blood loss assessed by the 
alkaline hematin method. 
Additional Scenarios (not depicted): 
• 
Patients whose first screening cycle menstrual blood loss is < 80 mL and whose second screening 
menstrual blood loss is ≥ 80 mL but < 160 mL may collect menstrual blood loss during a third 
screening cycle if the first collection was believed to be inadequate in a highly motivated patient. 
• 
Patients whose first screening cycle menstrual blood loss is ≥ 80 mL but < 160 mL and whose 
second screening menstrual blood loss is < 80 mL may collect menstrual blood loss during a third 
screening cycle if the second collection was believed to be inadequate in a highly motivated 
patient. 
• 
Patients whose first screening cycle menstrual blood loss is < 80 mL may collect menstrual blood 
loss during a second cycle if the first collection was believed to be inadequate in a highly 
motivated patient.  If the second screening menstrual blood loss is ≥ 160 mL, the patient should 
follow the top scenario visit schedule, and the patient does not need to collect menstrual blood 
loss for another cycle. 
 
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4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is one of two replicate studies designed to establish the efficacy and safety of 
relugolix 40 mg once daily in women with heavy menstrual bleeding associated with uterine 
fibroids.  This study will focus on the primary objective of demonstrating a reduction in heavy 
menstrual bleeding, the most common and burdensome symptom of uterine fibroids.  The study 
is designed to demonstrate the benefit and safety of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate (0.5 mg) for 24 weeks.  An additional relugolix arm 
dosed with 12 weeks of relugolix monotherapy 40 mg once daily followed by 12 weeks of 
relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
will be used to provide an assessment of the requirement for the low-dose hormonal add-back 
therapy to mitigate the adverse effects of relugolix monotherapy on bone mineral density loss 
and vasomotor symptoms.  An extension study is planned to provide additional safety and 
efficacy data through 48 weeks. 
Women with uterine fibroids and heavy menstrual blood loss by the alkaline hematin method of 
≥ 80 mL/cycle for two cycles or ≥ 160 mL in one cycle during screening will be enrolled in this 
study.  Randomization will be 1:1:1.  Placebo was selected as the appropriate control for the 
study because there is no standard of care medical therapy for the long-term treatment of women 
with uterine fibroids and heavy menstrual bleeding.  Commonly-used treatment options range 
from combined oral contraceptive pills, which are not effective in many cases, levonorgestrel-
containing intrauterine devices, and leuprolide therapy indicated for 3 months in the preoperative 
setting. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  This dose was selected for 
evaluation in phase 2 clinical studies based upon phase 1 data demonstrating similar estradiol 
and progesterone suppression in women treated with single doses of relugolix 40 mg or 80 mg, 
and data demonstrating that premenopausal women treated with multiple doses of 40 mg once 
daily relugolix over 14 days had estradiol levels suppressed to a median value of 3.68 pg/mL. 
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, as described above, a phase 
2 study of doses of relugolix 10, 20 and 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 
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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 48 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 48 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, 1992; 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 has demonstrated that this dose of add-back therapy maintains serum 
estradiol in the 25-50 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 PK 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) 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 is not included as a control arm as 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 
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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 will primarily assess the 
efficacy and safety of relugolix 40 mg co-administered with a low-dose of estradiol and 
norethindrone acetate compared with placebo at 24 weeks 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.  An additional arm with 
monotherapy relugolix administered for 12 weeks followed by 12 weeks of relugolix co-
administered with low-dose hormonal add-back therapy is included to provide data on the 
requirement for hormonal therapy to mitigate the adverse relugolix side effects of bone mineral 
density loss and hot flushes. 
All eligible women who complete the 24-week study will be offered the opportunity to enroll in 
an open-label extension study to obtain long-term safety and efficacy data over an additional 
28 weeks of treatment, providing approximately 1 year of safety data on the women originally 
randomized to relugolix. 
4.3. 
Selection of Study Population 
The study population will include approximately 390 premenopausal women aged 18 to 50 years 
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. 
4.3.1. 
Inclusion Criteria 
A woman will be eligible for randomization and enrollment in this study only if all of the 
following inclusion criteria apply and have been met at the time of the Baseline Day 1 visit, 
unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and 
dating the informed consent form; 
3. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 
38 days from the start of one menstrual period until the start of the next, by patient 
history for at least 3 months prior to the Screening 1 visit; 
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4. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal ultrasound 
performed during the screening period; at least one uterine fibroid must be verified by a 
central reader to meet at least one of the following criteria: 
a. Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter 
≥ 2 cm (longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3 
Note 1:  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. 
Note 2:  Saline or gel contrast is not required, but may be performed to demonstrate 
fibroids that meet the criterion for inclusion if these are not adequately visualized with 
transvaginal ultrasound alone. 
5. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a 
menstrual blood loss of ≥ 160 mL during 1 cycle or ≥ 80 mL per cycle for 2 menstrual 
cycles as measured by the alkaline hematin method during the screening period; 
6. Patient not expected to undergo gynecological surgery or ablation procedures for uterine 
fibroids within the 6 months following enrollment; 
7. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 
visits; 
8. Agrees to use contraception during the study and for 30 days following the last dose of 
study drug. Specifically agrees to use non-hormonal contraception, as described in 
Section 4.7 consistently during the Screening period and the Randomized Treatment 
Period and either nonhormonal or oral contraceptives after return of menses following 
treatment discontinuation.  However, the patient is not required to use specified non-
hormonal contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
screening period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the first screening visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram and no 
evidence of “post-Essure syndrome” in the investigator’s opinion); 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires 
the use of non-hormonal contraception as described in Section 4.7;  
9. Has an adequate endometrial (aspiration) biopsy performed during the screening period, 
with results showing no clinically significant endometrial pathology (hyperplasia, polyp, 
or endometrial cancer).  Note:  Patients for whom polyps are detected on biopsy but are 
either not evident on ultrasound or < 2 cm are eligible; 
10. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram 
(Breast Imaging Reporting and Data System category 1 or 2 or equivalent) during the 
screening period or within 6 months prior to the screening period. 
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4.3.2. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period 
demonstrating pathology other than uterine fibroids that could be responsible for or 
contributing to the patient’s heavy menstrual bleeding, such as uterine or cervical polyps 
≥ 2.0 cm, large simple ovarian cyst > 4.0 cm, endometrioma(s) > 4.0 cm, or any other 
clinically significant gynecological disorder determined by the investigator to require 
further evaluation and/or treatment during the study; 
Note:  Saline or gel contrast is not routinely required.  Use of such contrast is required 
only when the endometrium cannot be evaluated or when there are ambiguous and 
potentially exclusionary findings on the transvaginal or transabdominal ultrasound (eg, 
suspected intrauterine masses, equivocal endometrial findings, etc.); 
2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator; 
3. 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, as well as endometrial ablation for 
abnormal uterine bleeding within 6 months prior to the Screening 1 visit; 
4. 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 or spinal hardware in the lumbar spine); 
5. Has a baseline bone mineral density z-score < -2.0 at spine, total hip, or femoral neck; 
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low 
traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and 
ankle fractures are allowed).  Patients whose hyperparathyroidism or hyperthyroidism has 
been successfully treated or whose hyperprolactinemia has been successfully treated 
and/or who meet bone mineral density eligibility criteria for the study are allowed; 
7. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, 
teriparatide, denosumab, or any medication other than calcium and vitamin D 
preparations to treat bone mineral density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of 
more than 5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, 
ophthalmic, intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
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10. 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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(HAV IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV 
RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical 
glandular cells, atypical endocervical cells, atypical squamous cells favoring high grade.  
Of note, patients with atypical squamous cells of undetermined significance and low-
grade cervical neoplasia may be included in the study if high risk human papilloma virus 
testing is negative or if DNA testing for human papilloma virus 16 and 18 is negative; 
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with screening hemoglobin results < 8 g/dL may 
be prescribed iron supplements and have their hemoglobin levels retested prior to 
the Baseline Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper 
limit of normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical 
laboratory testing at either the Screening 1 or Screening 2 visit (or > 2.0 x ULN if 
secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome); 
c. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification of 
Diet in Renal Disease method;  
d. Hypocalcemia (< lower limit of normal [LLN]) or hypercalcemia (> ULN); 
e. Hypophosphatemia (< LLN) or hyperphosphatemia (> ULN); 
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14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina or significant coronary artery disease (ie, ≥ 50% stenosis); 
c. History of congestive heart failure; 
d. History of clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes, Mobitz II second 
degree or third degree heart block without a permanent pacemaker in place or 
untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec on the 
Screening visit or Baseline Day 1 ECG; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury 
(mmHg) on 2 repeat measures at least 15 minutes apart, or treated ongoing 
symptomatic orthostatic hypotension with > 20 mmHg decrease in systolic blood 
pressure one minute or more after assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg 
or diastolic blood pressure > 100 mmHg on 2 repeat measures at least 15 minutes 
apart at any screening visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram unless judged by the investigator to be due to physical fitness; 
15. Has been a participant in an investigational drug or device study within the 1 month prior 
to Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the 
following: 
a. Untreated thyroid dysfunction (patients with adequately treated hypothyroidism 
who are stable on medication are not excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than 
curatively treated nonmelanoma skin cancer or surgically cured Stage 0 in situ 
melanoma; 
c. Any current psychiatric disorder that would, in the opinion of the investigator or 
medical monitor, impair the ability of the patient to participate in the study or 
would impair interpretation of their data.  Patients with major depression, post-
traumatic stress disorder, bipolar disorder, schizophrenia or other psychotic 
disorders, based on Diagnostic and Statistical Manual of Mental Disorders-5 
criteria who have been unstable or not well controlled based on the investigator’s 
or mental health professional’s judgement or whose history or stability cannot be 
ascertained, or whose psychiatric drug regimen has changed during the 3 months 
prior to Screening or is expected to change during the study should not be 
enrolled;  
d. Has a systemic autoimmune disease (eg, systemic lupus erythematosus, Sjogren 
syndrome, rheumatoid arthritis, polymyositis, systemic sclerosis, psoriasis, 
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psoriatic arthritis, vasculitic syndromes, etc).  Psoriasis not requiring or 
anticipated to require systemic therapy is permitted; 
17. Is currently pregnant or lactating, or intends to become pregnant during the study period 
through 1 month after the last dose of study drug or intends to donate ova during the 
study period or within 2 months after the last dose of study drug; 
18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable 
exclusionary periods for these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or 
components thereof; or has a history of drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders-5 (all 
patients must be questioned about their drug and alcohol use and this should be 
documented in the electronic case report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship 
with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, or sibling); 
23. 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, including contraception requirements, as determined by the investigator, 
sub-investigator, or medical monitor; 
24. Has received a blood transfusion within 8 weeks prior to Screening Visit 1 or during the 
screening period. 
4.4. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the screening period.  Screening failures are patients who consent to participate in the 
clinical study but are never randomized. 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID Number 
After a patient is screened, the investigator determines that the patient is eligible for enrollment, 
the patient may undergo her Baseline Day 1 visit.  After confirming that all inclusion criteria and 
no exclusion criteria are met, the site will randomize the patient to treatment by using the 
Interactive Web Response System (IWRS) during the patient’s Baseline Day 1 visit.  The IWRS 
will assign the patient a study treatment kit number available at the site according to the 
randomization code.  The IWRS will also assign the Patient Identification Number 
(Randomization Number). 
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4.6. 
Removal of Patients from Therapy 
Completion of the Week 24 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 (Week 24 visit) on the Schedule of 
Activities 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 randomization 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%); 
• Corrected QTcF prolongation of more than 500 msec as read by a cardiologist; 
• Patients who have a clinically significant decrease in visual acuity as evaluated by an 
ophthalmologist; 
• Patients who are, in the opinion of the investigator or the medical monitor, grossly non-
compliant 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; missing multiple study visits; and 
persistent (> 2 consecutive months) with < 50% of the required number of days of eDiary 
completion;  
• Patients whose treatment assignment has been unblinded by the investigative site will be 
permanently discontinued from treatment; 
• 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 non-compliance.  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 
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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.” 
4.7. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones for contraception are excluded, and 
patients must agree to use non-hormonal contraception throughout the study, including through 30 
days following the last dose of study drug, unless any of the following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the Screening 
visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure), 
at least 4 months prior to the first Screening visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence 
of post-Essure syndrome; 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the use 
of non-hormonal contraception as noted below; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of contraception for those for whom one of the above methods do not 
apply are: 
• Condom (male or female condom) with or without spermicide (cream, spray, foam, gel, 
suppository or polymer film); 
• Diaphragm with spermicide (condom may or may not be used); 
• Cervical cap with spermicide (condom may or may not be used); or 
• Vaginal sponge impregnated with spermicide used with a condom. 
Patients will be provided with information on acceptable methods of contraception as part of the 
informed consent process and will confirm when they sign a consent form 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 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 study, patients will be randomized to receive one of the following blinded oral study 
treatments: 
• 24 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol 
and 0.5 mg norethindrone acetate; OR 
• 12 weeks of relugolix 40 mg tablet plus a placebo capsule followed by 12 weeks of 
relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol and 0.5 mg 
norethindrone acetate; OR 
• 24 weeks of relugolix placebo tablet plus a placebo capsule. 
Each patient will be instructed to take one tablet and one capsule per day.  The last dose of study 
drug will be taken on the day immediately before the Week 24 visit.  Note: Week 24 visit data is 
defined as the last day on which a Week 24 visit procedure is conducted. 
The placebo relugolix tablet is manufactured to match the relugolix tablet in size, shape, and 
color.  The placebo capsule is designed to match the over-encapsulated estradiol/norethindrone 
acetate active product in size, shape, color, and odor. 
Table 5-1 
Description of MVT-601-3001 Study Drugs 
Name of 
Investigational 
Product 
Relugolix 
Relugolix Placebo 
Estradiol / 
Norethindrone 
Acetate 
Estradiol / 
Norethindrone 
Acetate Placebo 
Formulation 
Description 
Round film-coated 
pink tablet 
Round film-coated 
pink tablet 
An Swedish 
orange, over-
encapsulated 
round film-coated 
white tablet with 
placebo back-fill 
material 
A Swedish orange 
capsule with 
placebo back-fill 
material 
Dosage Form 
Tablet 
Tablet 
Capsule 
Capsule 
Unit Dose 
Strength 
40 mg 
0 mg 
Estradiol 1.0 mg / 
norethindrone 
acetate 0.5 mg 
0 mg 
Route of 
Administration / 
Duration 
Oral once daily/ 
24 weeks 
Oral once daily/ 
24 weeks 
Oral once daily/ 
12 or 24 weeks 
Oral once daily/ 
12 or 24 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. 
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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. 
Placebo to match relugolix is a 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. 
Placebo to match the over-encapsulated estradiol/norethindrone acetate combination product is a 
capsule containing back-fill material only. 
5.3. 
Randomization and Stratification 
At the Baseline Day 1 visit, patients will be randomized in a 1:1:1 ratio to one of the following 
treatment arms: 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization 
Treatment 
Group 
Randomized Treatment 
Approximate 
Number of Patients 
Group A 
Relugolix 40 mg tablet co-administered with 1.0 mg estradiol / 
0.5 mg norethindrone acetate capsule for 24 weeks 
130 
Group B 
Relugolix 40 mg tablet co-administered with estradiol / 0.5 mg 
norethindrone acetate placebo tablet for 12 weeks followed by 
relugolix 40 mg tablet co-administered with 1.0 mg estradiol / 
0.5 mg norethindrone acetate capsule for 12 weeks 
130 
Group C 
Relugolix placebo tablet co-administered with 
estradiol/norethindrone acetate placebo capsule for 24 weeks 
130 
 
Randomization will be stratified by geographic region and mean screening menstrual blood loss 
as follows: 
• Geographic region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss measured by the alkaline hematin method: 
< 225 mL versus ≥ 225 mL. 
Patients are assigned to one of the three treatment arms in accordance with the randomization 
schedule (see additional information on randomization in Section 4.5). 
5.4. 
Directions for Administration 
All study patients will take a study treatment of one tablet and one capsule once daily. 
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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 selected clinic days, study drug will be administered in the clinic (refer to Sections 1.1 and 
Section 6.3) or the visits during which patients take study drug in the clinic rather than at home) 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
5.5. 
Dose Reduction/Dose Administration 
No toxicity-related dose reductions of study drug are permitted.  Patients who experience a 
grade 3 or greater toxicity that cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a grade 2 or lower severity.  
Patients may subsequently be re-started on study drug with the written approval of the sponsor 
(or designee). 
5.6. 
Storage, Packaging, and Labeling 
Study drug should be stored in an appropriate, limited-access, secure location within a 
temperature range of 20°C to 25°C with excursion to 15°C to 30°C permitted until it is used or 
returned to the sponsor (or designee).  Study drug should be stored protected from light.  A daily 
temperature log of the drug storage area must be maintained every working day.  Study drug 
must be stored under the conditions specified on the label, and remain in the original container 
until dispensed.  Only patients enrolled in the study may receive study drug, and only authorized 
site staff may supply or administer study drug.  Further guidance and information for final 
disposition of unused study drug are provided in the Study Reference Manual.  The investigator 
is responsible for study drug accountability, reconciliation, and record maintenance, including 
receipt, reconciliation, and final disposition records and their secure storage. 
Study drug will be labeled with the study protocol number, medication or kit number, contents, 
directions for use, storage directions, clinical study statement, and any other labeling required by 
regulatory bodies in the study locations and will list Myovant Sciences GmbH as the sponsor.  
Patients will be instructed to store study drug at room temperature out of the reach of children. 
All labels for relugolix, the estradiol/norethindrone acetate combination, relugolix placebo, and 
the estradiol/norethindrone acetate placebo to be distributed will meet all applicable 
requirements of the US 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 and relugolix placebo will be supplied to the study site in blister cards co-
packaged with the estradiol/norethindrone acetate or estradiol/norethindrone acetate placebo. 
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5.7. 
Blinding 
All patients, investigators, and sponsor staff or representatives involved in the conduct of the 
study will be blinded to treatment assignment, with the exception of an unblinded statistician(s) 
who is responsible for developing the randomization codes and presenting unblinded data to the 
Data and Safety Monitoring Board if requested.  The blind will be maintained during assessment 
of PK and pharmacodynamic testing; PK concentrations will be reported to the sponsor in a 
blinded fashion, or only after database lock and unblinding, or provisions will be made to 
provide data only to personnel approved for unblinding. 
Unblinding by the investigator for a given patient will occur only if the knowledge of treatment 
assignment will materially change the planned management of a medical emergency.  The 
decision to unblind a patient’s treatment assignment in an emergency situation resides with the 
investigator who has direct access to unblind a patient’s individual study treatment; however, the 
investigator should attempt to contact the medical monitor or appropriate study personnel to 
discuss options before unblinding the patient’s treatment assignment unless the urgency of the 
medical situation precludes this.  If unblinding by the investigator occurs before sponsor 
personnel can be consulted or notified, the Investigator must notify the sponsor as soon as 
possible after unblinding, but without revealing the treatment assignment of the unblinded 
patient.  Patients whose treatment assignment has been unblinded by the investigative site will be 
permanently discontinued from treatment. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study, and should bring all unused and used 
study drug to each study visit.  At the week 12 visit all unused and used study drug should be 
retained at the site and new study drug dispensed.  Study drug accountability will be conducted 
and results will be recorded.  If a patient is persistently noncompliant with the study treatment it 
may be appropriate to withdraw the patient from the study (see Section 4.6).  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. 
Treatment after the End of Study 
Patients who complete 24 weeks of treatment on this study and wish to continue therapy may be 
eligible to continue treatment in the extension study MVT-601-3003.  Eligibility criteria are set 
forth in that protocol. 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-3 provides examples of prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Consult the medical monitor if there is any uncertainty 
regarding patient use of a particular drug or drug class. 
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Table 5-3 
Prohibited Medications and Windows of Exclusion Prior to Screening 
Drug Class 
Examples 
Window/Comments 
Bisphosphonates 
alendronate 
etidronate 
zolendronic acid 
No prior use permitted 
GnRH Analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
3 months 
(6 months for sustained 3-monthly 
injections) 
Anti-Androgens 
danazol 
4 months 
Anti-convulsant drugs 
(specified) 
phenobarbital, carbamazepine, 
phenytoin, valproic acid, and 
primidone 
Note: All other anticonvulsants are 
allowed 
1 month 
Aromatase Inhibitors 
anastrozole 
letrozole 
4 months 
Progestins and progestin 
implants 
dienogest 
norethindrone 
medroxyprogesterone 
cyproterone 
etonogestrel  
 
2 months 
(6 months for depot subcutaneous 
or intramusclar injections) 
Estrogens 
estradiol valerate 
conjugated estrogens 
ethinyl estradiol 
2 months 
(6 months for depot subcutaneous 
or intramusclar injections) 
Hormonal 
Contraceptives, 
contraceptive patches and 
vaginal rings 
combined or progestin only 
Nuva Ring 
1 month for patients reporting a 
typical (for them) menstrual period 
within < 2 months prior to the 
Screening Visit; otherwise 
2 months 
Selective Estrogen 
Receptor Modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
2 months 
Selective Progesterone 
Receptor Modulators  
mifepristone 
ulipristal acetate 
6 months 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
1 week 
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Drug Class 
Examples 
Window/Comments 
Intrauterine Devices 
levonorgestrel 
copper 
2 months 
Bone Agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
No prior use if used for reduced 
bone mineral density 
Note:  Calcium and Vitamin D2 and 
Vitamin D3 (ergocalciferol and 
cholecalciferol) are allowed without 
restriction.  
 
Anti-Coagulants/ 
Platelets/Fibrinolytics 
warfarin 
clopidogrel 
tranexamic acid 
vitamin k preparations 
factor Xa inhibitors 
1 month 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
No window 
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. 
P-glycoprotein Inducers 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
tipranavir/ritonavir 
2 weeks 
Note:  For patients requiring a short 
course of these drugs during the study, 
investigator must contact the medical 
monitor for approval and guidance on 
study drug administration during this 
period.  
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Drug Class 
Examples 
Window/Comments 
Moderate and Strong 
P-glycoprotein Inhibitors 
amiodarone 
atazanavirf 
azithromycina 
captoprilb 
carvedilolg 
clarithromycina 
cobicistatf 
conivaptan 
cyclosporinc 
diltiazem 
dronedarone 
erythromycina 
felodipined 
itraconazolee 
ketoconazolee 
lopinavir/ritonavirf 
quercetin 
quinidine 
ranolazine 
ticagrelortg 
verapamil 
2 weeks 
(6 months for amiodarone) 
Note:  For patients requiring a short 
course of these drugs during the study, 
investigator must contact the medical 
monitor for approval and guidance on 
study drug administration during this 
period. 
Abbreviation:  GnRH, gonadotropin-releasing hormone 
a. 
Roxithromycin is allowed 
b. All other angiotensin converting enzyme inhibitors are allowed 
c. 
Tacrolimus is allowed 
d. Amlodipine and nifedipine are allowed 
e. 
Fluconazole is allowed 
f. 
Integrase inhibitors are allowed 
g. Metoprolol and atenolol are permitted 
 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded, including the drug generic 
name, dose amount, route of administration, start date, and stop date. 
5.10.2.1. 
Analgesics 
From the Screening 1 visit to the Week 24 (or Early Termination) visit, the recommended 
analgesics for uterine-fibroid associated pain are as follows: 
• First-line:  ibuprofen  
• Second-line:  non-ibuprofen non-steroidal anti-inflammatory drug or acetaminophen 
• Third-line:  opioid or opioid-acetaminophen combination  
• Fourth-line:  investigator discretion 
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The purpose of these recommendations is to standardize, to the extent possible, analgesic 
medication use to facilitate the effects on the secondary endpoint regarding of uterine-fibroid-
related pain. 
Patients should be instructed not to use analgesics for prophylactic purposes. 
5.10.2.2. 
Iron Therapy 
Women with a hemoglobin < 8.0 g/dL are excluded from participating in the study.  Women 
identified during the screening period to have a microcytic iron deficiency anemia defined as a 
hemoglobin ≥ 8 g/dL and ≤ 10 g/dL, a mean corpuscular volume below the lower limit of 
normal, and a low serum iron and ferritin, must be started on iron therapy, either oral or 
parenteral and then continued on treatment during the study.  Women who enter the screening 
period 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. If the hemoglobin is < 10 g/dL and mean 
corpuscular volume is below the lower limit of normal, a ferritin and iron level will be reported 
through the central lab.   
5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of uterine fibroids and use of intrauterine devices are prohibited from the 
Screening 1 visit until the patient’s final study visit unless urgently needed for patient safety. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities in 
the study synopsis (see Section 1.1).  Study procedures are briefly described within Section 6.8.  
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 in the study synopsis (see Section 1.1).  The study is divided into three periods:  
screening period, randomized treatment period, and Safety Follow-Up (to assess safety for 
patients who do not enroll in an open-label extension study; unscheduled visits may also occur as 
needed to evaluate patients). 
6.2. 
Screening Period 
Patients should have a diagnosis of uterine fibroids and a history of heavy menstrual bleeding 
with or without associated pain on a background of generally regular menses (ie, regularly 
occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days from the start of 
one menstrual period until the start of the next menstrual period) as reported by the patient for at 
least 3 months prior to the Screening 1 visit. 
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The screening period consists of the Screening 1, 2, 3, and 4 visits. 
See Figure 4-2 for details of the timing of the screening period visits as well as details of the 
feminine product dispensation and collection during screening.  The Screening 4 visit should be 
skipped if the menstrual blood loss is > 160 mL in the first screening cycle. 
6.2.1. 
Screening 1 Visit 
The Screening 1 visit will be conducted following the signing of the informed consent form and 
may occur at any time during the menstrual cycle.  The Screening 1 visit will include a full 
medical history (including menstrual history for 3 months prior to Screening and prior uterine 
imaging assessments), review of inclusion and exclusion criteria, collection of concomitant 
medications, study procedure-related adverse events and any serious adverse events.  In addition, 
vital signs, height, weight, temperature, a complete physical examination, visual acuity 
assessment, gynecology examination, ultrasound, endometrial biopsy, Papanicolaou test (if 
needed), clinical laboratory tests, urinalysis, and a urine pregnancy test will be done.  Feminine 
products will be dispensed with instructions to collect and return all products used during the 
next menses.  The paper diary will also be dispensed at this visit and should be completed daily 
starting with this visit.  The bone mineral density scan and mammogram should be scheduled at 
this time (or within a few days of this visit).  Bone densitometry should be scheduled to be prior 
to the Screening 3 visit and as early as feasible to ensure results are available prior to 
randomization. 
The order of procedures should be as follows.  Patients not meeting eligibility criteria after any 
procedure should not undergo subsequent procedures. 
• Medical history and review of prior uterine imaging studies 
• Review of concomitant medications (including supplements and over the counter 
medications) 
• Review of inclusion and exclusion criteria 
• Urine pregnancy test  
• Vital signs, weight, and height 
• Complete physical examination and visual acuity assessment 
• Ultrasound – do not proceed with additional procedures if no uterine fibroids are 
identified with the local/initial reading 
• Gynecology examination, Papanicolaou test (if need), endometrial biopsy, clinical 
laboratory tests, including TSH, urinalysis 
• Dispense feminine products and paper diary with instructions to begin recording starting 
information daily, starting on the Screening 1 visit day 
• Schedule mammogram (if needed) 
• Schedule bone densitometry 
The ultrasound will be a transvaginal ultrasound with or without a transabdominal ultrasound 
(see Section 4.3 ultrasound entry criteria), performed to assess for uterine fibroids.  Saline or gel 
contrast may be used but is not required (see Section 4.3 ultrasound entry criteria).  The anatomic 
location and size of the fibroid disease will be estimated by the local reader.  The ultrasound 
images will be submitted to the central reader for confirmation that the patient meets the 
inclusion criteria for a diagnosis of uterine fibroids (this confirmation must be received prior to 
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randomization).  The investigator, rather than the central reader, will determine if any 
exclusionary pathology is present.  If ultrasound fails to demonstrate fibroids on the local 
reading, do not proceed with additional Screening visit 1 procedures. 
The Papanicolaou test must be conducted for women without a test result within 2 years prior to 
the Screening 1 visit and the specimen is to be submitted to the central laboratory.  A repeat test 
should be performed for inadequate or false-positive results and submitted to the central 
laboratory.  
The endometrial biopsy will be obtained with an endometrial suction curette (eg, Pipelle) and 
submitted to the Central Laboratory. 
The mammogram must be done in patients ≥ 39 years of age by the time of the (anticipated) 
Baseline Day 1 visit if there is no record (and reading) from within 6 months prior to the 
screening period. 
If the hemoglobin is < 10 g/dL and mean corpuscular volume is below the lower limit of normal, 
a ferritin and iron level will be reported through the central lab.  Please see Section 5.10.2.2 for 
guidance on iron therapy. 
6.2.2. 
Screening 2 Visit 
Screening 2 visit is scheduled to occur within 5 (+2) days after cessation of the patient’s first 
menses following the Screening 1 visit.  Patients will return at Screening 2 visit to return their 
feminine products.  At this visit, clinical laboratory tests will be drawn, including a venous blood 
sample for use in the quantitation of menstrual blood loss.  Additional feminine products will be 
dispensed for collection of menstrual blood loss during the next menses.  If the hemoglobin is 
< 10 g/dL and mean corpuscular volume is below the lower limit of normal, a ferritin and iron 
level will be reported through the central lab.   Women whose laboratory testing reveals iron-
deficiency anemia as defined in the study must be started on iron therapy. 
Confirm the scheduling of the bone densitometry and mammogram (if needed) and review 
mammogram results, if available.  The mammogram must be normal (Breast Imaging Reporting 
and Data System category 1 or 2 or equivalent) in order for the patient to be eligible.  
Once the menstrual blood loss results from the first cycle are available, schedule Screening 3 
visit as soon as feasible and within 5 (+2) days of receiving results showing that the menstrual 
blood loss is ≥ 80 mL 
Patients will be dispensed feminine products to be gathered for the second cycle.  
6.2.3. 
Screening 3 Visit 
The patient will return for the Screening 3 visit if her menstrual blood loss from cycle 1 is 
≥ 80 mL and within ≤ 15 days after the Screening 2 visit.  At the Screening 3 visit, review of 
inclusion and exclusion criteria will be conducted to confirm continued eligibility.  Concomitant 
medication and adverse events will be assessed and vital signs taken.  A signs and symptoms 
directed physical examination, a 12-lead ECG and a urine pregnancy test will be performed.  At 
this visit, review the endometrial biopsy results and review mammogram results, if available.  
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Confirm that the bone densitometry scans have been submitted for central reading.  The 
mammogram and central bone densitometry results must be available prior to randomization.   
6.2.4. 
Screening 4 Visit 
The Screening 4 visit should be skipped if the menstrual blood loss is > 160 mL in the first 
screening cycle.  If not skipped, then the Screening 4 visit is scheduled to occur within 
5 (+2) days after cessation of the patient’s menses following Screening 3 visit.  At the Screening 
4 visit, the patient’s feminine products will be collected to submit for the quantitation of 
menstrual blood loss, and a blood sample will be drawn for hemoglobin assessment.  The 
patient’s eDiary data collection will be reviewed.  Laboratory and imaging evaluations will be 
reviewed to ensure eligibility for randomization. 
6.2.5. 
Menstrual Blood Loss Repeat Collection 
At the discretion of the investigator, the collection of menstrual blood loss can be repeated once 
during the screening period (either after the first or second screening cycle) if one menstrual 
cycle does not meet the heavy menstrual bleeding alkaline hematin criteria and it is thought to be 
due to an inadequate collection by a highly motivated patient. 
6.2.6. 
Re-Screening 
Patients who fail screening may be re-screened with approval of the medical monitor.  Patients 
undergoing re-screening will sign a new informed consent form and issued a new screening 
number.  For patients who begin re-screening within 10 weeks of signing the original informed 
consent form, transvaginal ultrasound, endometrial biopsy, and bone densitometry do not need to 
be repeated, if performed previously. 
6.2.7. 
Retesting 
Screening laboratory tests may be repeated once during the Screening period, if necessary, at the 
investigator’s discretion.  For laboratory-based entry criteria, the most recent value will be used 
to determine eligibility.  Additional laboratory retesting requires the approval of the medical 
monitor.  Retesting of other procedures (except once, as required, due to technical or logistical 
issues such as an inadequate sample) also require approval of the medical monitor. 
6.3. 
Randomized Treatment Period (Baseline to Week 24) 
At the Baseline Day 1 visit, patients will be randomized to one of the three study treatment arms 
(see Section 5.3).  Patients will take their randomized study treatment once daily, beginning on 
the day of the Baseline Day 1 visit and continuing through the Week 24 visit.  Patients will 
continue recording daily in their eDiary.  On-treatment study visits will occur every 4 weeks 
through the end of Week 24.  At each post-baseline visit, patients will return their feminine 
products for alkaline hematin testing.  Safety monitoring including signs and symptoms directed 
physical examination, waist circumference, ECGs, clinical laboratory tests, pregnancy tests, and 
adverse event collection will occur at each visit.  Bone densitometry will occur at the Week 12 
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and Week 24 visits.  A repeat transvaginal ultrasound (with or without a transabdominal 
ultrasound) and endometrial biopsy will be performed at the Week 24 visit.  The endometrial 
biopsy will be read centrally.  Study drug and eDiary compliance will be reviewed at each visit.  
Refer to the Schedule of Activities in the synopsis (see Section 1.1) for information about study 
procedures during the randomized treatment period. 
Sites should try to schedule patient visits during the morning, instructing patients to arrive before 
taking their study drug to allow for pre-dose PK/pharmacodynamic sampling on visits at which 
these specimens are drawn.  Patients must come to the clinic in the fasted state (eg, nothing to eat 
or drink other than water after midnight the day before the clinic visit) for the Baseline Day 1 
and Week 24/Early Termination visits. 
For visits other than Baseline Day 1 and Week 24/Early Termination, if the clinic visit cannot be 
scheduled for the morning, patients may eat in the morning but should not have eaten or had 
anything to drink other than water, coffee, or tea for at least 2 hours prior to the clinic visit and 
must not eat or drink (other than water, coffee or tea) for at least 1 hour after the clinic visit.  In 
these situations, the laboratory requisitions must indicate that the patient was not fasted for their 
chemistry and lipid testing. 
6.4. 
Continuation into Extension Study 
It is expected that most patients will enter the 28-week extension study (MVT-601-3003), which 
will be conducted under a separate protocol.  Patients will provide separate informed consent to 
participate in the extension study during which all patients will receive relugolix 40 mg co-
administered with 1.0 mg estradiol / 0.5 mg norethindrone acetate. 
6.5. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 24 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 24; however, for 
patients whose last dose of study drug is during Week 6 or earlier, the following procedures do 
not need to be performed:  transvaginal ultrasound (with or without a transabdominal 
ultrasound), endometrial biopsy, and bone densitometry.  These procedures may be performed, 
however, at the investigator’s discretion, if they aid in follow-up of ongoing adverse events. 
All patients who do not wish to or who are not eligible to enroll in the extension study 
(MVT-601-3003), 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 for uterine fibroids, 
whichever occurs first.  This visit will be used to assess safety after discontinuation of study 
treatment including adverse events, clinical safety laboratories, 12-lead ECG, and return of 
menstruation.  Patients who withdraw early from this study will also undergo 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.  Refer to the Schedule of 
Activities at the end of the synopsis (see Section 1.1) for individual study visit procedures during 
the Follow-up visit. 
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6.6. 
Additional Safety Follow-Up Procedures 
For patients not continuing into the extension study (MVT-601-3003), additional safety 
procedures are required in some circumstances as described below.  These procedures will be 
performed during unscheduled visits. 
• Patients whose menses has not resumed as of the Follow-Up visit for whom there is no 
explanation for the lack of resumption (eg, medical procedure or medications) will be 
contacted by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses 
has resumed and questioned about factors that may affect resumption of menses. 
• Patients with endometrial biopsy findings of endometrial hyperplasia or endometrial 
cancer on the endometrial biopsy at the Week 24/Early Termination visit will undergo a 
repeat biopsy in 3 to 6 months after the Week 24/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.  In addition, patients with endometrial hyperplasia 
with atypia will be evaluated and managed, as needed, by a gynecologist. 
• Patients who have had a bone mineral density loss of > 2% at the lumbar spine (L1-L4) 
or total hip at their Week 24/Early Termination visit relative to baseline 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 bone mineral density 
through the time of the repeat DXA scan.  The follow-up DXA scan will be submitted for 
central reading. 
6.7. 
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, PK and pharmacodynamic 
sampling, 12-lead ECG, study drug compliance and dispensation, etc. may be conducted as 
needed.  See Schedule of Events (Section 1.1) for tests that may be performed if indicated at an 
unscheduled visit.  Consult with the medical monitor, if needed, to discuss Unscheduled visit 
testing. 
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6.8. 
Study Procedures 
6.8.1. 
Efficacy-Related Procedures 
6.8.1.1. 
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.  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. 
6.8.1.2. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal with or without transabdominal ultrasound with or without saline or gel contrast is 
performed for the diagnosis of uterine fibroids, 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.  Transvaginal ultrasound will be performed.  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. 
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.  
At the Screening 1 visit, the longest diameter (D1) of the largest myoma will be noted and 
recorded.  Only the largest myoma among those measurable at the Screening 1 visit will be 
measured throughout the study. 
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Saline or gel contrast is not required, but may be performed to demonstrate fibroids that meet the 
criterion for inclusion if these are not adequately visualized with transvaginal ultrasound alone or 
when endometrium cannot be evaluated or when there are ambiguous and potentially 
exclusionary findings on the transvaginal or transabdominal ultrasound (eg, suspected 
intrauterine masses, equivocal endometrial findings, etc.).  If transabdominal ultrasound or 
ultrasound with saline or gel contrast is performed at Screening, it should also be performed at 
Week 24. 
6.8.1.3. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, estradiol, and progesterone 
will be collected pre-dose at the visits indicated in the study Schedule of Activities in the 
protocol synopsis (see Section 1.1).  These pharmacodynamic samples will be analyzed at a 
central laboratory.  For PK analysis of estradiol, a separate PK sample will be obtained to be 
analyzed at a PK laboratory (see Section 6.8.1.4).  To maintain blinding, concentrations of these 
hormones will be reported to the investigator, other vendors, and sponsor personnel only after 
database lock and unblinding. 
6.8.1.4. 
Pharmacokinetics Sample Collection 
Blood samples for PK analysis of relugolix, estradiol, and norethindrone will be collected pre-
dose at the visits indicated in the study Schedule of Activities in the protocol synopsis (see 
Section 1.1).  The actual date and time of each blood sample collection will be recorded. 
Patients will be instructed to hold their dose of study drug on clinic visit days and record the time 
of their previous dose (ie, the time they took their dose on the day before the clinic visit).  If the 
study patient inadvertently took drug at home on the morning of the clinic visit, the dosing 
history should be accurately recorded and a PK sample collected (which may be used for 
population PK modeling). 
To maintain blinding, PK concentrations will be reported to the sponsor in a blinded fashion, or 
only after database lock and unblinding.  Collection, processing, storage, and shipping 
procedures are provided in the Study Reference Manual.  Plasma and serum analysis will be 
performed by the sponsor (or designee). 
Plasma concentrations of relugolix and norethindrone and serum concentrations of estradiol will 
be determined in samples using a validated bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site.  Once a sample has been analyzed for relugolix, estradiol, or 
norethindrone, any remaining plasma may be analyzed for other compound-related metabolites 
and the results reported under a separate protocol. 
6.8.1.5. 
Patient Diary 
All women enrolled in the study will be provided with a device with an application for a patient 
eDiary, along with detailed instructions for its use.  Patients will complete daily eDiaries 
including compliance with study treatment, menstrual bleeding, use of feminine products, uterine 
fibroid-associated pain, and use of pain medication (analgesics) to treat uterine fibroid pain (see 
Appendix 2). 
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Queries will be handled by the vendor managing the eDiary data through the clinical site.  The 
eDiary data will be reviewed by the study staff.  
Patients will also receive a paper diary to enter information on menstruation status and feminine 
product use starting with Screening 1 visit and ending when they receive their eDiary at the 
Screening 3 visit. 
6.8.1.6. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire (MIQ) 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 3).  The MIQ has undergone psychometric 
validation.  Patients will complete the MIQ at each study visit during the randomized treatment 
period.  With exception of Baseline Day 1 (see Section 1.1), patients will complete the MIQ at 
each visit at the site before other study procedures. 
6.8.1.7. 
Uterine Fibroid Symptom – Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) score is used to 
evaluate the symptom severity and the quality of life of patients with uterine fibroids (see 
Appendix 4).  Patients will complete the UFS-QOL questionnaire at the site at the Baseline Day 
1 visit, Week 12 visit, and Week 24 visit. With the exception of Baseline Day 1 (see Section 
1.1), patients will complete the UFS-QOL before other study procedures. 
6.8.1.8. 
European Quality of Life Five-Dimension Five-Level Scale 
The European Quality of Life Five-Dimension Five-Level Scale (EQ-5D-5L) is a standardized 
instrument for use as a measure of health outcomes (see Appendix 5).  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 Baseline Day 1 visit and the 
Week 24 visit.  With the exception of Baseline Day 1 (see Section 1.1), patients will complete 
EQ-5D-5L before other study procedures.  
6.8.1.9. 
Patient Global Assessment for Symptoms and Patient Global Assessment for Function 
These simple questions are used by the patient to qualitatively describe severity of symptoms or 
effects on function (PGA) (see Appendix 6) on a schedule described in the Schedule of Activities 
(see Section 1.1).  With the exception of Baseline Day 1 (see Section 1.1), patients will answer 
these questions before other types of study procedures.   The PGA for function and PGA for 
symptoms will be completed on a paper questionnaire at the study site on a schedule described in 
the Schedule of Activities (see Section 1.1).  With the exception of Baseline Day 1, patients will 
answer these questions before other types of study procedures. The PGA for function and PGA 
for symptoms will be completed on a paper questionnaire at the study site.  
 
 
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6.8.1.10. 
Status of Menstruation Recovery 
If the patient does not continue into the extension study (MVT-601-3003), and the first 
menstruation after the end of study treatment administration is observed before the Follow-up 
visit, the date of onset of the first menstruation is recorded in the eCRF.   
Patients whose menses has not resumed as of the Follow-Up visit for whom there is no 
explanation for the lack of resumption (eg, medical procedure or medications) will be contacted 
by telephone 3 (+0.5) months after the Follow-Up visit to determine if menses has resumed and 
questioned about factors that may affect resumption of menses. 
 
6.8.1.11. 
Pharmacogenomics Sample Collection 
For possible exploratory investigation of markers enabling the prediction of drug response, one 
sample of blood will be collected and stored for future pharmacogenomic analyses, unless 
precluded by local law or regulations.  All patients will be eligible for collection of the 
pharmacogenomic sample, however, the sample may only be obtained and stored from patients 
who provide a separate informed consent form for pharmacogenomic sample collection.  Patient 
participation in the pharmacogenomic research is voluntary and refusal to participate will not 
preclude entry into the study or indicate withdrawal from the study.  
If possible, the pharmacogenomic sample should be drawn from consented patients at the 
Baseline Day 1 visit, but it may be drawn at any time during the study through Week 24 
(inclusive).  Patients can request their sample to be destroyed at any time.  A pharmacogenomic 
sample should not be collected from any patient who has received comparable bone marrow 
transplant or whole blood transfusion within 6 months before sample collection.  Refer to the 
Study Reference Manual for directions on collecting, handling, and storage of pharmacogenomic 
samples. 
6.8.2. 
Safety-Related Procedures 
6.8.2.1. 
Weight, Height, Waist Circumference, and Body Mass Index 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed.  Waist circumference should be measured with a measuring tape wrapped around the 
narrowest portion of the patient’s mid-section. 
6.8.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest and will include systolic and diastolic blood pressure and 
pulse rate. 
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6.8.2.3. 
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 the Baseline assessment.  The gynecologic 
examinations will include breast and pelvic exams.  A Papanicolaou test must be conducted for 
women without an available test result from within 2 years prior to the Screening 1 visit and 
submitted to the central laboratory.  A repeat test should be performed for inadequate or false-
positive results and submitted to the central laboratory. 
6.8.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities in the synopsis (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 
White Blood Cell (WBC) Count 
Protein 
Chloride 
WBC Differential 
Glucose 
Bicarbonate 
Red Blood Cell Count 
Blood 
Blood Urea Nitrogen 
Hemoglobin 
Urobilinogen 
Creatinine 
Hematocrit 
Bilirubin 
Glucose 
Mean Corpuscular Volume  
Color and Clarity 
Calcium 
Platelet Count 
pH 
Phosphate 
RBC morphology 
Leucocyte esterase 
Magnesium 
 
Ketones 
Sodium 
 
Nitrite 
Albumin 
 
 
Specific gravity 
 
 
Urine Microscopy 
Hemoglobin A1c 
 
Creatine Kinase 
Lipids 
Pregnancy 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Gamma-Glutamyl Transferase 
Alkaline phosphatase 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
Pregnancy test 
(human chorionic 
gonadotropin) 
Hormones 
Serology 
Iron Studies 
Thyroid-Stimulating Hormone 
Prolactin 
Luteinizing Hormone 
Follicle-Stimulating Hormone 
Estradiol 
Progesterone 
Vitamin D [25(OH)D] 
Hepatitis A antibody 
Hepatitis B surface antigen 
Hepatitis B Core antibody 
Hepatitis C antibody 
Iron 
Ferritin  
 
A separate sample will be collected at the Day 1 visit in all patients and will be banked for 
hepatitis serology (Table 6-1).  The samples will be analyzed, if requested, by the medical 
monitor for evaluation of abnormal liver tests during the study. 
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.  If the hemoglobin is < 10 g/dL and mean corpuscular volume is below the lower 
limit of normal, a ferritin and iron level will be reported through the central lab. 
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 for the laboratory or laboratories 
used. 
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6.8.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at the Screening 3 visit, the Baseline Day 1 visit, the Week 12 
visit, and at the Week 24 or early withdrawal and Follow-up visits, as well as if needed to 
evaluate any signs or symptoms.  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. 
6.8.2.6. 
Endometrial Biopsy 
An endometrial biopsy will be obtained using an endometrial suction curette (eg, Pipelle) and 
submitted to the central laboratory for reading.  If the biopsy is inadequate for diagnosis at either 
Screening or at Week 24, it should be repeated and sample submitted to the central laboratory.  If 
the second specimen is also inadequate for diagnosis at Screening, the patient is not eligible for 
the study.  Bone Mineral Density 
6.8.2.7. 
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). The scans 
will be read by the central radiology laboratory in accordance with the imaging charter.  
Training, quality review, and readings will be done by a central radiology laboratory as described 
in the central radiology charter for bone mineral density. 
Throughout the study, the same DXA apparatus will used at each site and operated in the same 
scan mode for all scans for an individual patient.  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 patient will be monitored by a central radiology laboratory over 
the course of the study.  Investigators will be notified if a patient experiences a bone mineral 
density loss from baseline of 7% or more at any of the anatomical sites assessed during the study.  
In this case, it is at the investigator’s discretion to consider the patient’s status and determine 
future management.  Detailed instructions for DXA scanning will be provided in the Study 
Reference Manual.   
 
Please see Section 6.6 for follow-up of patients who are not continuing into the extension study 
(MVT-601-3003) and whose bone mineral density has decreased by > 2% at the lumbar spine 
(L1-L4) or total hip at the Week 24/Early Termination visit relative to Baseline. 
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6.8.2.8. 
Visual Acuity 
Presenting visual acuity must be assessed with the supplied study eye chart.  If the patient uses 
corrective lenses, she should wear her usual prescription glasses or contact lenses during the 
assessment, and the same prescription lenses should be worn at subsequent visual testing, as 
possible. Perform the visual acuity testing using the entire eye chart. Do not stop at a visual 
acuity of 100 – continue as far as the patient can go per the testing instructions (see Study 
Reference Manual for additional details).  
Patients whose presenting visual acuity score is 90 or lower at the Baseline visit should be 
encouraged to obtain a diagnostic evaluation from an eye care provider, ie, an ophthalmologist or 
an optometrist.  Any findings (ie, diagnoses) from the eye examination should be recorded as 
medical history.   
Patients whose presenting visual acuity score at Week 24 /Early termination has decreased by 10 
or more points from Baseline should be referred to an ophthalmologist for a diagnostic 
evaluation.  A copy of the ophthalmology consultation must be submitted to the sponsor. 
6.8.3. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of blood collected for 
pharmacogenomics testing (see Section 6.8.1.11) will be stored frozen at an appropriate vendor 
facility identified by the sponsor. 
The need to conduct pharmacogenomic analysis may be identified after this study (or additional 
studies) has been completed.  For this reason, the collected samples will be retained for up to 
10 years after the last patient completes the study.  A patient may request the destruction of her 
sample at any time.  The sponsor may destroy the samples sooner than 10 years after the study 
completes. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), ECGs, bone mineral density assessments, endometrial biopsy results, 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; 
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• 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 being quantitatively 
measured as an efficacy endpoint, unless the event meets seriousness criteria. 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to Common Terminology Criteria for Adverse Events (CTCAE).  Episodic adverse 
events, such as vomiting, or those that occur repeatedly over a period of consecutive days are 
‘intermittent’.  All other events are ‘continuous’.  Additional information on detecting, 
documenting, and reporting adverse events and serious adverse events are provided below.   
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; 
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NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events which jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local Institutional Review Board (IRB) or 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 eDiary entries and answers to the UFS-QOL 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. 
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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 will be collected from the time the first dose of study drug is administered until 
the Follow-up visit approximately 30 days after the last dose of 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).  Study procedure-related adverse 
events will be collected from the signing of the informed consent form. 
Serious adverse events will be collected from the signing of the informed consent form until the 
safety follow-up visit approximately 30 days after the last dose of study drug.  Serious adverse 
events reported to the investigator after the safety reporting period should be reported to the 
sponsor if the investigator assesses the event as related to the study drug treatment. 
With the exception of adverse events that are considered related to study screening procedures, 
(which are to be recorded as adverse events), events occurring between signing of the informed 
consent form and the first dose of study drug will be recorded as medical history and in the 
patient’s clinical record for any patient who continues to meet eligibility criteria and proceeds to 
dosing with study drug. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
following definitions are to be used for the relationship of the adverse event to study drug: 
• Probably related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely attributed to concurrent 
disease or other drugs or chemicals, and that follows a clinically reasonable response on 
readministration (rechallenge) or withdrawal (dechallenge). 
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• Possibly related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug but that could also be explained 
by concurrent disease or other drugs or chemicals.  Information on drug withdrawal may 
be lacking or unclear. 
• Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable and/or in 
which other drugs, chemicals, or underlying disease provide a plausible explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
7.4. 
Assigning Severity Rating for Adverse Events 
Severity describes the intensity of a specific event (as in mild, moderate, or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance, such as a 
severe headache.  This is not the same as “serious,” which is based on patient/event outcome or 
action taken. 
The investigator must determine the severity of each adverse event according to the National 
Cancer Institute CTCAE.  For terms not specified with the CTCAE, the criteria in Table 7-1 
should be used to determine the grade severity. 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not Specified 
by the National Cancer Institute CTCAE  
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
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. 
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Any ALT or AST elevation of this degree or greater occurring during the randomized treatment 
period or the Follow-up visit should be reported to the sponsor using the Serious Adverse Event 
Form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), 
even if the event does not meet SAE criteria.  Additional instructions for evaluating patients 
with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 7. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or the 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%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1. AST or ALT increases to ≥ 3 x ULN; AND 
2. Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3. Alkaline phosphatase value does not reach 2 x ULN; AND 
4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus) 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms 
• Alcoholic hepatitis 
• Nonalcoholic steatohepatitis  
• Autoimmune hepatitis  
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If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
7.6. 
Serious Adverse Event Reporting 
Using a Safety Reporting Form, all serious adverse events must be reported within 24 hours of 
the study site personnel’s knowledge of the event, regardless of the investigator assessment of 
the relationship of the event to study drug. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose is available on the Serious Adverse Event report form and is as 
follows: 
Send completed Safety Report Forms to QuintilesIMS: 
Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary 
reporting method) 
All Regions 
 
  
 
For questions on Serious Adverse Event (SAE)/Adverse Event of Clinical Interest (AECI) 
reporting, please call: 
• 
North/South America: 
  
• 
Regional toll-free phone and fax lines distributed separately.  Please refer to Study 
Reference Manual. 
 
The initial report should include: 
• 
Study number (MVT-601-3001) 
• 
Site address and number 
• 
Investigator name 
• 
Patient ID number, sex, and age 
• 
Details of study drug administration 
• 
The date of the report 
• 
A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity) 
• 
Causal relationship to the study drug 
If the patient died, the report should include the cause of death as the event term (with death as 
outcome) and whether or not the event leading to death was related to study drug treatment, as 
well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
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initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 x the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form according to Section 7.6, whether or not the overdose 
is associated with an adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); 
• 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.  The investigator 
must inform the patient of her right to receive treatment information.  If the patient chooses to 
receive unblinded treatment information, the individual blind should be broken and the treatment 
assignment provided to the patient.  The study team will remain blinded to the patient’s treatment 
assignment. 
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 (blinded or 
unblinded, as applicable). 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  The 
expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result, and neonatal data, etc, should be included in this 
information, as available. 
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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 6.8.2 details the requirements for measurement of safety parameters including vital 
signs, physical and gynecologic examinations, clinical laboratory tests, electrocardiograms 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 
(QTc prolongation), hepatic enzyme increases, PLD, reproductive toxicity, and metabolic and 
cardiovascular changes (insulin resistance, dyslipidemia, increased weight) with an increased 
risk of diabetes mellitus and possible increased risk of cardiovascular disease.  Additionally, 
there are potential risks associated with the addition of estradiol/norethindrone acetate.  
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis,  
metabolic bone disease, 
and prior medical therapy 
for low bone mineral 
density. 
Bone mineral density will be 
monitored at the Baseline 
Day 1, Week 12, and End of 
Treatment visits and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-gp inhibitors/inducers. 
Collection of adverse events. 
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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF  
> 470 msec. 
12-lead ECG at Baseline 
Day 1, Week 12 and End of 
Treatment visits, and as 
clinically applicable; 
withdrawal for QTcF 
> 500 msec. 
Hepatic Enzyme Increase 
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 LFTs 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 LFTs (AST or 
ALT > 3 x ULN) that 
develop during the 
randomized treatment period 
will be reported within 24 
hours of study personnel 
awareness. 
Phospholipidosis 
Data from nonclinical studies in rats and 
monkeys showed histopathological 
changes consistent with PLD.  PLD by 
itself is not adverse.  No clinical evidence 
of relugolix-related PLD-associated 
toxicity has been observed nor was there a 
clinically meaningful increase in a 
biomarker of PLD assessed in phase 2 
clinical studies. 
Patients with significant 
underlying medical 
conditions are excluded. 
Routine safety monitoring 
including laboratory 
assessments, ECGs, and 
assessment of adverse 
events; visual acuity will be 
checked at the beginning and 
end of the 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. 
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. 
Monthly pregnancy testing; 
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 
Women with breast 
cancer or other estrogen-
dependent malignances, a 
history of deep vein 
thrombosis, pulmonary 
embolism, 
thromboembolic disease, 
liver dysfunction, prior 
Clinical chemistries 
assessing LFTs, 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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Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
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.  
hypersensitivity, migraine 
with aura, porphyria, and 
pregnancy are excluded.  
A mammogram, 
Papanicolaou test, 
physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed prior to 
enrollment. 
 
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). 
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Management of clinical data will be performed in accordance with applicable sponsor-approved 
standards and data cleaning procedures to ensure the integrity of the data (eg, removing errors 
and inconsistencies in the data). 
Adverse events and concomitant medications terms will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and the World Health Organization Drug Dictionary 
Enhanced, respectively. 
The investigator will retain original source documents and the sponsor will receive eCRF-
required data as electronic datasets.  Patient initials will not be collected or transmitted to the 
sponsor. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study.  The SAP will be prepared and finalized prior to unblinding of patients’ study 
treatment assignments. 
All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%.  
Methodology to be used to maintain study-wide type I error rate of 5% across primary and 
secondary endpoint testing will be described in the SAP. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 1:1:1 to relugolix plus low-
dose hormonal add-back therapy (Group A), relugolix monotherapy plus placebo followed by 
relugolix plus low-dose hormonal add-back therapy (Group B), and placebo (Group C).  
Randomization will be stratified by the following factors: 
• Geographic Region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss using alkaline hematin method:  < 225 mL versus 
≥ 225 mL. 
Statistical analyses for all efficacy endpoints will incorporate these stratification factors unless 
otherwise specified. 
9.2. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis. 
The Per-Protocol Population will consist of those members of the ITT Population who have no 
relevant major protocol violations, defined as a subset of all major protocol violations (details 
will be provided in the statistical analysis plan).  The Per-Protocol Population will not be 
analyzed if this population comprises more than 95% or less than 50% of the ITT Population.  
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This population will be used for confirmatory analysis of the primary efficacy endpoint.  The 
Per-Protocol Population will be identified prior to breaking the study blind. 
The primary population for safety analyses will be the Safety Population, which will consist of 
all patients who are randomized and took at least one dose of study treatment. 
9.3. 
Efficacy Analyses 
Inferential efficacy assessments will be made between the following groups and 24 Weeks of 
placebo: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate; 
• Relugolix Group B:  12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone 
acetate. 
Descriptive characterization of treatment effect will be assessed between both relugolix groups. 
9.3.1. 
Primary Endpoint Analysis 
The primary endpoint is the proportion of women in the relugolix Group A versus the placebo 
Group C who achieve both a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline in menstrual blood loss volume over the last 35 days of treatment 
as measured by the alkaline hematin method.  
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 as assessed by the alkaline hematin method.  The menstrual blood loss during the 
final study month is the total menstrual blood loss during the last 35 days on treatment as 
assessed by the alkaline hematin method.  The treatment comparison between the relugolix 
Group A and the placebo Group C will be analyzed using a Cochran-Mantel-Haenszel test 
statistic for stratified proportions.  The differences between the relugolix Group A and placebo 
Group C and 2-sided 95% confidence intervals will be estimated based on stratum-adjusted 
Mantel-Haenszel proportions. 
Patients who discontinue the study before Week 4 (28 days) will be considered as treatment 
failures for the primary endpoint.  The primary analyses will be based on the ITT Population.  In 
addition, analyses of the Per-Protocol Population will be used to support the primary efficacy 
analysis.  Details will be provided in the SAP.  Additional missing data imputations will be 
conducted as sensitivity analyses to support the primary analysis.  Details will be provided in the 
SAP. 
For the assessment of the superiority of relugolix Group A versus placebo Group C in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least 
a 50% reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size 
of ~130 patients in the relugolix Group A versus ~130 in the placebo Group C will provide 
greater than 99% power to detect a difference of greater than 30% using a 2-sided test at 
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significance level of 0.05.  The study will enroll 3 groups with a targeted 130 patients in each 
group for a total sample size of 390. 
9.3.2. 
Secondary Endpoint Analyses 
The secondary endpoints are listed below: 
• Proportion of women in the relugolix Group B versus the placebo Group C who achieve a 
menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline 
menstrual blood loss volume over the last 35 days of treatment, as measured by the 
alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix treatment group to 
placebo inferentially and relugolix Group A to Group B descriptively: 
• Time to achieving a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss volume as measured by the alkaline 
hematin method; 
• Change from Baseline to Week 24 in menstrual blood loss; 
• Proportion of women who achieve amenorrhea over the last 35 days of treatment; 
• Proportion of women with a hemoglobin below the lower limit of normal at Baseline who 
achieve an increase of ≥ 1 g/dL from Baseline at Week 24; 
• Change from Baseline to Week 24 in impact of uterine fibroids based on the UFS-QOL 
activities domain; 
• Change from Baseline to Week 24 in the interference of uterine fibroids with physical 
activities based on UFS-QOL Question 11; 
• Change from Baseline to Week 24 in the interference of uterine fibroids with social 
activities based on UFS-QOL Question 20; 
• Change from Baseline to Week 24 in embarrassment caused by uterine fibroids based on 
UFS-QOL Question 29; 
• Change from Baseline to Week 24 in uterine fibroid-related symptoms based on the 
Uterine Fibroid Scale – Symptom Severity; 
• Change from Baseline to Week 24 in uterine fibroid-related quality of life based on the 
Uterine Fibroid Scale –  Health-related Quality of Life; 
• Change in PGA for uterine fibroid related function from Baseline to Week 24; 
• Change in PGA for uterine fibroid symptoms from Baseline to Week 24; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
physical activities; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• Proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• 
Change from Baseline to Week 24 in uterine volume; and 
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• 
Change from Baseline to Week 24 in uterine fibroid volume. 
 
The analysis methods used for the primary endpoint will be applied to the analyses of the 
secondary endpoints of proportion of patients who achieve both a menstrual blood loss volume 
of < 80 mL AND at least a 50% reduction in menstrual blood loss volume over the last 35 days 
of treatment compared between relugolix Group B and placebo Group C, the proportion of 
patients with amenorrhea over the last 35 days, the proportion of women with a hemoglobin 
below the lower limit of normal at Baseline who achieve an increase of at least 1 g/dL at Week 
24 and the proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction from 
Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days prior to 
randomization. 
For the secondary endpoints of time to achieving a menstrual blood loss volume of < 80 mL 
AND at least a 50% reduction from baseline menstrual blood loss volume, time to event will be 
defined as weeks from randomization 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 and 
stratified log-rank test will be used to compare each relugolix arm to placebo.  Randomization 
stratification factors will be used to stratify inferential testing. 
Descriptive statistics will be provided for changes in menstrual blood loss, hemoglobin, UFS-
QOL score, PGA for function and symptoms, MIQ Score, Numerical Rating Scale score for 
uterine fibroid-associated pain, uterine volume, and uterine fibroid volume baseline.  The 
between treatment comparisons will be performed using model derived least squares means with 
treatment, stratification factors, baseline result accounted for in the model. 
Baseline Numerical Rating Scale score is defined as the average Numerical Rating Scale score 
from the 35 days of data collected prior to the date of first dose of study drug after 
randomization.  The Numerical Rating Scale score during the final study month is the average 
Numerical Rating Scale score during the last 35 days on treatment. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
9.4. 
Safety Analyses 
Safety analyses will be conducted using the safety population and summarized by treatment 
group as treated.  The treatment emergent period will be defined as the period of time from the 
first dose date of the randomized study drug treatment 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, or the date and time of the first dose of open-label extension (MVT-601-3003) study 
drug, 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 
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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 baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from baseline to each post-baseline study visit will be presented by treatment 
group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from baseline to each post-baseline study visit will be presented by treatment group 
for each parameter. 
ECGs will be read centrally.  The distributions of corrected QT interval will be summarized at 
each visit.  All data will be listed and summarized by visit.  The change from baseline to each 
post-baseline study visit will be presented by treatment group for each ECG parameter. 
Bone mineral density will be determined by the central radiology laboratory at the femoral neck, 
lumbar spine (L1-L4), and total hip.  Values at Baseline, Week 12, and Week 24 visits will be 
summarized by treatment group along with the absolute and percent changes from Baseline and 
associated 95% confidence intervals.  The number and percentage of patients meeting a bone 
mineral density decline of at least 7% by body area (lumbar, total hip, and femoral neck) will be 
presented with 95% confidence intervals by treatment group.  
To support the inclusion of add-back therapy in the treatment regimen, the safety endpoint of 
mean percent change from Baseline in bone mineral density lumbar spine at Week 12 will be 
analyzed using pooled data from the two replicate studies (MVT-601-3001 and MVT-601-3002) 
with a formal comparison of Group A versus Group B (see details in the joint statistical analysis 
plan).  
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by treatment arm. 
9.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
The PK concentration data (relugolix, estradiol [PK lab], and norethindrone) and serum 
pharmacodynamic data (LH, FSH, estradiol [central lab] and progesterone) will be listed and 
summarized descriptively by treatment arm and visit. 
Plasma relugolix PK data will be combined with data from other phase 1 and phase 2 studies for 
population PK analysis.  Full details will be provided in a separate Population PK SAP and 
reported separately.  Plasma PK parameters of relugolix will be derived and summarized.  The 
relationship between efficacy, safety, and exposure will be explored. 
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9.6. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoint.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoint will be assessed: 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-Dimension Five-
Level scale comparing each relugolix treatment group to placebo inferentially and the 
two relugolix groups descriptively. 
9.7. 
Interim Analyses 
There are no planned interim efficacy analyses. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International 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 United States 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 one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
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consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient. 
10.1.4. 
Confidentiality 
The investigator must assure that 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 IB, protocol, eCRFs and other study forms, the investigational drug, and any other study 
information, remain the sole and exclusive property of the sponsor during the conduct of the 
study and thereafter.  This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the sponsor.  The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
10.1.5. 
Study Committees and Communication 
There will be two formal committees for this study, a Steering Committee and a Data and Safety 
Monitoring Board. 
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.  Steering Committee 
members will remain blinded to patients’ treatment assignment and all unblinded data until the 
database is officially locked and unblinded. 
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An independent Data and Safety Monitoring Board will be established consisting of experts in 
women’s health, clinical study safety monitoring, and statistics.  This committee will evaluate 
the safety of study participants on an ongoing basis.  Further details on the composition and 
responsibility of the Data and Safety Monitoring Board will be outlined in a separate charter. 
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 IB, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents.  The required source data should include the following 
for each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, 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 IB, 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 
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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 the 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 (active and 
placebos).  This includes acknowledgment of receipt of each shipment of study product (quantity 
and condition), patient dispensing records, and returned or destroyed study product.  Dispensing 
records will document quantities received from the sponsor and quantities dispensed to patients, 
including lot number, date dispensed, Patient Identification Number, and the initials of the 
person dispensing the medication. 
At study initiation, the study monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with the 
sponsor requirements.  Drug may be returned or destroyed on an ongoing basis during the study 
if appropriate.  At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused study drug supplies, including 
empty containers, according to these procedures.  If the site cannot meet the sponsor’s 
requirements for disposal, arrangements will be made between the site and the sponsor (or 
designee) for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
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10.1.9. 
Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the sponsor or its representatives, to IRBs or 
IECs, or to regulatory authority or health authority inspectors. 
10.1.10. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of patients begins.  Results will be posted as required. 
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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The study monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them.  The monitor should have access to any patient records needed to 
verify the entries on the eCRFs.  The investigator agrees to cooperate with the study monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  Should this be necessary, the 
sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRBs/IECs.  In terminating the study, the sponsor and the investigator will 
assure that adequate consideration is given to the protection of the study participants’ interests. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 90 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 120 days in 
order to obtain patent protection if deemed necessary. 
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Archer DF, Chwalisz K, Feldman R, Stewart EA, Lukes AS, North J, Gao J, Williams LA, Jain 
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Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. American 
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Cardozo ER. The estimated annual cost of uterine leiomyomata in the United States. American 
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Food and Drug Administration (FDA). Guidance for Industry: Drug-Induced Liver Injury: 
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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 
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Wu D, Hu M, Hong L, Hong S, Ding W, Min J, Fang G, Guo W. Clinical efficacy of add-back 
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APPENDICES 
Appendix 1. 
Breast Imaging Reporting and Data System (BI-RADS) 
Category 
Assessment 
Follow-up 
0 
Need additional imaging evaluation:  means that more 
studies are necessary to gather more information. 
Additional imaging needed 
before a category can be 
assigned. 
1 
Negative:  means that there is no significant or 
noticeable abnormality to report. 
Continue annual screening 
mammography (for women 
over age 40). 
2 
Benign (noncancerous) finding:  means that there has 
been a finding, such as benign calcifications or 
fibroadenoma, which is not cancerous. 
Continue annual screening 
mammography (for women 
over age 40). 
3 
Probably benign:  means that there is a finding that is 
most likely benign, but should be followed in a shorter 
period of time to see if the area of concern changes. 
Receive a 6-month follow-up 
mammogram. 
4 
Suspicious abnormality:  means that there are 
suspicious findings that could turn out to be cancer. 
May require biopsy. 
5 
Highly suggestive of malignancy (cancer):  means that 
there are findings that look like and probably are 
cancer. 
Requires biopsy. 
6 
Known biopsy-proven malignancy (cancer):  means that 
any findings on the mammogram have already proven 
to be cancer through a biopsy. 
Biopsy confirms presence of 
cancer before treatment begins. 
 
 
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Appendix 2. 
Daily eDiary 
  
  
 
 
 
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Appendix 3. 
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 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 
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Appendix 5. 
European Quality of Life Five-Dimension Five-Level Scale 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
 
Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
 
 
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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Appendix 6. 
Patient Global Assessments 
 
 
 
Patient Global Assessment (for function)  
 
How much were your usual activities limited by uterine fibroids symptoms such as heavy 
bleeding over the last 4 weeks? 
 
1. No limitation at all 
2. Mild limitation 
3. Moderate limitation 
4. Quite a bit of limitation 
5. Extreme limitation 
 
  
 
Patient Global Assessment (for symptoms)  
 
How severe were your uterine fibroids symptoms such as heavy bleeding over the last 4 weeks? 
 
1. Not severe 
2. Mildly severe 
3. Moderately severe 
4. Very severe 
5. Extremely severe 
 
 
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Appendix 7. 
Assessment of Abnormal Liver Function Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) should be withheld for any liver test abnormality 
listed in Section 7.5.1, pending investigation of alternative causes of liver injury.  Follow-up 
should continue until the liver test abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations in 
Appendix Table 2.  If close monitoring is not possible, study drug should be withheld even if the 
results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]), Alkaline 
Phosphatase, and INR Tests 
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities 
improve 
If ALT or AST ≥ 3 × ULN and total 
bilirubin and INR are normal  
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve 
AND the patient is asymptomatic 
Frequency may decrease 
Abbreviations:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international 
normalized ratio; ULN, upper limit of normal 
h. 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 1:  An International Phase 3 Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate Relugolix Co-Administered with and without Low-
Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3001 
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): 
EudraCT # 2016-003727-27 
IND # 131161 
Version and 
Effective Date: 
Original:  10-NOV-2016 
Amendment 1:  08-FEB-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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PPD

Clinical Study Protocol:  MVT-601-3001 
 
Amendment 1, Effective:  08-FEB-2017 
Myovant Sciences GmbH 
3 
CONFIDENTIAL 
AMENDMENT 1:  SUMMARY OF CHANGES 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Study Title 
An International Phase 3 
Randomized, Double-Blind, 
Placebo-Controlled Efficacy and 
Safety Study to Evaluate 
Relugolix Co-Administered with 
and without Low-Dose Estradiol 
and Norethindrone Acetate in 
Women with Heavy Menstrual 
Bleeding Associated with 
Uterine Fibroids 
LIBERTY 1:  An International 
Phase 3 Randomized, Double-Blind, 
Placebo-Controlled Efficacy and 
Safety Study to Evaluate Relugolix 
Co-Administered with and without 
Low-Dose Estradiol and 
Norethindrone Acetate in Women 
with Heavy Menstrual Bleeding 
Associated with Uterine Fibroids 
To add the study 
moniker 
Sponsor 
Signature Page 
 
Biostatistics and Medical Director 
signatories added; CEO signatory 
removed 
To update 
signatories based 
on personnel 
additions 
IC #3; 
Synopsis, 4.1 
“Has a body mass index (BMI) 
within the range of 18.0 to 40.0 
kg/m2 (inclusive);” 
None 
Weight restriction, 
other than as 
related to DXA 
scanner 
accommodation 
(covered in EC #4) 
was not needed. 
IC #5 (now IC 
#4); 
Synopsis, 4.1, 
4.3.1, 6.2, 6.3, 
SOA footnote q 
“Has a diagnosis of uterine 
fibroids that is confirmed by a 
transvaginal and/or 
transabdominal ultrasound 
performed with saline or gel 
contrast during the screening 
period. At least one uterine 
fibroid must be verified by a 
central reader to meet at least 
one of the following criteria: 
a. Subserosal, intramural, 
submucosal non-pedunculated 
fibroid with a diameter ≥ 2 cm 
(longest diameter), or  
b. Multiple small fibroids with a 
total uterine volume of 
≥ 130 cm3” 
“Has a diagnosis of uterine fibroids 
that is confirmed by a transvaginal 
ultrasound performed during the 
screening period.  At least one 
uterine fibroid must be verified by a 
central reader to meet at least one of 
the following criteria: 
a. Subserosal, intramural, or <50% 
intracavitary submucosal fibroid 
with a diameter ≥ 2 cm (longest 
diameter), or  
b. Multiple small fibroids with a 
total uterine volume of ≥ 130 cm3; 
Note 1:  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. 
Note 2:  Saline or gel contrast is not 
required, but may be performed to 
demonstrate fibroids that meet the 
criterion for inclusion if these are not 
adequately visualized with 
To clarify 
situations in which 
a transabdominal 
ultrasound and 
saline or gel 
infusion should be 
performed 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
transvaginal ultrasound alone.” 
EC #5; 
Synopsis, 4.3.2 
Has a baseline bone mineral 
density z-score < -2.0 at spine or 
total hip 
Has a baseline bone mineral density 
z-score < -2.0 at spine, total hip, or 
femoral neck 
To exclude patients 
with baseline bone 
mineral density z-
score of < -2.0 at 
femoral neck 
Placebo 
Matching; 
Synopsis, 5.1 
Placebo and active tablets and 
capsules will matched for size, 
shape, color, and odor 
Placebo and active tablets and 
capsules will matched for size, shape, 
and color 
Odor is not being 
specifically tested. 
IC #4 (now IC 
#5); 
Synopsis, 4.1, 
4.2, 4.3, 4.3.1, 
Figure 4-1, 
Figure 4-2 
“Has heavy menstrual bleeding 
associated with uterine fibroids 
as evidenced by a menstrual 
blood loss of ≥ 80 mL per cycle 
as measured by the alkaline 
hematin method for 2 menstrual 
cycles during the screening 
period” 
“Has heavy menstrual bleeding 
associated with uterine fibroids as 
evidenced by a menstrual blood loss 
of ≥ 160 mL for 1 cycle or ≥ 80 mL 
per cycle for 2 menstrual cycles as 
measured by the alkaline hematin 
method during the screening period” 
To allow patients 
who have 
demonstrated 
menstrual blood 
loss that is double 
or more the 
screening 
requirement in a 
single cycle to 
enroll based on 
menstrual blood 
loss data from only 
one cycle, rather 
than two 
IC #7 (now IC 
#6); 
Synopsis, 4.1, 
4.3.1 
“…not expected to be a 
candidate for gynecological 
surgery or ablation 
procedures…” 
“…not expected to undergo 
gynecological surgery or ablation 
procedures for uterine fibroids…” 
To clarify the 
criterion’s intent 
IC #9 (now IC 
#8); 
Synopsis, 4.1, 
4.3.1, 4.7 
“Had a bilateral tubal occlusion 
(including ligation and blockage 
methods such as Essure™), at 
least 4 months prior to the first 
screening visit (patients with 
Essure must have prior 
confirmation of tubal occlusion 
by hysterosalpingogram” 
“Had a bilateral tubal occlusion 
(including ligation and blockage 
methods such as Essure™), at least 4 
months prior to the first screening 
visit (patients with Essure must have 
prior confirmation of tubal occlusion 
by hysterosalpingogram and no 
evidence of “post-Essure™ 
syndrome” in the investigator’s 
opinion)” 
To exclude women 
with the potential 
confounding factor 
of post-Essure 
syndrome 
IC #10 (now IC 
#9); 
Synopsis, 4.1, 
4.3.1 
“Has an adequate endometrial 
(aspiration) biopsy performed 
during the screening period, with 
results showing no clinically 
significant endometrial 
pathology (hyperplasia, polyp, 
endometritis, or endometrial 
cancer)” 
“Has an adequate endometrial 
(aspiration) biopsy performed during 
the screening period, with results 
showing no clinically significant 
endometrial pathology (hyperplasia, 
polyp, or endometrial cancer).  Note: 
polyps < 2.0 cm by ultrasound are 
not excluded.” 
To remove 
endometritis as an 
exclusion and to 
make polyp 
exclusion 
consistent with 
other entry criteria 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
IC #11 (now IC 
#10); 
Synopsis, SOA 
footnote p, 4.1, 
4.3.1, 6.2.1, 
6.2.2 
“If ≥ 39 years of age at the time 
of the Baseline Day 1 visit, has a 
normal mammogram (Breast 
Imaging Reporting and Data 
System category 1 to 3 or 
equivalent) during the screening 
period or within 3 months prior 
to the screening period.” 
“If ≥ 39 years of age at the time of 
the Baseline Day 1 visit, has a 
normal mammogram (Breast 
Imaging Reporting and Data System 
category 1 or 2 or equivalent) during 
the screening period or within 6 
months prior to the screening 
period.” 
To align with 
recommended 
mammography 
screening intervals, 
accounting for an 
~6-month 
Treatment Period; 
Disallow patients 
with BI-RADS 3 
readings due to 
their higher risk 
IC #12; 
Synopsis, 4.3.1 
A randomization authorization 
form has been signed by a study 
medical monitor approving the 
patient for randomization into 
the trial. 
None 
To define the use 
of randomization 
authorization in the 
study procedural 
documents rather 
than in the protocol 
EC #1; 
Synopsis, 4.1, 
4.3.2, 6.2, SOA 
footnote q 
“Has transvaginal and/or 
transabdominal ultrasound 
during the screening period 
demonstrating pathology other 
than uterine fibroids that could 
be responsible for or 
contributing to the patient’s 
heavy menstrual bleeding, such 
as uterine or cervical polyps or 
any other clinically significant 
gynecological disorder 
determined by the investigator to 
require further evaluation and/or 
treatment.” 
“Has transvaginal and/or 
transabdominal ultrasound during the 
screening period demonstrating 
pathology other than uterine fibroids 
that could be responsible for or 
contributing to the patient’s heavy 
menstrual bleeding, such as uterine 
or cervical polyps >2.0 cm, large 
simple ovarian cyst >4.0 cm, 
endometrioma(s) >4.0 cm, or any 
other clinically significant 
gynecological disorder determined 
by the investigator to require further 
evaluation and/or treatment during 
the study. 
Note:  Saline or gel contrast is not 
routinely required. Use of such 
contrast is required only when the 
endometrium cannot be evaluated or 
when there are ambiguous and 
potentially exclusionary findings on 
the transvaginal or transabdominal 
ultrasound (e.g., suspected 
intrauterine masses, equivocal 
endometrial findings, etc.).” 
To add examples of 
common findings 
that would be 
considered 
exclusionary; 
To clarify 
situations in which 
saline or gel 
infusion should be 
performed; 
To allow patients 
with finding not 
requiring 
immediate 
evaluation or 
treatment to enroll 
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CONFIDENTIAL 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
EC #2; 
Synopsis, 4.3.2 
“Has unexplained vaginal 
bleeding outside of the patient’s 
regular menstrual cycle” 
“Has known rapidly enlarging uterine 
fibroids in the opinion of the 
investigator” 
To remove an 
exclusion that may 
be a disease-state 
manifestation and 
to add an exclusion 
for uterine fibroids 
at higher risk to be 
malignant 
EC #10g, h; 
Synopsis, 4.3.2 
none 
“Migraine with aura” 
“History of porphyria” 
To add migraine 
with aura as an 
example of a 
contraindication to 
treatment with low-
dose estradiol and 
norethindrone 
acetate and to add 
an exclusion for 
porphyria, which is 
listed in the 
prescribing 
information in 
some countries 
EC #12; 
Synopsis, 4.3.2 
“Has any of the following 
cervical pathology:  high grade 
cervical neoplasia, atypical 
glandular cells, atypical 
endocervical cells, atypical 
squamous cells favoring high 
grade.  Of note, patients with 
atypical squamous cells of 
undetermined significance and 
low-grade cervical neoplasia 
may be included in the study.” 
“Has any of the following cervical 
pathology:  high grade cervical 
neoplasia, atypical glandular cells, 
atypical endocervical cells, atypical 
squamous cells favoring high grade.  
Of note, patients with atypical 
squamous cells of undetermined 
significance and low-grade cervical 
neoplasia may be included in the 
study if high risk human papilloma 
virus testing is negative or if DNA 
testing for human papilloma virus 16 
and 18 is negative.” 
To incorporate 
high-risk human 
papilloma virus 
reflexive testing 
that will be 
performed by the 
central laboratory 
into the criterion 
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CONFIDENTIAL 
Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
EC #14b, d, h; 
Synopsis, 4.3.2 
“History of angina” 
“History of clinically significant 
ventricular arrhythmias such as 
ventricular tachycardia, 
ventricular fibrillation, or 
torsades de pointes, or history of 
permanent pacemaker, Mobitz II 
second degree or third degree 
heart block without a permanent 
pacemaker in place or untreated 
supraventricular tachycardia 
(heart rate ≥ 120 beats per 
minute)” 
“Bradycardia as indicated by a 
heart rate of < 45 beats per 
minute on the screening 
electrocardiogram” 
“History of angina or significant 
coronary artery disease (i.e. >50% 
stenosis)” 
“History of clinically significant 
ventricular arrhythmias such as 
ventricular tachycardia, ventricular 
fibrillation, or torsades de pointes, or 
Mobitz II second degree or third 
degree heart block without a 
permanent pacemaker in place or 
untreated supraventricular 
tachycardia (heart rate ≥ 120 beats 
per minute)” 
Bradycardia as indicated by a heart 
rate of < 45 beats per minute on the 
screening electrocardiogram unless 
judged by the investigator to be due 
to physical fitness” 
To add an 
exclusion for 
significant 
coronary artery 
disease (#14b), to 
remove the 
exclusion for 
pacemaker 
(criterion was 
internally 
inconsistent) 
(#14d), and to 
allow for 
physiologically 
appropriate 
bradycardia in 
physically-fit 
patients (#14h) 
EC #16c; 
Synopsis, 4.3.2 
“History of major depression or 
other major psychiatric disorder 
at any time including bipolar 
disorder, schizophrenia, or post-
traumatic stress disorder 
(patients without a history of 
major depression treated with a 
selective serotonin-reuptake 
inhibitor antidepressant may be 
enrolled if stable for over 
1 year)” 
“Any current psychiatric disorder 
that would, in the opinion of the 
investigator or medical monitor, 
impair the ability of the patient to 
participate in the study or would 
impair interpretation of their data. 
Patients with major depression, post-
traumatic stress disorder, bipolar 
disorder, schizophrenia or other 
psychotic disorders, based on 
Diagnostic and Statistical Manual of 
Mental Disorders-5 criteria who have 
been unstable or not well controlled 
based on the investigator’s or mental 
health professional’s judgement or 
whose history or stability cannot be 
ascertained, or whose psychiatric 
drug regimen has changed during the 
3 months prior to Screening or is 
expected to change during the study 
should not be enrolled.” 
To broaden the 
ability for patients 
with remote 
psychiatric 
disorders and 
current psychiatric 
disorders who are 
able to participate 
in the trial to be 
enrolled 
EC #17; 
Synopsis, 4.3.2 
“Is currently pregnant or 
lactating, or intends to become 
pregnant or to donate ova during 
the study period or within 1 
month after the end of the study” 
“Is currently pregnant or lactating, or 
intends to become pregnant or to 
donate ova during the study period or 
within 2 months after the last dose of 
study drug” 
To clarify timing 
relative to last dose 
of study drug 
Study 
Completion; 
4.6 
None 
Added definition of study completion 
(completion of Week 24 visit) 
To include a 
definition 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Removal of 
Patients from 
Therapy; 
4.6, 6.7.2.6 
Patients who have percent 
change from Baseline in bone 
mineral density at either the 
Week 12 or Week 24 visit (or 
any unscheduled visit) at the 
lumbar spine (average L1-L4), 
total hip, or femoral neck of < -
4.0 that is repeated and 
confirmed (ie, both values are 
< -4.0) 
Replaced with alert notifications 
from the central radiology readers to 
the investigator for a 7% or greater 
decline in bone mineral density at 
any time point (added to section 
6.7.2.6) 
To allow for use of 
clinical risk 
assessment by the 
investigator in 
determining 
whether 
withdrawal is 
warranted and 
determination of 
future 
management. 
The study is 
conducted in 
patients generally 
considered at low 
risk for fracture; 
Patients with 
history of 
osteoporosis, or 
baseline bone 
mineral density Z-
scores < -2.0 are 
excluded. 
Identification of 
Investigational 
Product; 
5.0. Table 5-1 
No color listed 
Estradiol (1.0 mg) and 
norethindrone acetate (0.5 mg) is 
a fixed-dose combination 
product (Activella™ or 
ActivelleTM). 
“Swedish orange” added in the 
description for the placebo and active 
low-dose add back capsule 
Estradiol (1.0 mg) and norethindrone 
acetate (0.5 mg) is a fixed-dose 
combination product (Activella™ or 
ActivelleTM). 
To add product 
details 
Product 
Characteristics; 
Section 5.2.1 
Relugolix has no chiral centers.  
The compound is slightly to 
partially soluble in acidic 
solutions but essentially 
insoluble at neutral pH (pH 7) 
and above.  It is partially soluble 
in polar organic solvents.  The 
compound is provided as an 
immediate-release pink tablet 
using the United States 
Pharmacopeia and the National 
Formulary (USP/NF) excipients. 
“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. 
Placebo to match relugolix is a pink 
tablet using common excipients.” 
To facilitate review 
of the protocol in 
European 
countries, USP 
language was made 
more general 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Study Drug 
Storage; 
5.6 
“Study drug should be stored in 
an appropriate, limited-access, 
secure location within a 
temperature range of 1°C to 
30°C until it is used or returned 
to the sponsor (or designee).” 
“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).” 
To narrow the 
storage 
temperatures for 
both 
relugolix/placebo 
and estradiol/ 
norethindrone to 
match the 
temperature 
requirements for 
Activella 
Study Drug 
Administration; 
5.4, 6.3 
None 
Fasting does not require withholding 
of water.  On clinic visit days that are 
not in the morning, patients should 
fast for at least 2 hours prior to the 
visit and for 1 hour taking the study 
drug. 
To provide 
clarifications on 
study procedures 
Blinding; 
5.7 
Investigator to determine if 
treatment assignment of a site-
unblinded patient should be 
revealed to the sponsor. Sponsor 
may unblind for a serious 
adverse event. 
Investigator not to reveal treatment 
assignment of a site-unblinded 
patient to the sponsor. 
Sponsor unblinding for serious 
adverse events described in the 
Safety Management Plan. 
To make this 
decision a sponsor 
responsibility; 
To provide details 
and context for 
unblinding of 
serious adverse 
events by the 
Sponsor in the 
Safety 
Management Plan, 
rather than in the 
protocol 
Prohibited 
Medications; 
5.10.1 
None 
Contact the medical monitor for 
approval and guidance on study drug 
administration if a short course of a 
prohibited P-glycoprotein inhibitor or 
inducer is required during the study 
To provide 
additional guidance 
for such situations 
Prohibited 
Medications; 
5.10.1 
None 
Addition of bazedoxifene, zoledronic 
acid, and factor Xa inhibitors to 
Table 5-3 
To include 
additional 
examples of 
prohibited 
medications 
Prohibited 
Medications; 
5.10.1 
Oral contraceptive exclusion 
period 2 months 
Oral contraceptive exclusion period 
typical (for them) menstrual period 
within < 2 months prior to the 
Screening Visit; otherwise 2 months 
To shorten 
exclusionary period 
for patients 
following 
resumption of 
menses 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Prohibited 
Medications; 
5.10.1 
Selective progesterone receptor 
modulator exclusion period 2 
months 
Selective progesterone receptor 
modulator exclusion period 6 months 
To avoid possible 
confounding 
related to the 
endometrial effects 
of these drugs 
Prohibited 
Medications; 
5.10.1 
Bone agent exclusion period 
2 months prior to Screening 
Bone agent exclusion period 
indefinite if used for low bone 
mineral density 
To make consistent 
with eligibility 
criteria 
Prohibited 
Medications; 
5.10.1 
None 
Addition of 1-week exclusionary 
window for over the counter and 
herbal products with known 
hormonal activity 
To reduce possible 
confounding of 
efficacy and safety 
due to these 
products 
Analgesic 
Medications; 
5.10.2.1 
Specific required medications 
for uterine fibroid pain and other 
pain 
Requirements changed to 
recommendations for allowed 
medications for uterine fibroid pain. 
Restriction on analgesics for other 
pain conditions removed. 
To liberalize 
restrictions based 
on site feedback 
while encouraging 
consistency in 
analgesic use 
Adverse Event 
Reporting 
Period; 
6.2, 7.2.1, SOA 
footnote f 
Non-serious adverse events 
occurring after signing of the 
informed consent form and prior 
to start of study drug should be 
recorded as medical history 
Non-serious adverse events occurring 
after signing of the informed consent 
form and prior to start of study drug 
should be recorded as adverse events 
rather than medical history if they are 
considered related to study 
procedures; otherwise, they should 
be recorded as medical history. 
To capture study 
procedure-related 
adverse events as 
adverse events 
Waist 
Circumference; 
SOA, 6.3. 
6.7.2.1 
None 
Waist circumference measured at 
Baseline Day 1  
To obtain data to 
characterize 
patients with 
metabolic 
syndrome 
Ultrasound 
Procedures; 
6.2 
None 
Addition of clarification that the 
investigator, rather than the central 
reader, will determine if any 
exclusionary pathology is present. 
Clarification 
Pathology 
Specimens; 
SOA footnotes i 
and r, 6.2, 6.3, 
6.7.1.3 
Whether the Papanicolaou test 
and would be locally or centrally 
read was not specified 
Endometrial biopsy to be read 
locally (or centrally read if 
requested) 
Papanicolaou test and endometrial 
biopsy will be centrally read 
To improve 
consistency of 
readings and to 
facilitate site 
logistics 
Unscheduled 
None 
Reminder add to obtain unscheduled 
iron studies at Visit 2 if hemoglobin 
To improve 
adherence to the 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Iron Studies; 
6.2 
is < 10 g/dL and mean corpuscular 
volume is below the lower limit of 
normal. 
protocol 
requirements 
Pre-Screening 
Procedures; 
6.2 
Pre-screening procedures 
None 
To allow sites to 
utilize site-specific 
practices for pre-
screening 
Re-Screening 
Procedures; 
6.2, SOA 
None 
Certain screening procedures do not 
need to be repeated for patients who 
re-screen within 10 weeks of the 
signing the original informed consent 
form: transvaginal ultrasound, 
endometrial biopsy, and bone 
densitometry. 
To reduce patient 
procedural burden 
Early 
Termination 
Procedures; 
6.5, SOA 
footnote s 
None 
Certain early termination visit 
procedures are not required for 
patients whose last dose of study 
drug is during Week 6 or earlier 
(transvaginal ultrasound, endometrial 
biopsy, and bone densitometry). 
These procedures may be done if 
they will aid in the evaluation of an 
ongoing adverse event 
To reduce patient 
procedural burden 
Unscheduled 
Visit Procedures; 
6.6, SOA 
List of procedures to be done to 
further evaluate adverse events  
Adverse events are to be evaluated 
and concomitant medications, and 
reason for visit are to be recorded. 
Other procedures may be done as 
needed. 
Clarification of 
required and 
optional procedures 
at Unscheduled 
Visits 
Clinical 
Laboratory 
Tests; 
6.7.2.4, 
Table 6-1, SOA 
footnote j 
Subset of central laboratory tests 
All central laboratory tests 
To include full list 
of clinical 
laboratory tests and 
to add Vitamin D 
at Baseline Day 1 
Bone Mineral 
Density; 
6.7.2.6 
Incomplete details of bone 
mineral density acquisition and 
reporting included in this 
section. 
Details of bone mineral density 
acquisition and reporting moved to 
the imaging charter. 
To have a single 
document with the 
full details of this 
procedure 
Endometrial 
Biopsy 
6.7.1.3 
None 
Specification that a pipelle should be 
used for the endometrial biopsy 
To have greater 
uniformity in the 
specimen 
acquisition 
Pregnancy; 
7.2 
 
Requirement for reporting partner 
pregnancies removed 
All study patients 
will be women 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Serious Adverse 
Event Logistics; 
7.6 
None 
Contact information for serious 
adverse event reporting added 
To update with the 
serious adverse 
event vendor’s 
logistical details 
Safety Analyses; 
9.4 
The number and percentage of 
patients meeting a bone mineral 
density decline of at least 4%, 
5% or 6% by body area (lumbar, 
total hip, and femoral neck) will 
be estimated with 95% 
confidence intervals by 
treatment group.  The number 
and percentage of patients 
meeting a T-score of < -2.5 by 
body area will also be estimated 
with 95% confidence interval by 
treatment group.  
The number and percentage of 
patients meeting a bone mineral 
density decline of at least 4%, 5%, 
6%, or 7% by body area (lumbar, 
total hip, or femoral neck) will be 
estimated with 95% confidence 
intervals by treatment group. 
To align with the 
statistical analysis 
plan and remove 
references to 
analyses based on 
cut-offs for T-
scores; analyses 
based on Z-scores 
will be detailed in 
the SAP 
Schedule of 
Papanicolaou 
Testing; 
SOA 
Screening and Week 24/Early 
Termination 
Screening 
Procedure not 
needed because 
cervical dysplasia 
not a safety risk in 
this trial 
Schedule of PD 
Measurements; 
SOA 
Screening 1 visit, Day 1, Weeks 
4, 8, 12, 16, 20, 24, and Follow-
up 
Day 1, Weeks 4, 12, 24, and Follow-
up 
To remove 
unneeded sampling 
time points 
Visit Windows; 
SOA, Figure 4-2, 
6.2 
Screening 3 visit:  Window < 10 
days after Screening 2 visit 
Transvaginal ultrasound, 
gynecology examination, 
papanicolaou test, endometrial 
biopsy, mammogram, bone 
densitometry: Visit 3 
Screening 1, 2, and 4 visits to 
occur within 4 days of end of 
menses and Baseline Day 1 visit 
to occur within 4 days of end of 
menses 
Screening 3 visit:  Window < 15 days 
after Screening 2 visit. 
Transvaginal ultrasound, gynecology 
examination, papanicolaou test, 
endometrial biopsy, mammogram 
(schedule appointment), bone 
densitometry (schedule 
appointment): Visit 1 
Screening 2 and 4 visits to occur 
within 5(+2) days of end of menses. 
Screening visit 1 not timed with 
menses. 
Screening 4 visit may be skipped if 
menstrual blood loss with the first 
cycle collection is >160 mL. 
To improve site 
logistics and to 
accommodate 
turnaround time for 
patients collecting 
1 cycle of 
menstrual blood 
loss 
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Item; 
Section(s) 
Original 
Amendment 1 
Rationale 
Schedule of 
Visual Acuity 
Testing and 
eDiary; 
SOA footnote u 
and v, 6.2 
Visual acuity at Screening and 
on Day 1 
eDiary:  dispense at Screening 3 
visit 
Visual acuity on Day 1 
Paper diary:  dispense at Screening 1 
visit 
eDiary: dispense at Screening 1 visit 
To remove an 
unneeded 
procedure; visual 
acuity is not an 
eligibility criterion; 
therefore, not 
needed at 
Screening 
To allow fuller data 
capture of menses 
dates and daily 
feminine product 
use 
eDiary; 
Appendix 2 
eDiary question text 
eDiary screenshots, which also 
include analgesic medication dose, 
route, and frequency questions 
To update with 
final e-diary 
content 
UFS-QoL; 
Appendix 4 
 
 
To update with 
correct version of 
the instrument 
CTCAE and IB 
version; 
2.4.2.2 and 
various 
CTCAE, Version 5.0 
IB Version 9.0, dated 09 
November 2016 
CTCAE version not specified in 
protocol, but the version to be used 
will be in the study reference manual 
and noted in the statistical analysis 
plan. 
CTCAE version 
5.0 not yet 
published at the 
time of study start; 
IB version 
removed to avoid 
discrepancies that 
may occur when IB 
is updated during 
the study 
Minor Edits; 
Various 
 
Corrections of typos, minor 
clarifications, minor inconsistencies, 
and minor wording changes 
To improve 
readability and 
understandability. 
Abbreviations:  BI-RADS, Breast Imaging Reporting and Data System; CEO, Chief Executive Officer; CTCAE, 
Common Terminology Criteria for Adverse Events, DXA, dual x-ray absorptiometry; EC, exclusion criterion; IB, 
investigator brochure; IC, inclusion criterion; PD, pharmacodynamic; SOA, schedule of activities; UFS-QoL, 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
 
MVT-601-3001 CSR - Appendix 16.1.1. Protocol and Protocol Amendments
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1 
 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
LIBERTY 1:  An International Phase 3 Randomized, Double-
Blind, Placebo-Controlled Efficacy and Safety Study to 
Evaluate Relugolix Co-Administered with and without Low-
Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3001 
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): 
EudraCT # 2016-003727-27 
IND # 131161 
Version and 
Effective Date: 
Original:  10-NOV-2016 
Amendment 1:  08-FEB-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. 
MVT-601-3001 CSR - Appendix 16.1.1. Protocol and Protocol Amendments
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Clinical Study Protocol: MVT -601-300 I 
Amendment I, Effective: 08-FEB-2017 
SPONSOR SIGNATURE PAGE 
LIBERTY 1: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy 
and Safety Study to Evaluate Relugolix Co-Administered with and without Low-Dose Estradiol 
and Norethindrone Acetate in Women with Heavy Menstrual Bleeding Associated with Uterine 
Fibroids 
Protocol Number: MVT-601-3001 
This protocol has been approved by Myovant Sciences GmbH. The following signatures 
document this approval. 
Myovant Sciences GmbH 
Date 
Date 
Date 
2 
CONFIDENTIAL 
MVT-601-3001 CSR - Appendix 16.1.1. Protocol and Protocol Amendments
Page 149
PPD

Clinical Study Protocol:  MVT-601-3001 
 
Amendment 1, Effective:  08-FEB-2017 
Myovant Sciences GmbH 
3 
CONFIDENTIAL 
INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
 
Date 
 
Site 
 
 
 
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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 .................................................................................................................................... 8 
LIST OF ABBREVIATIONS .................................................................................................................... 9 
1. 
PROTOCOL SYNOPSIS ............................................................................................................ 11 
1.1. 
Schedule of Activities ................................................................................................................ 21 
2. 
INTRODUCTION ....................................................................................................................... 26 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding ..................................................................... 26 
2.2. 
Relugolix ................................................................................................................................... 27 
2.2.1. 
Indication .......................................................................................................................... 27 
2.2.2. 
Pharmacology ................................................................................................................... 27 
2.2.3. 
Nonclinical Toxicology .................................................................................................... 28 
2.2.4. 
Previous Human Experience ............................................................................................. 29 
3. 
STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 33 
4. 
INVESTIGATIONAL PLAN ..................................................................................................... 35 
4.1. 
Overall Study Design................................................................................................................. 35 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group ......... 39 
4.3. 
Selection of Study Population ................................................................................................... 41 
4.3.1. 
Inclusion Criteria .............................................................................................................. 41 
4.3.2. 
Exclusion Criteria ............................................................................................................. 43 
4.4. 
Screening ................................................................................................................................... 46 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID Number ............................. 46 
4.6. 
Removal of Patients from Therapy ............................................................................................ 46 
4.7. 
Contraception/Pregnancy Avoidance ........................................................................................ 47 
5. 
TREATMENTS ........................................................................................................................... 48 
5.1. 
Treatments Administered .......................................................................................................... 48 
5.2. 
Identity of Investigational Product ............................................................................................ 49 
5.2.1. 
Product Characteristics ..................................................................................................... 49 
5.3. 
Randomization and Stratification .............................................................................................. 50 
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5.4. 
Directions for Administration .................................................................................................... 50 
5.5. 
Dose Reduction/Dose Administration ....................................................................................... 51 
5.6. 
Storage, Packaging, and Labeling ............................................................................................. 51 
5.7. 
Blinding ..................................................................................................................................... 51 
5.8. 
Study Drug Accountability and Treatment Compliance ........................................................... 52 
5.9. 
Treatment after the End of Study .............................................................................................. 52 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies ................................................. 52 
5.10.1. 
Prohibited Medications ..................................................................................................... 52 
5.10.2. 
Permitted Medications ...................................................................................................... 55 
5.10.3. 
Prohibited Non-Drug Therapies ........................................................................................ 55 
6. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 55 
6.1. 
Schedule of Observations and Procedures ................................................................................. 56 
6.2. 
Screening Period ........................................................................................................................ 56 
6.2.1. 
Screening 1 Visit ............................................................................................................... 56 
6.2.2. 
Screening 2 Visit ............................................................................................................... 57 
6.2.3. 
Screening 3 Visit ............................................................................................................... 58 
6.2.4. 
Screening 4 Visit ............................................................................................................... 58 
6.2.5. 
Menstrual Blood Loss Repeat Collection ......................................................................... 58 
6.2.6. 
Re-Screening ..................................................................................................................... 58 
6.3. 
Randomized Treatment Period (Baseline to Week 24) ............................................................. 58 
6.4. 
Continuation into Extension Study ............................................................................................ 59 
6.5. 
Early Termination Visit and Follow-up Visit ............................................................................ 59 
6.6. 
Unscheduled Visits .................................................................................................................... 60 
6.7. 
Study Procedures ....................................................................................................................... 60 
6.7.1. 
Efficacy-Related Procedures ............................................................................................. 60 
6.7.2. 
Safety-Related Procedures ................................................................................................ 63 
Biological Sample Retention and Destruction ........................................................................................ 66 
7. 
SAFETY CONSIDERATIONS .................................................................................................. 67 
7.1. 
Adverse Event Definitions ......................................................................................................... 67 
7.1.1. 
Adverse Event ................................................................................................................... 67 
7.1.2. 
Serious Adverse Event ...................................................................................................... 68 
7.2. 
Adverse Event Reporting........................................................................................................... 69 
7.2.1. 
Adverse Event Reporting Period ...................................................................................... 69 
7.3. 
Assigning Causal Relationship to Study Drug .......................................................................... 70 
7.4. 
Assigning Severity Rating for Adverse Events ......................................................................... 70 
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7.5. 
Adverse Events of Clinical Interest Reporting .......................................................................... 71 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 71 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities ..................................................................................................................................... 72 
7.6. 
Serious Adverse Event Reporting .............................................................................................. 72 
7.7. 
Study Drug Overdose Management .......................................................................................... 73 
7.8. 
Pregnancy Reporting ................................................................................................................. 74 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, Electrocardiograms, and Bone 
Mineral Density Measures ........................................................................................................ 74 
7.10. 
Benefit/Risk Assessment ........................................................................................................... 75 
8. 
DATA QUALITY ASSURANCE ............................................................................................... 77 
8.1. 
Clinical Procedures .................................................................................................................... 77 
8.2. 
Monitoring ................................................................................................................................. 77 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ........................................... 77 
9.1. 
Randomization Methods ............................................................................................................ 78 
9.2. 
Analysis Populations ................................................................................................................. 78 
9.3. 
Efficacy Analyses ...................................................................................................................... 78 
9.3.1. 
Primary Endpoint Analysis ............................................................................................... 79 
9.3.2. 
Secondary Endpoint Analyses .......................................................................................... 79 
9.4. 
Safety Analyses ......................................................................................................................... 81 
9.5. 
Pharmacokinetic Analyses ......................................................................................................... 82 
9.6. 
Exploratory Analyses ................................................................................................................ 82 
9.7. 
Interim Analyses ........................................................................................................................ 82 
10. 
RESPONSIBILITIES .................................................................................................................. 82 
10.1. 
Investigator Responsibilities ...................................................................................................... 82 
10.1.1. 
Good Clinical Practice ...................................................................................................... 82 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ............................. 83 
10.1.3. 
Informed Consent ............................................................................................................. 83 
10.1.4. 
Confidentiality .................................................................................................................. 83 
10.1.5. 
Study Committees and Communication ........................................................................... 84 
10.1.6. 
Study Files and Retention of Records ............................................................................... 84 
10.1.7. 
Electronic Case Report Forms .......................................................................................... 85 
10.1.8. 
Investigational Product Accountability ............................................................................. 85 
10.1.9. 
Inspections ........................................................................................................................ 86 
10.1.10. 
Protocol Compliance ......................................................................................................... 86 
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10.2. 
Sponsor Responsibilities............................................................................................................ 86 
10.2.1. 
Protocol Modifications ..................................................................................................... 86 
10.2.2. 
Study Report ..................................................................................................................... 87 
10.2.3. 
Posting of Information on Publically Available Clinical Trial Registers ......................... 87 
10.3. 
Joint Investigator/Sponsor Responsibilities ............................................................................... 87 
10.3.1. 
Access to Information Monitoring .................................................................................... 87 
10.3.2. 
Access to Information for Auditing or Inspections ........................................................... 87 
10.3.3. 
Study Discontinuation ....................................................................................................... 87 
10.3.4. 
Publications ....................................................................................................................... 87 
REFERENCES .......................................................................................................................................... 89 
APPENDICES ........................................................................................................................................... 91 
Appendix 1. 
Breast Imaging Reporting and Data System (BI-RADS) ............................................. 91 
Appendix 2. 
Daily eDiary ................................................................................................................. 92 
Appendix 3. 
Menorrhagia Impact Questionnaire .............................................................................. 97 
Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire ...................................... 98 
Appendix 5. 
European Quality of Life Five-Dimension Five-Level Scale ..................................... 101 
Appendix 6. 
Assessment of Abnormal Liver Function Tests ......................................................... 103 
 
LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-3001 ............................................................. 21 
Table 5-1 
Description of MVT-601-3001 Study Drugs .................................................................... 49 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization ............................................ 50 
Table 5-3 
Prohibited Medications and Windows of Exclusion Prior to Screening ........................... 52 
Table 6-1 
Clinical Laboratory Tests .................................................................................................. 65 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ......................................................... 71 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies ....................................................... 75 
 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury .................... 103 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............................ 104 
 
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LIST OF FIGURES 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001) ......................... 30 
Figure 4-1 
MVT-601-3001 Study Schematic ..................................................................................... 37 
Figure 4-2 
Schematic of MVT-601-3001 Screening Visit Scenarios ................................................. 38 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
EQ-5D 
European Quality of Life Five-Dimension Five-Level 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
di-22:6-BMP 
di-22:6-bis(monoacylglycerol)phosphate 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EQ-5D 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HDL 
high-density lipoprotein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
Intent-to-Treat (Population) 
IVRS/IWRS 
Interactive Voice/Web Recognition Service 
LFT 
liver function tests 
LH 
luteinizing hormone 
MBL 
menstrual blood loss 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIQ 
Menstrual Impact Questionnaire 
mmHg 
millimeters of mercury 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
PBAC 
Pictorial Blood Loss Assessment Chart 
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Term 
Explanation 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
SD 
standard deviation 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
VAS 
visual analogue score 
WBC 
white blood cells 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
LIBERTY 1:  An International Phase 3 Randomized, Double-Blind, Placebo-
Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered 
with and without Low-Dose Estradiol and Norethindrone Acetate in Women 
with Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number 
MVT-601-3001 
Location 
Multinational, including North and South America, Europe, and Australia 
Study Centers 
Approximately 120 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 50 years diagnosed with heavy menstrual bleeding 
associated with uterine fibroids 
Number of Patients 
Planned 
Approximately 390 (~ 130 relugolix co-administered with low-dose estradiol 
and norethindrone acetate, ~ 130 relugolix monotherapy followed by relugolix 
co-administered with low-dose estradiol and norethindrone acetate, and 
~ 130 placebo) 
Study Objectives 
Primary Efficacy Objective 
• 
To determine the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding associated with uterine 
fibroids. 
 
Secondary Efficacy Objectives 
• 
To determine the benefit of relugolix 40 mg once daily for 12 weeks 
followed by 12 weeks of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate compared with placebo for 
24 weeks on heavy menstrual bleeding associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo for 24 weeks on the 
following: 
o Achievement of amenorrhea; 
o Change in hemoglobin; 
o Impact of heavy menstrual bleeding on social, leisure, and physical 
activities; 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
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Safety Objectives 
• 
To determine the safety of 24 weeks of relugolix 40 mg once daily 
co-administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate in women with heavy menstrual bleeding associated 
with uterine fibroids compared with placebo for 24 weeks; 
• 
To determine the change in bone mineral density of women with heavy 
menstrual bleeding associated with uterine fibroids treated with 24 weeks 
of relugolix 40 mg once daily co-administered with either 12 or 24 weeks 
of low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks. 
 
Pharmacokinetic and Pharmacodynamic Objectives 
• 
To evaluate the pharmacokinetic (PK) and pharmacodynamic effects of 
24 weeks of relugolix 40 mg once daily when co-administered with either 
12 or 24 weeks of low-dose estradiol and norethindrone acetate. 
 
Exploratory Objectives 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo on patient-reported quality 
of life outcome measures. 
Study Design 
This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety 
study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-dose estradiol 
and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
compared with 24 weeks of placebo.  Approximately 390 women with heavy menstrual bleeding 
associated with uterine fibroids will be enrolled and randomized 1:1:1 to the relugolix plus low-dose 
hormonal add-back therapy group (Group A; N ≈ 130), the relugolix monotherapy followed by co-
administration with low-dose hormonal add-back therapy group (Group B; N ≈ 130), or placebo group 
(Group C; N ≈ 130).  Stratification variables will include:  geographic region (North America versus 
Rest of World) and mean screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the 
alkaline hematin method. 
The study consists of a screening period (up to ~13 weeks), a randomized treatment period (24 weeks), 
and a follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) may be arranged for 
patients with study-related safety concerns and as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by centrally-reviewed 
transvaginal (with or without a transabdominal ultrasound).  Heavy menstrual bleeding will be defined 
as menstrual blood loss of ≥ 80 mL per cycle for 2 cycles or ≥ 160 mL during 1 cycle during the 
screening period.  During the randomized treatment period, study participants will take blinded study 
treatment orally once daily for 24 weeks.  Women with iron-deficient microcytic anemia and 
hemoglobin ≥ 8 g/dL and ≤ 10 g/dL at Screening must be treated with oral or parenteral iron 
replacement therapy.  Between the Baseline Day 1 and Week 24 visits, patients will attend visits 
monthly (ie, every 4 weeks).  At the Screening, Week 12, and Week 24 visits, patients will have an 
assessment of bone mineral density with dual-energy x-ray absorptiometry (DXA).  An endometrial 
biopsy will also be performed at Screening.  A transvaginal ultrasound (with or without a 
transabdominal ultrasound) will be performed at Week 24, followed by a repeat endometrial biopsy.  
Patients will have paired baseline and end-of-treatment endometrial biopsies, independent of ultrasound 
results.  Feminine products will be standardized and will be collected and assessed for blood loss by the 
alkaline hematin method.  Complete blood counts and chemistries will be collected monthly and uterine 
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and uterine fibroid volumes will be assessed at the Screening and Week 24 visits.  Patients will 
complete daily electronic diaries (eDiary) including compliance with study treatment, menstrual 
bleeding, use of feminine products for menstrual bleeding, uterine fibroid-associated pain by the 
Numerical Rating Scale, and use of pain medication to treat pain caused by uterine fibroids.  Quality of 
life questionnaires will be completed according to the Schedule of Activities. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, endometrial 
biopsies, and assessments of bone mineral density.  Height will be measured at the Screening 1 visit 
and weight will be measured at specified intervals. 
Samples will be collected for PK assessment of relugolix, estradiol, and norethindrone and for the 
pharmacodynamic assessment of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
estradiol, and progesterone. 
All patients completing the Week 24 visit, including women randomized to placebo, will be offered the 
opportunity to enroll in an open-label extension study in which all eligible patients will receive 
relugolix co-administered with low-dose estradiol and norethindrone acetate.  Patients who do not 
enroll into the extension study will have a follow-up visit approximately 30 days after the end of 
treatment (ie, after the patient’s last dose of study medication). 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization unless otherwise 
specified): 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or 
study-specific procedures; 
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating the 
informed consent form; 
3. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days 
from the start of one menstrual period until the start of the next, by patient history for at least 
3 months prior to the Screening 1 visit; 
4. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal ultrasound performed during 
the screening period; at least one uterine fibroid must be verified by a central reader to meet at 
least one of the following criteria: 
a. Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter ≥ 2 cm 
(longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3 
Note 1:  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.   
Note 2:  Saline or gel contrast is not required, but may be performed to demonstrate fibroids 
that meet the criterion for inclusion if these are not adequately visualized with transvaginal 
ultrasound alone;  
5. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a menstrual blood 
loss of ≥ 160 mL during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the 
alkaline hematin method during the screening period; 
6. Patient is not expected to undergo gynecological surgery or ablation procedures for uterine fibroids 
within the 6 months following enrollment; 
7. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 visits; 
8. Agrees to use two forms of non-hormonal contraception (dual contraception, as described in 
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Section 4.7) consistently during the screening period, and the randomized treatment period.  
However, the patient is not required to use dual contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the screening period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure™), at 
least 4 months prior to the first screening visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram and no evidence of “post-Essure 
syndrome” in the investigator’s opinion); 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires the use of 
dual non-hormonal contraception as noted above; or 
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; periodic abstinence 
is not acceptable; 
9. Has an adequate endometrial (aspiration) biopsy performed during the screening period, with 
results showing no clinically significant endometrial pathology (hyperplasia, polyp, or endometrial 
cancer).  Note:  polyps < 2.0 cm by ultrasound are not excluded; 
10. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram (Breast 
Imaging Reporting and Data System category 1 or 2 or equivalent) during the screening period or 
within 6 months prior to the screening period. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating 
pathology other than uterine fibroids that could be responsible for or contributing to the patient’s 
heavy menstrual bleeding, such as uterine or cervical polyps ≥ 2.0 cm, large simple ovarian cyst 
> 4.0 cm, endometrioma(s) > 4.0 cm, or any other clinically significant gynecological disorder 
determined by the investigator to require further evaluation and/or treatment during the study. 
Note:  Saline or gel contrast is not routinely required.  Use of such contrast is required only when 
the endometrium cannot be evaluated or when there are ambiguous and potentially exclusionary 
findings on the transvaginal or transabdominal ultrasound (eg, suspected intrauterine masses, 
equivocal endometrial findings, etc.); 
2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator; 
3. 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, as well as endometrial ablation for abnormal uterine bleeding 
within 6 months prior to the Screening 1 visit; 
4. Has a weight that exceeds the weight limit of the DXA scanner; 
5. Has a baseline bone mineral density z-score < -2.0 at spine, total hip, or femoral neck; 
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic 
(from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures are 
allowed).  A history of successfully treated hyperparathyroidism, hyperprolactinemia, or 
hyperthyroidism is allowed if the patient’s bone mineral density is within normal limits; 
7. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, 
denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral 
density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of more than 
5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, ophthalmic, 
intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
10. Has any contraindication to treatment with low-dose estradiol and norethindrone acetate, 
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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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A (HAV 
IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical glandular 
cells, atypical endocervical cells, atypical squamous cells favoring high grade.  Of note, patients 
with atypical squamous cells of undetermined significance and low-grade cervical neoplasia may 
be included in the study if high risk human papilloma virus testing is negative or if DNA testing 
for human papilloma virus 16 and 18 is negative;  
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with initial screening hemoglobin results < 8 g/dL may be 
prescribed iron supplements and have their hemoglobin levels retested prior to the Baseline 
Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of normal 
(ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical laboratory testing at either the 
Screening 1 or Screening 2 visit (or > 2.0 x ULN if secondary to Gilbert syndrome or pattern 
consistent with Gilbert syndrome); 
c. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification of Diet in Renal 
Disease method; 
14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina or significant coronary artery disease (ie, > 50% stenosis); 
c. History of congestive heart failure; 
d. History of clinically significant ventricular arrhythmias such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes, or Mobitz II second degree or third degree heart 
block without a permanent pacemaker in place or untreated supraventricular tachycardia (heart 
rate ≥ 120 beats per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury (mmHg) on 
2 repeat measures at least 15 minutes apart, or treated ongoing symptomatic orthostatic 
hypotension with > 20 mmHg decrease in systolic blood pressure one minute or more after 
assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg on 2 repeat 
measures at least 15 minutes apart or diastolic blood pressure > 100 mmHg at any screening 
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visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram unless judged by the investigator to be due to physical fitness; 
15. Has been a participant in an investigational drug or device study within the 1 month prior to 
Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the following: 
a. Untreated thyroid dysfunction or palpable thyroid abnormality (patients with adequately 
treated hypothyroidism who are stable on medication are not excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than curatively 
treated nonmelanoma skin cancer or surgically cured Stage 0 in situ melanoma; 
c. Any current psychiatric disorder that would, in the opinion of the investigator or medical 
monitor, impair the ability of the patient to participate in the study or would impair 
interpretation of their data.  Patients with major depression, post-traumatic stress disorder, 
bipolar disorder, schizophrenia or other psychotic disorders, based on Diagnostic and 
Statistical Manual of Mental Disorders-5 criteria who have been unstable or not well 
controlled based on the investigator’s or mental health professional’s judgement or whose 
history or stability cannot be ascertained, or whose psychiatric drug regimen has changed 
during the 3 months prior to Screening or is expected to change during the study should not be 
enrolled; 
17. Is currently pregnant or lactating, or intends to become pregnant or to donate ova during the study 
period or within 2 months after the last dose of study drug; 
18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable exclusionary 
window periods for these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or medical 
monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse disorder 
according to Diagnostic and Statistical Manual of Mental Disorders V (all patients must be 
questioned about their drug and alcohol use and this should be documented in the electronic case 
report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship with a study 
site employee who is involved in the conduct of this study (eg, spouse, parent, child, or sibling); 
23. Is inappropriate for participation in this study for other reasons, as determined by the investigator 
or sub-investigator or medical monitor. 
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Dose and Route of 
Administration 
Test Product (Group A and Group B) 
• 
Group A:  Relugolix 40 mg tablet will be co-administered orally once 
daily with 1.0 mg estradiol/0.5 mg norethindrone acetate in a co-
formulated tablet.  The low-dose hormonal add-back therapy will be over-
encapsulated. 
• 
Group B:  Relugolix 40 mg tablet co-administered orally once daily with a 
placebo capsule designed to match the over-encapsulated active low-dose 
hormonal add-back therapy in size, shape, and color for 12 weeks, 
followed by relugolix 40 mg tablet co-administered orally once daily with 
1.0 mg estradiol/0.5 mg norethindrone acetate.  The active low-dose 
hormonal add-back therapy will be over-encapsulated. 
Reference Product (Group C) 
• 
Group C:  Placebo relugolix manufactured to match relugolix in size, 
shape, and color will be co-administered orally once daily with a placebo 
capsule designed to match the over-encapsulated active low-dose 
hormonal add-back therapy in size, shape, and color. 
Duration of 
Treatment 
Study treatment will be administered for 24 weeks (randomized treatment 
period).  For women who do not to enroll in an open-label extension study, 
there is a 30-day follow-up period after the end of treatment (ie, after the 
patient’s last dose of study medication). 
Criteria for 
Evaluation 
Inferential efficacy assessments will be made between the following groups 
and placebo after 24 weeks of study treatment: 
• 
Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-
administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• 
Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each 
relugolix group and placebo for safety outcomes and between each of the two 
relugolix groups for both efficacy and safety.  
 
Primary Efficacy Endpoint 
• 
Proportion of women in the relugolix Group A versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
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Secondary Efficacy Endpoints 
• 
Proportion of women in the relugolix Group B versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix 
treatment group to placebo inferentially and relugolix Group A to Group B 
descriptively: 
• 
Time to achieving a menstrual blood loss volume of < 80 mL AND at 
least a 50% reduction from baseline menstrual blood loss volume as 
measured by the alkaline hematin method; 
• 
Change from Baseline to Week 24 in menstrual blood loss; 
• 
Proportion of women who achieve amenorrhea over the last 35days of 
treatment as measured by the alkaline hematin method; 
• 
Time to amenorrhea as measured by the by the alkaline hematin method; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at Baseline who achieve an increase of ≥ 1 g/dL from Baseline at 
Week 24; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for physical activities; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for social and leisure activities; 
• 
Proportion of women who achieve a mean Numerical Rating Scale score 
for uterine fibroid-associated pain over the last 35 days of treatment that is 
at least a 30% reduction from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days prior to randomization; 
• 
Change from Baseline to Week 24 in uterine volume; and 
• 
Change from Baseline to Week 24 in uterine fibroid volume. 
 
Safety Endpoints 
• 
Treatment-emergent adverse events, change in vital signs (including 
weight), clinical laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Weeks 12 and 24 in bone mineral density 
at the spine (average of L1-L4), total hip, and femoral neck as assessed by 
DXA; 
• 
Incidence of vasomotor symptoms. 
 
Pharmacokinetic and Pharmacodynamic Endpoints 
• 
Pre-dose trough concentrations (Cτ) of relugolix, estradiol, and 
norethindrone from Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-dose concentrations of LH, 
FSH, estradiol, and progesterone. 
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Exploratory Endpoints 
• 
Change from Baseline to Week 24 in the Uterine Fibroid Scale – Quality 
of Life Symptom Severity and Health-related Quality of Life subscales 
comparing each relugolix treatment group to placebo inferentially and the 
two relugolix groups descriptively; 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-
Dimension Five-Level scale comparing each relugolix treatment group to 
placebo inferentially and the two relugolix groups descriptively. 
Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) Population defined as all 
randomized patients, unless otherwise specified in the statistical analysis plan.  Randomization will be 
1:1:1 with the stratification variables of geographic region and mean screening menstrual blood loss 
volume (mL per alkaline hematin method) as follows: 
• 
Geographic Region:  North America versus Rest of World; 
• 
Mean screening menstrual blood loss volume:  < 225 mL versus ≥ 225 mL. 
The randomization stratification factors will be incorporated into inferential testing of all efficacy 
endpoints, unless otherwise specified. 
The primary hypothesis tested in this study is whether relugolix co-administered with 1.0 mg estradiol 
and 0.5 mg norethindrone acetate is superior to placebo in the percentage of women who achieve both a 
menstrual blood loss volume of < 80 mL AND at least a 50% reduction in menstrual blood loss volume 
over the last 35 days on treatment as compared with Baseline. 
The point estimate and 2-sided 95% confidence interval of the difference in the proportion will be 
calculated between the relugolix Group A and placebo Group C.  The between-treatment comparisons 
will be performed using the Cochran-Mantel-Haenszel method. 
The comparisons of the relugolix arms versus placebo will be performed for the secondary efficacy and 
safety endpoints using appropriate statistical methods.  Comparisons between the two relugolix arms 
will be descriptive.  A closed testing procedure will be used to control the overall type I error rate of 
5% across primary and secondary endpoint testing.  Details of this procedure will be provided in the 
statistical analysis plan. 
Sample Size 
Assuming a placebo control response rate of 25%, the assessment of the superiority of relugolix 40 mg 
co-administered with low-dose hormonal add-back therapy (Group A) versus placebo (Group C) in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size of 260 (130 
patients in each of the relugolix and placebo arms) will provide > 99% power to detect a difference of 
greater than 30 percentage points using a 2-sided test at significance level of 0.05.  The total sample 
size for the study will be approximately 390 patients (130 patients in each of the 3 arms). 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs, physical examinations, 
clinical laboratory tests, 12-lead electrocardiograms, endometrial biopsies, and assessments of bone 
mineral density.  Safety analyses will be based on all randomized patients who receive any amount of 
study drug (safety population).  Drug exposure will be summarized by descriptive statistics.  Severity 
of all treatment-emergent adverse events will be evaluated by the investigator based on the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) and will be coded to 
preferred term, higher level term, and system organ class using the Medical Dictionary for Regulatory 
Activities (MedDRA).  The number and percentage of patients with adverse events will be presented by 
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MedDRA system organ class and preferred term, relationship to study drug, and severity.  Descriptive 
statistics will be used rather than inferential statistics.  Laboratory values also will be classified by 
toxicity grade based on the National Cancer Institute’s CTCAE.  Laboratory shift tables of the 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), total hip, and femoral neck at the Baseline, Week 12, and Week 
24 visits and the absolute, percent, and standardized changes from baseline will be summarized.  
Vasomotor adverse events will be separately summarized. 
A chartered independent Data and Safety Monitoring Board will monitor all available safety data, 
including bone density assessments, on an ongoing basis during this study. 
Pharmacokinetics and Pharmacodynamics 
The PK concentration data (relugolix, estradiol, and norethindrone pre-dose) and pharmacodynamics 
concentration data (LH, FSH, estradiol, and progesterone pre-dose) will be listed and summarized by 
treatment arm and visit.  In addition, the PK data from this study will be combined with PK data from 
other studies to define a population PK model, which will be reported separately.  Exposure-response 
analyses of the primary efficacy endpoint and safety will be conducted to assess the effect of relugolix 
exposure on outcomes. 
 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3001 
 
SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upf 
(~30 days 
after last 
dose of 
study 
drug) 
Day of Study Drug 
Treatment 
 
 
 
 
1 
29 
57 
85 
113 
141 
169 
 
197 
Visit Window Timing (days) 
 
Within 5 
(+2) days 
after com-
pletion of 
Screening 
1 menses 
Within 
≤ 15 days 
after 
Screening 
2 visit 
Within 5 
(+2) days 
after com-
pletion of 
2nd 
Screening 
menses 
Within 
7 days of 
the start of 
menses 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
 
-3 to + 10 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe  
X 
Waist circumference 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
 
 
X 
Xe  
X 
Temperature 
X 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
Adverse Event Collectiong 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Acuityh 
 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upf 
(~30 days 
after last 
dose of 
study 
drug) 
Complete Physical excluding 
GYN Examination 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
GYN Examination with Pap 
Test, if applicable 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Signs and Symptoms-Directed
Physical Exam 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
Xe 
X 
12-Lead Electrocardiogram 
 
 
X 
 
X 
 
 
X 
 
 
X 
Xe 
X 
Clinical Laboratory Testsj 
X 
X 
 
 
Xk 
X 
X 
X 
X 
X 
Xl 
Xe 
X 
PK Samplem 
 
 
 
 
X 
X 
 
X 
 
 
X 
Xe 
 
PD Samplen  
 
 
 
 
X 
X 
 
X 
 
 
X 
Xe 
X 
Daily Study Drug 
Administration 
 
 
 
 
X 
Xe 
 
Administer Dose of Study 
Drug in Clinic  
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
PGx Sampleo 
 
 
 
 
X 
 
 
 
 
 
 
Xe 
 
Pregnancy Test (Urine) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
 
 
 
Xe 
 
Mammogramp 
schedule 
X  
 
 
 
 
 
 
 
 
 
 
Transvaginal Ultrasound 
(with or without 
Transabdominal Ultrasound)q 
X 
 
 
 
 
 
 
 
 
 
Xs 
Xe 
 
Endometrial Biopsyr 
X 
 
 
 
 
 
 
 
 
 
Xs 
Xe 
 
Bone Densitometryt 
schedule 
X 
 
 
 
 
X 
 
 
Xs 
Xe 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Feminine Products 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
(Skip if 
MBL ≥ 
160 mL at 
1st 
Screening 
menses) 
Baseline 
Day 1d 
(if MBL is 
≥ 80 mL in 
2 cycles or 
≥ 160 mL 
in 1 cycle  
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upf 
(~30 days 
after last 
dose of 
study 
drug) 
Dispense Study Treatment 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Xe 
 
Patient paper diary/ eDiaryu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
Feminine Product Collection 
and Venous Blood Samplev 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Xe 
 
MIQ 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xe 
 
UFS-QoL 
 
 
 
 
X 
 
 
X 
 
 
X 
Xe 
 
EQ-5D 
 
 
 
 
X 
 
 
 
 
 
X 
Xe 
 
Treatment Compliance 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Xe 
 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Notes: 
Abbreviations:  EQ-5D, European Quality of Life Five-Dimension Five-Level Scale; MBL, menstrual blood loss; MIQ, Menorrhagia Impact Questionnaire; Pap, 
Papanicolaou; PD, pharmacodynamics; PGx, pharmacogenomics; PK, pharmacokinetics; GYN, gynecology; UFS-QoL, Uterine Fibroid Symptom and Health-
Related Quality of Life 
For patients who are re-screening, please see Section 6.2.6 for abbreviated screening procedures. 
 
a. 
The screening period should be initiated after the informed consent form is signed and any exclusionary windows for prohibited medications has been 
confirmed. 
b. Visit to occur within 5 (+2) days of the completion of menses.  Visit 4 should be skipped if the menstrual blood loss is > 160 mL in the first screening cycle. 
c. 
Visit to occur within ≤ 15 days after Screening 2 visit; eDiary dispensation must occur at least 7 days prior to Baseline Day 1.  The alkaline hematin 
menstrual blood loss collection may be repeated once at the discretion of the investigator if one menstrual cycle does not meet menstrual blood loss criteria 
thought to be due to inadequate collection for a highly motivated patient. 
d. The Baseline Day 1 visit should occur within 7 days of the onset of menses.  Collect clinical laboratory, PK sample, pre-dose pharmacodynamic sample, 
pregnancy and urinalysis test samples prior to first dose of study drug.  The patient must complete MIQ, UFS-QoL, and EQ-5D questionnaires prior other 
study procedures and prior to first dose of study drug. 
e. 
For an Unscheduled visit, these procedures will be performed as needed, based on the reason(s) for the Unscheduled visit. 
f. 
Follow-up visit:  For women who do not continue into the open-label extension study (MVT-601-3003) and/or terminate early from the study, a follow-up 
visit to assess safety will be scheduled approximately 30 days after the last dose of study drug, or prior to the date of initiation of another investigational 
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agent or hormonal therapy affecting the hypothalamic-pituitary-gonadal axis or surgical intervention for uterine fibroids, whichever occurs first (ie, ~Week 
28 for patients who complete the study or ~4 weeks after an Early Termination visit). 
g. Collect serious adverse event information from the time of signed informed consent 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.  Collect nonserious adverse event information from the Baseline Day 1 visit (or from the time of signed informed consent if 
event was related to a screening study procedure) through approximately 30 days after the last dose of 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. 
h. Visual acuity must be assessed with the study eye chart.  The patient should wear any prescription glasses or contacts during the assessment. 
i. 
Papanicolaou test must be conducted for women without a test result within 6 months prior to the Screening 1 visit.  The specimen should be submitted to 
the central laboratory during screening.  Another test should be performed for inadequate or false-positive results and be submitted to the central laboratory.  
j. 
Clinical laboratory tests at each visit include clinical chemistries and a complete blood count.  Samples should be obtained in the fasted state (no food or 
drink other than water after midnight) for the Baseline and Week 24 visit clinical laboratory tests. 
k. At the Baseline Day 1 visit, obtain clinical laboratory tests after an overnight fast (other than water) of at least 8 hours.  In addition to clinical chemistries 
and a complete blood count, include a lipid profile, levels of parathyroid hormone, thyroid-stimulating hormone, prolactin, Vitamin D, iron, ferritin, and 
hemoglobin A1c.  An additional sample will be collected at this visit in all patients and stored for possible future testing for presence of hepatitis A, B, and C 
if required per request from medical monitor to assess etiology of liver test abnormalities. 
l. 
At the Week 24 visit or Early Termination visit, obtain clinical laboratory tests after an overnight fast (other than water) of at least 8 hours.  In addition to 
clinical chemistries and a complete blood count, include a lipid profile, thyroid-stimulating hormone, prolactin, and hemoglobin A1c. 
m. Pharmacokinetics samples:  Samples should be obtained in the fasted state since study drug is administered on an empty stomach (see Section 5.4).  Collect 
pre-dose samples for PK analysis of relugolix, estradiol (PK lab), and norethindrone.  Instruct the patient not to take her study treatment at home on these 
visit days and to record the time of her previous dose (ie, the dose taken the day before the visit).  Administer study drug after PK and pharmacodynamics 
sample collections are complete. 
n. Pharmacodynamic samples:  Samples should be obtained in the fasted state since study drug is administered on an empty stomach (see Section 5.4).  Collect 
pre-dose samples for analysis of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations.  Administer study drug after 
PK and pharmacodynamic sample collections are complete (with the exception of Early Termination and Follow Up visits when no dose is administered). 
o. Pharmacogenomics sample:  a separate pharmacogenomics consent is required before this sample may be collected.  If possible, the pharmacogenomic 
sample should be collected from consented patients at the Baseline Day 1 visit, but it may be collected at any time during the study through Week 24 
(inclusive) 
p. Patients ≥ 39 years of age at the time of the anticipated Baseline Day 1 visit must have a normal mammogram (Breast Imaging Reporting and Data System 
category 1 or 2 or equivalent) during the screening period or within 6 months prior to the screening period; if not, schedule at the Screening 1 visit. 
q. Transvaginal ultrasound with or without transabdominal ultrasound must be performed to confirm the presence of uterine fibroids and the absence of any 
other pathology that might be responsible for the increase in menstrual bleeding, such as uterine or cervical polyps ≥ 2.0 cm, large simple ovarian cyst > 4.0 
cm, endometrioma(s) > 4.0 cm.  Results must be submitted to and uterine fibroid criteria confirmed by a central reader prior to randomization into the study.  
Note:  Transvaginal ultrasound is required.  See inclusion criterion #5 and exclusion criterion #1 for guidance as to when to perform a transabdominal 
ultrasound and saline or gel contrast.  If saline or gel contrast is performed at Screening, it should also be performed at Week 24. 
r. 
Obtain sample with a pipelle.  Endometrial biopsy is performed at Screening 1 visit and Week 24 Visit and submitted to the central laboratory.   
s. 
Procedure not required at the Early Termination Visit in patients whose last dose of study drug was during Week 6 or earlier.  The procedure may be done if 
it will aid in the evaluation of an ongoing adverse event  
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t. 
Bone densitometry (L1-L4, total hip, femoral neck) will be assessed during the screening period and the central results will be available prior to 
randomization.  Schedule the test at or shortly after the Screening 1 visit.  Bone densitometry should be completed prior to the Screening 3 visit and as early 
as possible to ensure results are available prior to randomization. 
u. Patient paper diary:  Patients enter diary information on menstruation status and feminine product use starting with Screening 1 visit and ending when they 
receive their eDiary at the Screening 3 visit.  Patient eDiary:  Ensure that eDiary data collection begins at least 7 days prior to Day 1.  Patients enter eDiary 
information on a daily basis for their compliance with (study treatment starting at Baseline/Day 1), menstrual bleeding and use of feminine products for 
menstrual bleeding, uterine fibroid-associated pain by the Numerical Rating Scale, and use of pain medications (analgesics) starting at Screening 3 visit and 
compliance with study treatment starting at Baseline/Day 1 through Week 24 or Early Termination. 
v. Hemoglobin:  a venous blood sample must be collected each time feminine products are collected to be sent to the central laboratory conducting the alkaline 
hematin assessment. 
 
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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. 
Combined hormonal contraceptives and progestational agents are commonly prescribed to 
regulate abnormal uterine bleeding, but appear to have limited efficacy in the treatment of 
uterine fibroids [Carr, 1993].  Although no randomized studies evaluating the use of 
levonorgestrel-releasing intrauterine system devices for the treatment of heavy menstrual 
bleeding related to uterine fibroids have been conducted, observational studies have reported a 
reduction in uterine volume and bleeding and this system is approved for use by the United 
States (US) Food and Drug Administration (FDA). 
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 
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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, non-steroidal anti-inflammatory medications, and danazol. 
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 250,000 hysterectomies are performed in the US for uterine fibroids.  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 United States 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 
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 (also known as TAK-385) is an orally-active, potent, highly-selective high-affinity 
small molecule GnRH receptor antagonist with a novel structure.  Relugolix was discovered and 
initially studied by Takeda Pharmaceutical Company, Limited, before development rights 
outside of Japan and certain East Asian countries were licensed to Myovant Sciences GmbH. 
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Relugolix antagonizes 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 
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. 
2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level (NOEL) for liver findings in the 39-week 
monkey toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (AUC) in women receiving 
40 mg once daily (0.101 μg⋅hr/mL), the dose of relugolix to be administered in this study.  Both 
the liver and PLD findings demonstrated evidence of reversibility following a 13-week recovery 
period in monkeys.  No evidence of PLD has been observed in clinical studies.  The relugolix 
toxicology program supports the conduct of clinical studies up to the NOAEL (15 mg/kg/day) 
exposure (5.2 μg⋅hr/mL) for liver toxicity in monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥ 100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
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2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and 3 phase 2 studies (including 1 in women with 
uterine fibroids and 1 in women with endometriosis) have been completed.  In addition, 6 
clinical studies evaluating relugolix are ongoing, including 2 phase 1 studies, 2 phase 2 studies in 
men with prostate cancer (US and Europe), and 2 phase 3 studies in women with uterine fibroids 
in Japan.  More than 1380 patients and healthy volunteers have received at least 1 dose of 
relugolix, including 158 women receiving relugolix 40 mg once daily (the proposed phase 3 
dose) for at least 28 days and at least 200 men receiving relugolix at doses of 80 mg or 120 mg 
once daily for at least 24 weeks and for as long as 48 weeks.  Eighty-eight women have been 
treated with relugolix 40 mg once daily for 24 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of estradiol in female subjects and testosterone in male subjects.  After oral 
administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The pharmacokinetics (PK) and pharmacodynamics of relugolix have 
been evaluated, and appear to be similar in American and Japanese volunteers, despite the lower 
mean body mass index observed in Japanese volunteers. 
A phase 1 study (TAK-385_101) in healthy US premenopausal women demonstrated the 
tolerability of single doses of relugolix 1 to 80 mg, and once-daily dosing of relugolix at 10, 20, 
and 40 mg for 2 weeks.  Plasma concentrations of relugolix increased in a slightly greater than 
dose-proportional manner.  Suppression of serum estradiol was similar after single doses of 40 or 
80 mg once daily relugolix.  The serum concentrations of LH, FSH, estradiol, and progesterone 
rapidly decreased and remained at low levels with multiple doses of relugolix with the majority 
of women having estradiol levels < 10 pg/mL in the 40-mg dose group.  Based on these hormone 
reductions, oral relugolix 40 mg once daily was chosen as the high dose for further study in 
phase 2. 
A 6-week phase 1 study (MVT-601-1001) in healthy US premenopausal women was conducted 
to evaluate the safety, PK, and pharmacodynamics profile of oral relugolix 40 mg once daily and 
relugolix 40 mg once daily in combination with estradiol/norethindrone acetate (1 mg/0.5 mg 
once daily).  Median pre-dose trough concentrations of estradiol in the relugolix alone arm were 
~6 pg/mL; with the addition of 1 mg estradiol once daily, these were increased to ~26 pg/mL, 
and median peak concentrations were ~45 pg/mL.  This trough and peak concentration range is 
consistent with the estradiol range associated with reduced loss of bone mineral density 
[Barbieri, 1992].  Relugolix PK and norethindrone acetate PK were similar to historic data.  The 
estrogenic metabolite of norethindrone, ethinyl estradiol, was below the limit of quantitation in 
almost all PK samples collected.  The adverse event profile was similar to prior phase 1 studies, 
with a marked reduction in hot flushes noted in the relugolix plus hormonal add-back therapy in 
comparison with the relugolix alone arm. 
Relugolix is to be administered in the fasted state, as food decreases the extent of relugolix 
absorption (AUC) by approximately 19%.  The exposure of relugolix is increased by inhibitors 
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of P-glycoprotein (P-gp) up to 6-fold, but relugolix does not significantly impact the exposure of 
cytochrome P450 1A2, 2C9, 2D6, or 3A4 substrates.  In a dedicated study, relugolix did not 
prolong the corrected (QTc) interval. 
2.2.4.2. 
Clinical Studies in Women with Uterine Fibroids or Endometriosis and Men with 
Prostate Cancer 
A phase 2 study (TAK-385/CCT-001) evaluated the efficacy, safety, PK, and pharmacodynamics 
of relugolix 10, 20, and 40 mg once daily for 12 weeks in 216 Japanese women with uterine 
fibroids and heavy menstrual bleeding.  Heavy menstrual bleeding was defined for enrollment 
into the study as a score on the Pictorial Blood Loss Assessment Chart (PBAC) of at least 120; 
uterine fibroids were confirmed by ultrasound, magnetic resonance imaging, computed 
tomography, or laparoscopy.  For the primary endpoint (proportion of patients with a total PBAC 
score of < 10 from Week 6 to 12), statistically significant dose-dependent differences were 
observed in all relugolix treatment groups compared to placebo (Figure 2-1).  The proportion 
was higher in the relugolix 40 mg group (83.6%) compared with 0% in the placebo group 
(p < 0.0001).  In the relugolix 20 mg group, 43.6% of women responded and in the 10 mg group 
20.8% responded, demonstrating a dose-response relationship.  Of the women in the relugolix 
40 mg group, 72.7% achieved amenorrhea from Week 6 to Week 12.  Similarly, improvement 
with increasing dose was also observed in the secondary endpoints including change in myoma 
and uterine volumes and blood concentration of hemoglobin. 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001) 
 
Notes:  Data shown is Pictorial Blood Loss Assessment Chart (PBAC) method of assessing blood loss during Week 
6 to Week 12.  Primary endpoint is proportion of patients with PBAC score < 10. 
Statistically significant difference with p < 0.001 observed for each relugolix treatment arm versus placebo. 
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In the phase 2 uterine fibroid study, the most common treatment-emergent adverse events 
(occurring > 10% in any treatment group and more than placebo) were hot flush, metrorrhagia, 
menorrhagia, headache, genital hemorrhage, menstruation irregular and nasopharyngitis.  With 
the exception of the incidence of nasopharyngitis in all treatment groups, these common adverse 
events were thought to be caused by the pharmacological effect of relugolix.  The adverse events 
associated with menstruation were primarily reported in the first 28 days.  Most of the adverse 
events were mild or moderate, and no serious treatment-emergent adverse event considered 
related to study drug was observed.  Adverse events resulted in study drug discontinuation in 2 
patients (hemoglobin decreased in a placebo patient and tinnitus, libido decreased, menopausal 
depression and hyperhidrosis in one patient treated with relugolix 20 mg once daily).  Bone 
mineral density decreases appeared to correlate with increasing doses of relugolix.  Women 
treated with placebo for 12 weeks had a mild loss of bone mineral density (mean ± standard 
deviation [SD]) of -0.24 ± 2.218% compared with -0.75 ± 2.350%, -2.01 ± 2.334%, and -2.28 ± 
2.194% in the relugolix 10, 20, and 40 mg once daily groups, respectively.  One patient had a 
positive pregnancy test after receiving approximately 46 days of relugolix 10 mg once daily (a 
dose that does not fully suppress estradiol).  Study drug was discontinued.  An ultrasound 
determined that the patient was 7 weeks pregnant.  The patient subsequently had an uneventful 
pregnancy and delivered a healthy infant at 39 weeks. 
In a phase 2 study of women with endometriosis (TAK-385/CCT-101), 487 women were 
randomized to relugolix doses of 10, 20, or 40 mg or placebo, administered orally once daily 
over a 12-week period, or to leuprolide acetate (every 4-week injection) administered for 
12 weeks.  The study demonstrated dose-dependent decreases in pelvic pain as assessed by a 
100 mm visual analogue score (VAS).  The pain scores for pelvic pain were well-balanced across 
the groups at baseline and the means ranged from 14.6 to 15.6 mm.  The changes from baseline 
in the VAS score (mean ± SD) were -10.418 ± 11.0171 mm in the relugolix 40 mg group vs. -
3.753 ± 10.5018 mm in the placebo group (p < 0.0001).  All doses were better than placebo, with 
the greatest benefit observed at the highest dose evaluated, 40 mg once daily.  The decrease in 
mean VAS pain score for the leuprolide group (-10.460 ± 10.3013 mm) was similar to that of the 
relugolix 40 mg group.  The effects of relugolix on pain were maintained following an additional 
12 weeks of treatment in the extension study (total of 24 weeks).  Estradiol levels were 
suppressed for the duration of the study. 
In the 12-week phase 2 endometriosis study (CCT-101) and the companion 12-week extension 
study (OCT-101; total of 24 weeks of treatment), the safety profile of the relugolix 40 mg once 
daily dose was comparable to that of leuprolide treatment.  The most commonly reported 
treatment-emergent adverse events in the relugolix groups than in the placebo group included hot 
flush, metrorrhagia, and menstruation irregular, and were considered to be due to the 
pharmacological effects of relugolix.  The events of menstrual bleeding were primarily reported 
in the first 28 days.  Bone mineral density changes from baseline (mean ± standard deviation 
[SD]) observed after 24 weeks of treatment were -0.23 ± 1.986% in the placebo group, -1.61 ± 
2.338%, -2.58 ± 2.936%, and -4.90 ± 2.912% in the relugolix 10, 20, and 40 mg groups 
respectively, and -4.43 ± 2.157% in the leuprolide group.  Bone mineral density changes from 
baseline in the relugolix 40 mg group at 12 and 24 weeks were comparable to those in the 
leuprolide group for the same durations.  Two patients had liver test abnormalities considered 
study drug-related by the investigator and that resulted in discontinuation of study drug. 
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Two phase 3 studies evaluating relugolix in women with uterine fibroids are ongoing in Japan.  
One study is assessing the effect of relugolix in women with moderate to severe pain associated 
with uterine fibroids, and the other is evaluating women with heavy menstrual bleeding 
associated with uterine fibroids.  Data from these ongoing studies are not available. 
Two phase 2 clinical studies of relugolix (C27002 and C27003) in men with advanced prostate 
cancer requiring androgen deprivation therapy were initiated in North America in 2014.  Study 
C27002, which remains ongoing, enrolled patients with advanced prostate cancer.  In this open-
label, parallel group study, men were randomized to receive oral relugolix at a dose of 80 mg or 
120 mg once daily after a single oral loading dose of 320 mg (N = 50 in each arm) or to the 
GnRH agonist therapy, leuprolide acetate, 22.5 mg administered subcutaneously every 12 weeks, 
(N = 25) for up to 48 weeks.  Study C27003, in which the last clinical study visits have been 
completed, enrolled men in North America or the United Kingdom requiring six months of 
androgen deprivation therapy as neoadjuvant and adjuvant therapy to external beam radiation 
therapy.  Patients were randomized to relugolix 120 mg once daily (after a single oral loading 
dose of 320 mg) (N = 65) or to degarelix 80 mg subcutaneously every four weeks (N = 38) for 
24 weeks (after a single loading dose of 240 mg).  Results from the C27002 final analysis 
demonstrated that both doses of oral relugolix, 80 mg and 120 mg once daily, rapidly reduced 
testosterone levels below the castration threshold (≤ 50 ng/dL) and maintained these levels 
through at least 24 weeks.  These 24-week data were comparable to testosterone levels achieved 
by leuprolide 22.5 mg administered by injection every 3 months.  Study C27003 also 
demonstrated rapid and sustained suppression of testosterone levels by relugolix for the 24-week 
treatment duration. 
In an interim analysis of the phase 2 prostate cancer study C27002, the most common treatment-
emergent adverse events occurring in at least 10% of men with advanced prostate cancer in the 
relugolix 80 mg or 120 mg once daily arms or leuprolide arm included hot flush, alanine 
aminotransferase increase, fatigue, aspartate aminotransferase, diabetes mellitus, hyperhidrosis, 
muscle spasm, injection site reaction, and frequent daytime urination.  The common adverse 
events observed with relugolix in men with prostate cancer were generally consistent with its 
mechanism of action and those observed with leuprolide.  A biomarker for PLD, di-22:6-
bis(monoacylglycerol)phosphate (di-22:6-BMP), was monitored in this study due to findings of 
PLD in nonclinical toxicity studies.  There were no systematic increases in post-baseline serum 
or urinary di-22:6-BMP levels and no changes exceeding 2-fold observed in any patients. 
No clinical evidence of relugolix-related PLD-associated toxicity has been observed regarding 
the heart, liver, central nervous system, or muscle in any clinical study. 
Relugolix has been generally well tolerated.  The serious identified risk associated with relugolix 
treatment is loss of bone mineral density in women.  Nonserious adverse events related to 
relugolix class effects include hot flush and headache in both sexes; reproductive system events 
(abnormal uterine bleeding, genital hemorrhage, menorrhagia or heavy menstrual bleeding, 
menstruation irregular, and oligomenorrhea), arthralgia, and hyperhidrosis in women with 
uterine fibroids or endometriosis; and vision blurred, hepatic enzyme increased, libido decreased, 
and anxiety in men. 
More detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Investigator Brochure, along with a full discussion of the safety profile of relugolix. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Inferential efficacy assessments will be made between the following groups and placebo 
Group C after 24 weeks of study treatment: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with 
1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each relugolix group (Group A 
and Group B) and placebo (Group C) for safety outcomes and between each of the two relugolix 
groups for both efficacy and safety. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on heavy 
menstrual bleeding associated with uterine 
fibroids. 
• 
Proportion of women in the relugolix 
Group A versus the placebo Group C who 
achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
baseline menstrual blood loss volume over 
the last 35days of treatment, as measured by 
the alkaline hematin method. 
Secondary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily for 12 weeks followed by 12 
weeks of relugolix 40 mg once daily co-
administered with low-dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding 
associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on the following: 
o Achievement of amenorrhea; 
o Change in hemoglobin; 
o Impact of heavy menstrual bleeding on 
social, leisure, and physical activities; 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
• 
Proportion of women in the relugolix 
Group B versus the placebo Group C who 
achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
baseline menstrual blood loss volume over 
the last 35 days of treatment, as measured by 
the alkaline hematin method. 
The following secondary endpoints will be 
assessed comparing each relugolix treatment 
group to placebo inferentially and relugolix 
Group A to Group B descriptively: 
• 
Time to achieving a menstrual blood loss 
volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss 
volume as measured by the alkaline hematin 
method; 
• 
Change from Baseline to Week 24 in 
menstrual blood loss; 
• 
Proportion of women who achieve 
amenorrhea over the last 35 days of treatment 
as measured by the alkaline hematin method; 
• 
Time to amenorrhea as measured by the by 
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Objective(s) 
Endpoint(s) 
the alkaline hematin method; 
• 
Proportion of women with a hemoglobin 
below the lower limit of normal at Baseline 
who achieve an increase of ≥ 1 g/dL from 
Baseline at Week 24; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
physical activities; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• 
Proportion of women who achieve a mean 
Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days 
of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• 
Change from Baseline to Week 24 in uterine 
volume; and 
• 
Change from Baseline to Week 24 in uterine 
fibroid volume. 
Safety 
• 
To determine the safety of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate in women 
with heavy menstrual bleeding associated 
with uterine fibroids compared with placebo 
for 24 weeks; 
• 
To determine the change in bone mineral 
density of women with heavy menstrual 
bleeding associated with uterine fibroids 
treated with 24 weeks of relugolix 40 mg 
once daily co-administered with either 12 or 
24 weeks of low dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks. 
• 
Treatment-emergent adverse events, change 
in vital signs (including weight), clinical 
laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Weeks 12 
and 24 in bone mineral density at the spine 
(average of L1-L4), total hip, and femoral 
neck as assessed by DXA; 
• 
Incidence of vasomotor symptoms. 
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Objective(s) 
Endpoint(s) 
Pharmacokinetic and Pharmacodynamic 
• 
To evaluate the pharmacokinetic (PK) and 
pharmacodynamic effects of 24 weeks of 
relugolix 40 mg once daily when co-
administered with either 12 or 24 weeks of 
low-dose estradiol and norethindrone acetate. 
• 
Pre-dose trough concentrations (Cτ) of 
relugolix, estradiol, and norethindrone from 
Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-
dose concentrations of LH, FSH, estradiol, 
and progesterone. 
Exploratory 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo on patient-reported quality of 
life outcome measures. 
• 
Change from Baseline to Week 24 in the 
Uterine Fibroid Scale – Quality of Life 
Symptom Severity and Health-related 
Quality of Life subscales comparing each 
relugolix treatment group to placebo 
inferentially and the two relugolix groups 
descriptively; 
• 
Change from Baseline to Week 24 in the 
European Quality of Life Five-Dimension 
Five-Level scale comparing each relugolix 
treatment group to placebo inferentially and 
the two relugolix groups descriptively. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and 
safety study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate compared with 24 weeks of placebo.  Approximately 
390 women with heavy menstrual bleeding associated with uterine fibroids will be enrolled and 
randomized 1:1:1 to the relugolix plus low-dose hormonal add-back therapy group (Group A; 
N ≈ 130), the relugolix monotherapy followed by co-administration with low-dose hormonal 
add-back therapy group (Group B; N ≈ 130), or the placebo group (Group C; N ≈ 130).  
Stratification variables will include:  geographic region (North America versus Rest of World) 
and mean screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the alkaline 
hematin method. 
The study consists of a screening period (up to ~13 weeks), a randomized treatment period 
(24 weeks), and a follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) 
may be arranged for patients with study-related safety concerns and as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by a centrally-
reviewed transvaginal ultrasound (with or without a transabdominal ultrasound).  Heavy 
menstrual bleeding will be defined as menstrual blood loss of ≥ 80 mL per cycle for 2 cycles or 
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> 160 mL for 1 cycle collected during the screening period.  During the randomized treatment 
period, study participants will take blinded study drug orally once daily for 24 weeks.  Women 
with iron-deficient microcytic anemia with a hemoglobin ≤ 10 g/dL at Screening must be treated 
with oral or parenteral iron replacement therapy.  Between the Baseline and Week 24 visits, 
patients will attend visits monthly (ie, every 4 weeks).  At the Screening, Week 12, and Week 24 
visits, patients will have an assessment of bone mineral density with dual-energy x-ray 
absorptiometry (DXA).  An endometrial biopsy will also be performed at the Screening visit.  A 
transvaginal ultrasound (with or without a transabdominal ultrasound) will be performed at Week 
24, followed by a repeat endometrial biopsy.  Feminine products will be standardized and will be 
collected and assessed for blood loss by the alkaline hematin method.  Complete blood counts 
and chemistries will be collected monthly and uterine and uterine fibroid volumes will be 
assessed at the Screening and Week 24 visits.  Patients will complete daily electronic diaries 
(eDiary) including compliance with study treatment, menstrual bleeding, use of feminine 
products for menstrual bleeding, uterine fibroid-associated pain by the Numerical Rating Scale, 
and use of pain medication to treat pain caused by uterine fibroids.  Quality of life questionnaires 
will be completed according to the Schedule of Activities. 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, 
endometrial biopsies, and assessments of bone mineral density.  Samples will also be collected 
for PK assessment of relugolix, estradiol, and norethindrone, and for the pharmacodynamic 
assessment of LH, FSH, estradiol, and progesterone. 
All patients completing the Week 24 visit, including women randomized to placebo, will be 
offered the opportunity to enroll in an open-label extension study in which all eligible patients 
will receive relugolix co-administered with low-dose estradiol and norethindrone acetate.  
Patients who do not enroll into the extension study will have a follow-up visit to assess safety 
approximately 30 days after the end of treatment (ie, after the patient’s last dose of study 
medication). 
A schematic of the overall study design is provided as Figure 4-1.  Details of the screening 
period visits are provided in Figure 4-2. 
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Figure 4-1 
MVT-601-3001 Study Schematic 
 
 
 
Screening 
UF confirmed 
by ultrasound 
280mlper 
cycle for 2 
cycles or 2 160 
ml for 1 cycle 
I 
I 
I 
Baseline Visit 
I 
I 
I 
I 
I 
I 
I 
I 
I 
U/S 
EMB 
DXA 
Baseline 
Week4 
Screening 
Period 
UF: Uterine Fibroids 
EM S: Endom et rial Biopsy 
U/S: Transvagina l and/ or Tra nsabdominal Ultrasound 
DXA: Duai·Energy X·Ray Absorpt iometry 
On-Treatment Visits 
(Wee k 4 Visit, Week 8 Visit, etc.) 
Week 8 
Week 12 
Week 16 
Randomized Treatment Period 
24 weeks 
Week 24 Visit 
\ II • • 
Follow-up Visit 
(Safety follow-up 
for pat ients w ho 
do not enroll in 
extension study) 
Week 20 
Week24 
days 
Open-Label 
24 weeks 
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Figure 4-2 
Schematic of MVT-601-3001 Screening Visit Scenarios  
 
Figure 4-2 
Screening visit 1 may be conducted at any time during the pre-screening cycle. 
Top scenario: 
• 
Eligibility is based on 2 consecutive screening cycles, each with > 80 mL of menstrual blood loss 
assessed by the alkaline hematin method where the first screening cycle menstrual blood loss is 
also < 160 mL. 
Bottom scenario: 
• 
Eligibility is based on first screening cycle with > 160 mL menstrual blood loss assessed by the 
alkaline hematin method. 
• 
Patients whose first screening cycle MBL is < 80 mL and whose second screening cycle 
menstrual blood loss is > 160 mL will follow the bottom scenario visit schedule. 
Additional Scenarios (not depicted): 
• 
Patients whose first screening cycle menstrual blood loss is < 80 mL and whose second screening 
menstrual blood loss is > 80 mL but < 160 mL may collect menstrual blood loss during a third 
screening cycle if the first collection was believed to be inadequate in a highly motivated patient. 
• 
Patients whose first screening cycle menstrual blood loss is > 80 mL but < 160 mL and whose 
second screening menstrual blood loss is < 80 mL may collect menstrual blood loss during a third 
screening cycle if the second collection was believed to be inadequate in a highly motivated 
patient. 
• 
Patients whose first screening cycle menstrual blood loss is < 80 mL may collect menstrual blood 
loss during a second cycle if the first collection was believed to be inadequate in a highly 
motivated patient.  If the second screening menstrual blood loss is ≥ 160 mL, the patient should 
follow the top scenario visit schedule. 
 
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4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control 
Group 
This phase 3 study is one of two replicate studies designed to establish the efficacy and safety of 
relugolix 40 mg once daily in women with heavy menstrual bleeding associated with uterine 
fibroids.  This study will focus on the primary objective of demonstrating a reduction in heavy 
menstrual bleeding, the most common and burdensome symptom of uterine fibroids.  The study 
is designed to demonstrate the benefit and safety of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate (0.5 mg) for 24 weeks.  An additional relugolix arm 
dosed with 12 weeks of relugolix monotherapy 40 mg once daily followed by 12 weeks of 
relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
will be used to provide an assessment of the requirement for the low-dose hormonal add-back 
therapy to mitigate the adverse effects of relugolix monotherapy on bone mineral density loss 
and vasomotor symptoms.  An extension study is planned to provide additional safety and 
efficacy data through 48 weeks. 
Women with uterine fibroids and heavy menstrual blood loss by the alkaline hematin method of 
≥ 80 mL/cycle for two cycles or ≥ 160 mL in one cycle during screening will be enrolled in this 
study.  Randomization will be 1:1:1.  Placebo was selected as the appropriate control for the 
study because there is no standard of care medical therapy for the long-term treatment of women 
with uterine fibroids and heavy menstrual bleeding.  Commonly-used treatment options range 
from combined oral contraceptive pills, which are not effective in many cases, levonorgestrel-
containing intrauterine devices, and leuprolide therapy indicated for 3 months in the preoperative 
setting. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  This dose was selected for 
evaluation in phase 2 clinical studies based upon phase 1 data demonstrating similar estradiol 
and progesterone suppression in women treated with single doses of relugolix 40 mg or 80 mg, 
and data demonstrating that premenopausal women treated with multiple doses of 40 mg once 
daily relugolix over 14 days had estradiol levels suppressed to a median value of 3.68 pg/mL. 
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, as described above, a phase 
2 study of doses of relugolix 10, 20 and 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 
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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 48 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 48 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, 1992; 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 has demonstrated that this dose of add-back therapy maintains serum 
estradiol in the 25-50 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 PK 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) 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 is not included as a control arm as 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 
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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 will primarily assess the 
efficacy and safety of relugolix 40 mg co-administered with a low-dose of estradiol and 
norethindrone acetate compared with placebo at 24 weeks 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.  An additional arm with 
monotherapy relugolix administered for 12 weeks followed by 12 weeks of relugolix co-
administered with low-dose hormonal add-back therapy is included to provide data on the 
requirement for hormonal therapy to mitigate the adverse relugolix side effects of bone mineral 
density loss and hot flushes. 
All eligible women who complete the 24-week study will be offered the opportunity to enroll in 
an open-label extension study to obtain long-term safety and efficacy data over an additional 
28 weeks of treatment, providing approximately 1 year of safety data on the women originally 
randomized to relugolix. 
4.3. 
Selection of Study Population 
The study population will include approximately 390 premenopausal women aged 18 to 50 years 
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. 
4.3.1. 
Inclusion Criteria 
A woman will be eligible for randomization and enrollment in this study only if all of the 
following inclusion criteria apply and have been met at the time of the Baseline Day 1 visit, 
unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and 
dating the informed consent form; 
3. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 
38 days from the start of one menstrual period until the start of the next, by patient 
history for at least 3 months prior to the Screening 1 visit; 
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4. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal ultrasound 
performed during the screening period; at least one uterine fibroid must be verified by a 
central reader to meet at least one of the following criteria: 
a. Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter 
≥ 2 cm (longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3 
Note 1:  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. 
Note 2:  Saline or gel contrast is not required, but may be performed to demonstrate 
fibroids that meet the criterion for inclusion if these are not adequately visualized with 
transvaginal ultrasound alone. 
5. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a 
menstrual blood loss of ≥ 160 mL during 1 cycle or ≥ 80 mL per cycle for 2 menstrual 
cycles as measured by the alkaline hematin method during the screening period; 
6. Patient not expected to undergo gynecological surgery or ablation procedures for uterine 
fibroids within the 6 months following enrollment; 
7. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 
visits; 
8. Agrees to use two forms of non-hormonal contraception (dual contraception, as described 
in Section 4.7) consistently, the screening period, and the randomized treatment period.  
However, the patient is not required to use dual contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
screening period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the first screening visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram and no 
evidence of “post-Essure syndrome” in the investigator’s opinion; 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires 
the use of dual non-hormonal contraception as noted above; or 
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; 
periodic abstinence is not acceptable; 
9. Has an adequate endometrial (aspiration) biopsy performed during the screening period, 
with results showing no clinically significant endometrial pathology (hyperplasia, polyp, 
or endometrial cancer).  Note:  polyps < 2.0 cm by ultrasound are not excluded; 
10. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram 
(Breast Imaging Reporting and Data System category 1 or 2 or equivalent) during the 
screening period or within 6 months prior to the screening period. 
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4.3.2. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period 
demonstrating pathology other than uterine fibroids that could be responsible for or 
contributing to the patient’s heavy menstrual bleeding, such as uterine or cervical polyps 
≥ 2.0 cm, large simple ovarian cyst > 4.0 cm, endometrioma(s) > 4.0 cm, or any other 
clinically significant gynecological disorder determined by the investigator to require 
further evaluation and/or treatment during the study; 
Note:  Saline or gel contrast is not routinely required.  Use of such contrast is required 
only when the endometrium cannot be evaluated or when there are ambiguous and 
potentially exclusionary findings on the transvaginal or transabdominal ultrasound (eg, 
suspected intrauterine masses, equivocal endometrial findings, etc.); 
2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator; 
3. 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, as well as endometrial ablation for 
abnormal uterine bleeding within 6 months prior to the Screening 1 visit; 
4. Has a weight that exceeds the weight limit of the DXA scanner; 
5. Has a baseline bone mineral density z-score < -2.0 at spine, total hip, or femoral neck; 
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low 
traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and 
ankle fractures are allowed).  A history of successfully treated hyperparathyroidism, 
hyperprolactinemia, or hyperthyroidism is allowed if the patient’s bone mineral density is 
within normal limits; 
7. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, 
teriparatide, denosumab, or any medication other than calcium and vitamin D 
preparations to treat bone mineral density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of 
more than 5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, 
ophthalmic, intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
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10. 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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(HAV IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV 
RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical 
glandular cells, atypical endocervical cells, atypical squamous cells favoring high grade.  
Of note, patients with atypical squamous cells of undetermined significance and low-
grade cervical neoplasia may be included in the study if high risk human papilloma virus 
testing is negative or if DNA testing for human papilloma virus 16 and 18 is negative; 
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with initial screening hemoglobin results 
< 8 g/dL may be prescribed iron supplements and have their hemoglobin levels 
retested prior to the Baseline Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper 
limit of normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical 
laboratory testing at either the Screening 1 or Screening 2 visit (or > 2.0 x ULN if 
secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome); 
c. Estimated glomerular filtration rate < 60 mL/min/m2 using the Modification of 
Diet in Renal Disease method; 
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14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina or significant coronary artery disease (ie, > 50% stenosis); 
c. History of congestive heart failure; 
d. History of clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes, Mobitz II second 
degree or third degree heart block without a permanent pacemaker in place or 
untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury 
(mmHg) on 2 repeat measures at least 15 minutes apart, or treated ongoing 
symptomatic orthostatic hypotension with > 20 mmHg decrease in systolic blood 
pressure one minute or more after assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg 
on 2 repeat measures at least 15 minutes apart or diastolic blood pressure > 100 
mmHg at any screening visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram unless judged by the investigator to be due to physical fitness; 
15. Has been a participant in an investigational drug or device study within the 1 month prior 
to Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the 
following: 
a. Untreated thyroid dysfunction or palpable thyroid abnormality (patients with 
adequately treated hypothyroidism who are stable on medication are not 
excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than 
curatively treated nonmelanoma skin cancer or surgically cured Stage 0 in situ 
melanoma; 
c. Any current psychiatric disorder that would, in the opinion of the investigator or 
medical monitor, impair the ability of the patient to participate in the study or 
would impair interpretation of their data.  Patients with major depression, post-
traumatic stress disorder, bipolar disorder, schizophrenia or other psychotic 
disorders, based on Diagnostic and Statistical Manual of Mental Disorders-5 
criteria who have been unstable or not well controlled based on the investigator’s 
or mental health professional’s judgement or whose history or stability cannot be 
ascertained, or whose psychiatric drug regimen has changed during the 3 months 
prior to Screening or is expected to change during the study should not be 
enrolled; 
17. Is currently pregnant or lactating, or intends to become pregnant or to donate ova during 
the study period or within 2 months after the last dose of study drug; 
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18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable 
exclusionary periods for these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or 
components thereof; or has a history of drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders-5 (all 
patients must be questioned about their drug and alcohol use and this should be 
documented in the electronic case report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship 
with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, or sibling); 
23. Is inappropriate for participation in this study for other reasons, as determined by the 
investigator or sub-investigator or medical monitor. 
4.4. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the screening period.  Screening failures are patients who consent to participate in the 
clinical study but are never randomized. 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID Number 
After a patient is screened, the investigator determines that the patient is eligible for enrollment, 
the patient may undergo her Baseline Day 1 visit.  After confirming that all inclusion criteria and 
no exclusion criteria are met, the site will randomize the patient to treatment by using the 
Interactive Voice/Web Recognition Service (IVRS/IWRS) during the patient’s Baseline Day 1 
visit.  The IWRS will assign the patient a study treatment kit number available at the site 
according to the randomization code.  The IVRS/IWRS will also assign the Patient Identification 
Number. 
4.6. 
Removal of Patients from Therapy 
Completion of the Week 24 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 (Week 24 visit) on the Schedule of 
Activities 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). 
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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 randomization 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%); 
• Corrected QTcF prolongation of more than 500 msec as read by a cardiologist; 
• Patients who have a clinically significant decrease in visual acuity as evaluated by an 
ophthalmologist; 
• Patients who are, in the opinion of the investigator or the medical monitor, grossly non-
compliant with the protocol’s requirements; 
• 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 non-compliance.  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.” 
4.7. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones are excluded, and patients must 
agree to use two forms of non-hormonal contraception (dual contraception), unless any of the 
following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the Screening 
visit; 
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• Had a bilateral tubal occlusion (including ligation and blockage methods such as Essure), 
at least 4 months prior to the first Screening visit (patients with Essure must have prior 
confirmation of tubal occlusion by hysterosalpingogram) and there must be no evidence 
of post-Essure syndrome; 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the use 
of dual non-hormonal contraception as noted above; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of dual contraception are: 
• Condom with 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 when they sign a consent form 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 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). 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
In this study, patients will be randomized to receive one of the following blinded oral study 
treatments: 
• 24 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol 
and 0.5 mg norethindrone acetate; OR 
• 12 weeks of relugolix 40 mg tablet plus a placebo capsule followed by 12 weeks of 
relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol and 0.5 mg 
norethindrone acetate; OR 
• 24 weeks of relugolix placebo tablet plus a placebo capsule. 
Each patient will be instructed to take one tablet and one capsule per day. 
The placebo relugolix tablet is manufactured to match the relugolix tablet in size, shape, and 
color.  The placebo capsule is designed to match the over-encapsulated estradiol/norethindrone 
acetate active product in size, shape, color, and odor. 
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Table 5-1 
Description of MVT-601-3001 Study Drugs 
Name of 
Investigational 
Product 
Relugolix 
Relugolix Placebo 
Estradiol / 
Norethindrone 
Acetate 
Estradiol / 
Norethindrone 
Acetate Placebo 
Formulation 
Description 
Round film-coated 
pink tablet 
Round film-coated 
pink tablet 
An Swedish 
orange, over-
encapsulated 
round film-coated 
white tablet with 
placebo back-fill 
material 
A Swedish orange 
capsule with 
placebo back-fill 
material 
Dosage Form 
Tablet 
Tablet 
Capsule 
Capsule 
Unit Dose 
Strength 
40 mg 
0 mg 
Estradiol 1.0 mg / 
norethindrone 
acetate 0.5 mg 
0 mg 
Route of 
Administration / 
Duration 
Oral once daily/ 
24 weeks 
Oral once daily/ 
24 weeks 
Oral once daily/ 
12 or 24 weeks 
Oral once daily/ 
12 or 24 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. 
Placebo to match relugolix is a 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. 
Placebo to match the over-encapsulated estradiol/norethindrone acetate combination product is a 
capsule containing back-fill material only. 
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5.3. 
Randomization and Stratification 
At the Baseline Day 1 visit, patients will be randomized in a 1:1:1 ratio to one of the following 
treatment arms: 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization 
Treatment 
Group 
Randomized Treatment 
Approximate 
Number of Patients 
Group A 
Relugolix 40 mg tablet co-administered with 1.0 mg estradiol / 
0.5 mg norethindrone acetate capsule for 24 weeks 
130 
Group B 
Relugolix 40 mg tablet co-administered with relugolix placebo 
tablet for 12 weeks followed by relugolix 40 mg tablet co-
administered with 1.0 mg estradiol / 0.5 mg norethindrone 
acetate capsule for 12 weeks 
130 
Group C 
Relugolix placebo tablet co-administered with 
estradiol/norethindrone acetate placebo capsule for 24 weeks 
130 
 
Randomization will be stratified by geographic region and mean screening menstrual blood loss 
as follows: 
• Geographic region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss by the alkaline hematin method: < 225 mL versus ≥ 
225 mL. 
Patients are assigned to one of the three treatment arms in accordance with the randomization 
schedule (see additional information on randomization in Section 4.5). 
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) 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 clinic days, patients should be instructed not to eat or drink (other than water) prior to their 
clinic visit if the appointment is in the morning.  If the appointment is later in the day, patients 
should not eat for at least 2 hours before the appointment and should also not to eat or drink 
(other than water) for at least 1 hour after administration of the study drug. 
Patients should take any oral iron supplementation with meals. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK and pharmacodynamic samples are 
collected. 
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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 35°C with excursion to 15°C to 30°C permitted until it is used or 
returned to the sponsor (or designee).  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, medication or kit number, contents, 
directions for use, storage directions, clinical study statement, and any other labeling required by 
regulatory bodies in the study locations and will list Myovant Sciences GmbH as the sponsor.  
Patients will be instructed to store study drug at room temperature out of the reach of children. 
All labels for relugolix, the estradiol/norethindrone acetate combination, relugolix placebo, and 
the estradiol/norethindrone acetate placebo to be distributed will meet all applicable 
requirements of the US 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 and relugolix placebo will be supplied to the study site in blister cards co-
packaged with the estradiol/norethindrone acetate or estradiol/norethindrone acetate placebo. 
5.7. 
Blinding 
All patients, investigators, and sponsor staff or representatives involved in the conduct of the 
study will be blinded to treatment assignment, with the exception of an unblinded statistician(s) 
who is responsible for developing the randomization codes and presenting unblinded data to the 
Data and Safety Monitoring Board if requested.  The blind will be maintained during assessment 
of PK and pharmacodynamic testing; PK concentrations will be reported to the sponsor in a 
blinded fashion, or only after database lock and unblinding, or provisions will be made to 
provide data only to personnel approved for unblinding. 
Unblinding by the investigator for a given patient will occur only if the knowledge of treatment 
assignment will materially change the planned management of a medical emergency.  
Investigators will have direct access to a given patient’s individual study treatment, however, the 
investigator should make every effort to first contact the medical monitor or appropriate study 
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personnel to discuss options before unblinding the patient’s treatment assignment.  If unblinding 
by the investigator occurs before sponsor personnel can be consulted or notified, the Investigator 
must notify the sponsor as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded patient.  Patients whose treatment assignment has been unblinded by 
the investigative site will be permanently discontinued from treatment. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and prior to each visit, and should bring 
all unused and used study drug to each study visit.  At the week 12 visit all unused and used 
study drug should be retained at the site and new study drug dispensed.  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. 
Treatment after the End of Study 
Patients who complete 24 weeks of treatment on this study and wish to continue therapy may be 
eligible to continue treatment in the extension study MVT-601-3003.  Eligibility criteria are set 
forth in that protocol. 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
Table 5-3 provides examples of prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Consult the medical monitor if there is any uncertainty 
regarding patient use of a particular drug or drug class. 
Table 5-3 
Prohibited Medications and Windows of Exclusion Prior to Screening 
Drug Class 
Examples 
Window/Comments 
Bisphosphonates 
alendronate 
etidronate 
zolendronic acid 
No prior use permitted 
GnRH Analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
3 months 
(6 months for sustained 3-monthly 
injections) 
Anti-Androgens 
danazol 
4 months 
Anti-convulsant drugs 
(specified) 
phenobarbital, carbamazepine, 
phenytoin, valproic acid, and 
primidone 
1 month 
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Drug Class 
Examples 
Window/Comments 
Aromatase Inhibitors 
anastrozole 
letrozole 
4 months 
Progestins 
dienogest 
norethindrone 
medroxyprogesterone 
2 months 
(6 months for depot subcutaneous 
or intramusclar injections) 
Estrogens 
estradiol valerate 
conjugated estrogens 
2 months 
(6 months for depot subcutaneous 
or intramusclar injections) 
Oral Contraceptives 
combined or progestin only 
1 month for patients reporting a 
typical (for them) menstrual period 
within < 2 months prior to the 
Screening Visit; otherwise 
2 months 
Selective Estrogen 
Receptor Modulators 
raloxifene 
bazedoxifene 
lasofoxifene 
clomifene 
tamoxifen 
2 months 
Selective Progesterone 
Receptor Modulators  
mifepristone 
ulipristal acetate 
6 months 
Over-the-counter and 
herbal products/teas with 
known hormonal activity 
plant-based estrogen products 
“natural” thyroid supplements 
dihyroepiandrosterone (DHEA) 
1 week 
Intrauterine Devices 
levonorgestrel 
copper 
2 months 
Bone Agents 
calcitonin 
calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
No prior use if used for reduced 
bone mineral density 
Anti-Coagulants/ 
Platelets/Fibrinolytics 
warfarin 
tranexamic acid 
vitamin k preparations 
factor Xa inhibitors  
1 month 
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Drug Class 
Examples 
Window/Comments 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
No window 
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. 
P-glycoprotein Inducers 
carbamazepine 
rifampin 
St John’s wort 
2 weeks 
Patients requiring a short course of 
these drugs during the study must 
contact the medical monitor for 
approval and guidance on study 
drug administration during this 
period. 
Moderate and Strong 
P-glycoprotein Inhibitors 
amiodarone 
azithromycin 
captopril 
carvedilol 
clarithromycin 
conivaptan 
cyclosporin 
diltiazem 
dronedarone 
erythromycin 
felodipine 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
quercetin 
quinidine 
ranolazine 
ticagrelort 
verapamil 
2 weeks 
(6 months for amiodarone) 
Patients requiring a short course of 
these drugs during the study must 
contact the medical monitor for 
approval and guidance on study 
drug administration during this 
period. 
Abbreviation:  GnRH, gonadotropin-releasing hormone 
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5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded, including the drug generic 
name, dose amount, route of administration, start date, and stop date. 
5.10.2.1. 
Analgesics 
From the Screening 1 visit to the Week 24 (or Early Termination) visit, the recommended 
analgesics for uterine-fibroid associated pain are as follows: 
• First-line:  ibuprofen  
• Second-line:  non-ibuprofen non-steroidal anti-inflammatory drug or acetaminophen 
• Third-line:  opioid or opioid-acetaminophen combination  
• Fourth-line:  investigator discretion 
The purpose of these recommendations is to standardize, to the extent possible, analgesic 
medication use to facilitate the effects on the secondary endpoint regarding of uterine-fibroid-
related pain. 
Patients should be instructed not to use analgesics for prophylactic purposes. 
5.10.2.2. 
Iron Therapy 
Women with a hemoglobin < 8.0 g/dL are excluded from participating in the study.  Women 
identified during the screening period to have a microcytic iron deficiency anemia defined as a 
hemoglobin ≥ 8 g/dL but ≤ 10 g/dL, a mean corpuscular volume below the lower limit of normal, 
and a low serum iron and ferritin, must be started on iron therapy, either oral or parenteral and 
then continued on treatment during the study.  Women who enter the screening period 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. 
5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of uterine fibroids and use of intrauterine devices are prohibited from the 
Screening 1 visit until the patient’s final study visit unless urgently needed for patient safety. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities in 
the study synopsis (see Section 1.1).  Study procedures are briefly described within Section 6.7.  
Further details of the procedures are provided in the Study Reference Manual. 
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6.1. 
Schedule of Observations and Procedures 
Assessments should be completed at the designated visit/time points as described in the Schedule 
of Activities in the study synopsis (see Section 1.1).  The study is divided into three periods:  
screening period, randomized treatment period, and Safety Follow-Up (to assess safety for 
patients who do not enroll in an open-label extension study; unscheduled visits may also occur as 
needed to evaluate patients). 
6.2. 
Screening Period 
Patients should have a diagnosis of uterine fibroids and a history of heavy menstrual bleeding 
with or without associated pain on a background of generally regular menses (ie, regularly 
occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days from the start of 
one menstrual period until the start of the next menstrual period) as reported by the patient for at 
least 3 months prior to the Screening 1 visit. 
The screening period consists of the Screening 1, 2, 3, and 4 visits. 
See Figure 4-2 for details of the timing of the screening period visits as well as details of the 
feminine product dispensation and collection during screening.  The Screening 4 visit should be 
skipped if the menstrual blood loss is > 160 mL in the first screening cycle. 
6.2.1. 
Screening 1 Visit  
The Screening 1 visit will be conducted following the signing of the informed consent form and 
may occur at any time during the menstrual cycle.  The Screening 1 visit will include a full 
medical history (including menstrual history for 3 months prior to Screening and prior uterine 
imaging assessments), review of inclusion and exclusion criteria, collection of concomitant 
medications, study procedure-related adverse events and any serious adverse events.  In addition, 
vital signs, height, weight, temperature, a complete physical examination, gynecology 
examination, ultrasound, endometrial biopsy, Papanicolaou test (if needed), clinical laboratory 
tests, urinalysis, and a urine pregnancy test will be done.  Feminine products will be dispensed 
with instructions to collect and return all products used during the next menses.  The paper diary 
will also be dispensed at this visit and should be completed daily starting with this visit.  The 
bone mineral density scan and mammogram should be scheduled at this time (or within a few 
days of this visit).  Bone densitometry should be scheduled to be prior to the Screening 3 visit 
and as early as feasible to ensure results are available prior to randomization. 
The order of procedures should be as follows.  Patients not meeting eligibility criteria after any 
procedure should not undergo subsequent procedures. 
• Medical history and review of prior uterine imaging studies 
• Review of concomitant medications (including supplements and over the counter 
medications) 
• Review of inclusion and exclusion criteria 
• Urine pregnancy test  
• Vital signs, weight, and height 
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• Ultrasound – do not proceed with additional procedures if no uterine fibroids are 
identified with the local/initial reading 
• Gynecology examination, Papanicolaou test (if need), endometrial biopsy 
• Clinical laboratory tests, urinalysis 
• Dispense feminine products and paper diary with instructions to begin recording starting 
information daily, starting on the Screening 1 visit day 
• Schedule mammogram (if needed) 
• Schedule bone densitometry 
The ultrasound will be a transvaginal ultrasound (with or without a transabdominal ultrasound 
(see Section 4.3 ultrasound entry criteria), performed to assess for uterine fibroids.  Saline or gel 
contrast may be used but is not required (see Section 4.3 ultrasound entry criteria).  The anatomic 
location and size of the fibroid disease will be estimated by the local reader.  The ultrasound 
images will be submitted to the central reader for confirmation that the patient meets the 
inclusion criteria for a diagnosis of uterine fibroids (this confirmation must be received prior to 
randomization).  The investigator, rather than the central reader, will determine if any 
exclusionary pathology is present.  If ultrasound fails to demonstrate fibroids on the local 
reading, do not proceed with additional Screening visit 1 procedures. 
The Papanicolaou test must be conducted for women without a test result within 6 months prior 
to the Screening 1 visit and the specimen is to be submitted to the central laboratory.  A repeat 
test should be performed for inadequate or false-positive results and submitted to the central 
laboratory.  
The endometrial biopsy will be obtained using a pipelle and submitted to the Central Laboratory. 
The mammogram must be done in patients ≥ 39 years of age by the time of the (anticipated) 
Baseline Day 1 visit if there is no record (and reading) from within 6 months prior to the 
screening period. 
6.2.2. 
Screening 2 Visit 
Screening 2 visit is scheduled to occur within 5 (+2) days after cessation of the patient’s first 
menses following the Screening 1 visit.  Patients will return at Screening 2 visit to return their 
feminine products.  At this visit, clinical laboratory tests will be drawn, including a venous blood 
sample for use in the quantitation of menstrual blood loss.  Additional feminine products will be 
dispensed for collection of menstrual blood loss during the next menses.  If the hemoglobin is 
< 10 g/dL and mean corpuscular volume is below the lower limit of normal, a ferritin and iron 
level will be obtained as an unscheduled test.  Women whose laboratory testing reveals iron-
deficiency anemia as defined in the study must be started on iron therapy. 
Confirm the scheduling of the bone densitometry and mammogram (if needed) and review 
mammogram results, if available.  The mammogram must be normal (Breast Imaging Reporting 
and Data System category 1 or 2 or equivalent) in order for the patient to be eligible.  
Once the menstrual blood loss results from the first cycle are available, schedule Screening 3 
visit as soon as feasible and within 5 (+2) days of receiving results showing that the menstrual 
blood loss is ≥ 80 mL. 
Patients will be dispensed feminine products to be gathered for the second cycle. 
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6.2.3. 
Screening 3 Visit 
The patient will return for the Screening 3 visit if her menstrual blood loss from cycle 1 is 
≥ 80 mL and within ≤ 15 days after the Screening 2 visit.  At the Screening 3 visit, review of 
inclusion and exclusion criteria will be conducted confirmation of continued eligibility.  
Concomitant medication and adverse events will be assessed and vital signs taken.  A signs and 
symptoms directed physical examination, a 12-lead ECG and a urine pregnancy test will be 
performed.  At this visit, review the endometrial biopsy results and review mammogram results, 
if available.  Confirm that the bone densitometry scans have been submitted for central reading.  
The mammogram and central bone densitometry results must be available prior to 
randomization. 
6.2.4. 
Screening 4 Visit 
The Screening 4 visit should be skipped if the menstrual blood loss is > 160 mL in the first 
screening cycle.  If not skipped, then the Screening 4 visit is scheduled to occur within 
5 (+2) days after cessation of the patient’s menses following Screening 3 visit.  At the Screening 
4 visit, the patient’s feminine products will be collected to submit for the quantitation of 
menstrual blood loss, and a blood sample will be drawn for hemoglobin assessment.  The 
patient’s eDiary data collection will be reviewed.  Laboratory and imaging evaluations will be 
reviewed to ensure eligibility for randomization. 
6.2.5. 
Menstrual Blood Loss Repeat Collection 
At the discretion of the investigator, the collection of menstrual blood loss can be repeated once 
during the screening period (either after the first or second screening cycle) if one menstrual 
cycle does not meet the heavy menstrual bleeding alkaline hematin criteria and it is thought to be 
due to an inadequate collection by a highly motivated patient. 
6.2.6. 
Re-Screening 
Patients who fail screening may be re-screened with approval of the medical monitor.  Patients 
undergoing re-screening will sign a new informed consent form and issued a new screening 
number.  For patients who begin re-screening within 10 weeks of signing the original informed 
consent form, transvaginal ultrasound, endometrial biopsy, and bone densitometry do not need to 
be repeated, if performed previously. 
6.3. 
Randomized Treatment Period (Baseline to Week 24) 
At the Baseline Day 1 visit, patients will be randomized to one of the three study treatment arms 
(see Section 5.3).  Patients will take their randomized study treatment once daily, beginning on 
the day of the Baseline Day 1 visit and continuing through the Week 24 visit.  Patients will 
continue recording daily in their eDiary.  On-treatment study visits will occur every 4 weeks 
through the end of Week 24.  At each post-baseline visit, patients will return their feminine 
products for alkaline hematin testing.  Safety monitoring including signs and symptoms directed 
physical examination, waist circumference, ECGs, clinical laboratory tests, pregnancy tests, and 
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adverse event collection will occur at each visit.  Bone densitometry will occur at the Week 12 
and Week 24 visits.  A repeat transvaginal ultrasound (with or without a transabdominal 
ultrasound) and endometrial biopsy will be performed at the Week 24 visit.  The endometrial 
biopsy will be read centrally.  Study drug and eDiary compliance will be reviewed at each visit.  
Refer to the Schedule of Activities in the synopsis (see Section 1.1) for information about study 
procedures during the randomized treatment period. 
Sites should try to schedule patient visits during the morning, instructing patients to arrive before 
taking their study drug to allow for pre-dose PK/pharmacodynamic sampling.  Patients must 
come to the clinic in the fasted state (eg, nothing to eat or drink other than water after midnight 
the day before the clinic visit) for the Baseline Day 1 and Week 24/Early Termination visits. 
For visits other than Baseline Day 1 and Week 24/Early Termination, if the clinic visit cannot be 
scheduled for the morning, patients may eat in the morning but should not have eaten or had 
anything to drink other than water for at least 2 hours prior to the clinic visit and must not eat or 
drink (other than water) for at least 1 hour after the clinic visit.  In these situations, the laboratory 
requisitions must indicate that the patient was not fasted for their chemistry and lipid testing. 
6.4. 
Continuation into Extension Study 
It is expected that most patients will enter the 28-week extension study (MVT-601-3003), which 
will be conducted under a separate protocol.  Patients will provide separate informed consent to 
participate in the extension study during which all patients will receive relugolix 40 mg co-
administered with 1.0 mg estradiol / 0.5 mg norethindrone acetate. 
6.5. 
Early Termination Visit and Follow-up Visit 
All patients withdrawing from the study prior to Week 24 will complete an Early Termination 
visit.  The Early Termination visit procedures are identical to those of Week 24; however, for 
patients whose last dose of study drug is during Week 6 or earlier, the following procedures do 
not need to be performed:  transvaginal ultrasound (with or without a transabdominal 
ultrasound), endometrial biopsy, and bone densitometry.  These procedures may be performed, 
however, at the investigator’s discretion, if they aid in follow-up of ongoing adverse events. 
All patients who do not wish to or who are not eligible to enroll in the extension study 
(MVT-601-3003), 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 for uterine fibroids, 
whichever occurs first.  This visit will be used to assess safety after discontinuation of study 
treatment including adverse events, clinical safety laboratories, 12-lead ECG, and return of 
menstruation.  Patients who withdraw early from this study will also undergo 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.  Refer to the Schedule of 
Activities at the end of the synopsis (see Section 1.1) for individual study visit procedures during 
the Follow-up visit. 
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6.6. 
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, PK and pharmacodynamic 
sampling, 12-lead ECG, study drug compliance and dispensation, etc. may be conducted as 
needed.  See Schedule of Events (Section 1.1) for tests that may be performed if indicated at an 
unscheduled visit.  Consult with the medical monitor, if needed, to discuss Unscheduled visit 
testing. 
6.7. 
Study Procedures 
6.7.1. 
Efficacy-Related Procedures 
6.7.1.1. 
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.  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. 
6.7.1.2. 
Transvaginal and Transabdominal Ultrasound 
Transvaginal with or without transabdominal ultrasound with or without saline or gel contrast is 
performed for the diagnosis of uterine fibroids, 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.  Transvaginal ultrasound will be performed.  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. 
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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.  
At the Screening 1 visit, the longest diameter (D1) of the largest myoma will be noted and 
recorded.  Only the largest myoma among those measurable at the Screening 1 visit will be 
measured throughout the study. 
6.7.1.3. 
Endometrial Biopsy 
An endometrial biopsy is to be performed during the pelvic examination at the Screening 3 visit.  
A pipelle should be used to obtain the specimen.  A second biopsy is to be performed at the 
Week 24 visit.  The biopsies will be read centrally. 
6.7.1.4. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, estradiol, and progesterone 
will be collected pre-dose at the visits indicated in the study Schedule of Activities in the 
protocol synopsis (see Section 1.1).  These pharmacodynamic samples will be analyzed at a 
central laboratory.  For PK analysis of estradiol, a separate PK sample will be obtained to be 
analyzed at a PK laboratory (see Section 6.7.1.5).  To maintain blinding, concentrations of these 
hormones will be reported to the investigator, other vendors, and sponsor personnel only after 
database lock and unblinding. 
6.7.1.5. 
Pharmacokinetics Sample Collection 
Blood samples for PK analysis of relugolix, estradiol, and norethindrone will be collected pre-
dose at the visits indicated in the study Schedule of Activities in the protocol synopsis (see 
Section 1.1).  The actual date and time of each blood sample collection will be recorded. 
Patients will be instructed to hold their dose of study drug on clinic visit days and record the time 
of their previous dose (ie, the time they took their dose on the day before the clinic visit).  If the 
study patient inadvertently took drug at home on the morning of the clinic visit, the dosing 
history should be accurately recorded and a PK sample collected (which may be used for 
population PK modeling). 
To maintain blinding, PK concentrations will be reported to the sponsor in a blinded fashion, or 
only after database lock and unblinding.  Collection, processing, storage, and shipping 
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procedures are provided in the Study Reference Manual.  Plasma and serum analysis will be 
performed by the sponsor (or designee). 
Plasma concentrations of relugolix and norethindrone and serum concentrations of estradiol will 
be determined in samples using a validated bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site.  Once a sample has been analyzed for relugolix, estradiol, or 
norethindrone, any remaining plasma may be analyzed for other compound-related metabolites 
and the results reported under a separate protocol. 
6.7.1.6. 
Patient Diary 
All women enrolled in the study will be provided with a device with an application for a patient 
eDiary, along with detailed instructions for its use.  Patients will complete daily eDiaries 
including compliance with study treatment, menstrual bleeding, use of feminine products, uterine 
fibroid-associated pain, and use of pain medication (analgesics) to treat uterine fibroid pain (see 
Appendix 2). 
Queries will be handled by the vendor managing the eDiary data through the clinical site.  The 
eDiary data will be reviewed by the investigator to identify any potential adverse events. 
Patients will also receive a paper diary to enter information on menstruation status and feminine 
product use starting with Screening 1 visit and ending when they receive their eDiary at the 
Screening 3 visit. 
6.7.1.7. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire (MIQ) 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 3).  The MIQ has undergone psychometric 
validation.  Patients will complete the MIQ at each study visit during the randomized 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. 
6.7.1.8. 
Uterine Fibroid Symptom – Quality of Life 
The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) score is used to 
evaluate the symptom severity and the quality of life of patients with uterine fibroids (see 
Appendix 4).  Patients will complete the UFS-QoL questionnaire at the site at the Baseline Day 1 
visit, Week 12 visit, and Week 24 visit before other study procedures, such as blood draws and 
physical examinations, are performed. 
6.7.1.9. 
European Quality of Life Five-Dimension Five-Level Scale 
The European Quality of Life Five-Dimension Five-Level Scale (EQ-5D) is a standardized 
instrument for use as a measure of health outcomes (see Appendix 5).  Mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression are each assessed on 3-point categorical scales 
ranging from “no problem” to “severe problem.” 
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Patients will complete the EQ-5D questionnaire at the site at the Baseline Day 1 visit and the 
Week 24 visit before other study procedures, such as blood draws and physical examinations, are 
performed. 
6.7.1.10. 
Status of Menstruation Recovery 
If the patient does not continue into the extension study (MVT-601-3003), and the first 
menstruation after the end of study treatment administration is observed before the Follow-up 
visit, the date of onset of the first menstruation is recorded in the eCRF.  After the Follow-up 
visit, additional follow-up for the status of menstruation recovery will not be continued, 
6.7.1.11. 
Pharmacogenomics Sample Collection 
For possible exploratory investigation of markers enabling the prediction of drug response, one 
sample of blood will be collected and stored for future pharmacogenomic analyses.  All patients 
will be eligible for collection of the pharmacogenomic sample, however, the sample may only be 
obtained and stored from patients who provide a separate informed consent form for 
pharmacogenomic sample collection.  Patient participation in the pharmacogenomic research is 
voluntary and refusal to participate will not preclude entry into the study or indicate withdrawal 
from the study. 
If possible, the pharmacogenomic sample should be drawn from consented patients at the 
Baseline Day 1 visit, but it may be drawn at any time during the study through Week 24 
(inclusive).  Patients can request their sample to be destroyed at any time.  A pharmacogenomic 
sample should not be collected from any patient who has received comparable bone marrow 
transplant or whole blood transfusion within 6 months before sample collection.  Refer to the 
Study Reference Manual for directions on collecting, handling, and storage of pharmacogenomic 
samples. 
6.7.2. 
Safety-Related Procedures 
6.7.2.1. 
Weight, Height, Waist Circumference, and Body Mass Index 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed.  Waist circumference should be measured with a measuring tape wrapped around the 
narrowest portion of the patient’s mid-section. 
6.7.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, and temperature, should be measured in the 
seated position after 5 minutes of rest and will include systolic and diastolic blood pressure and 
pulse rate. 
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6.7.2.3. 
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 the Baseline assessment.  Visual acuity will be 
checked at the beginning and end of the study by a standard visual eye chart.  The patient should 
wear any prescribed glasses or contacts during the visual acuity assessment.  The gynecologic 
examinations will include breast and pelvic exams.  A Papanicolaou test must be conducted for 
women without an available test result from within 6 months prior to the Screening 1 visit and 
submitted to the central laboratory.  A repeat test should be performed for inadequate or false-
positive results and submitted to the central laboratory. 
6.7.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities in the synopsis (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 
White Blood Cell (WBC) Count 
Protein 
Chloride 
WBC Differential 
Glucose 
Bicarbonate 
Red Blood Cell Count 
Blood 
Blood Urea Nitrogen 
Hemoglobin 
Urobilinogen 
Creatinine 
Hematocrit 
Bilirubin 
Glucose 
Mean Corpuscular Volume  
Color and Clarity 
Calcium 
Platelet Count 
pH 
Phosphate 
RBC morphology 
Leucocyte esterase 
Magnesium 
 
Ketones 
Sodium 
 
Nitrite 
Albumin 
 
Specific gravity 
Creatinine kinase 
 
Urine Microscopy 
Hemoglobin A1c 
 
Creatine Kinase 
Lipids 
Pregnancy 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase 
Gamma-Glutamyl Transferase 
Alkaline phosphatase 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
Pregnancy test 
(human chorionic 
gonadotropin) 
Hormones 
Serology 
Iron Studies 
Thyroid-Stimulating Hormone 
Intact Parathyroid Hormone 
Prolactin 
Luteinizing Hormone 
Follicle-Stimulating Hormone 
Estradiol 
Progesterone 
Vitamin D [25(OH)D] 
Hepatitis A antibody 
Hepatitis B surface antigen 
Hepatitis B Core antibody 
Hepatitis C antibody 
Iron 
Ferritin  
 
A separate sample will be collected at the Day 1 visit in all patients and will be banked for 
hepatitis serology (Table 6-1) in all patients.  The samples will be analyzed, if requested, by the 
medical monitor for evaluation of abnormal liver tests during the study. 
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. 
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6.7.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at the Screening 3 visit, the Baseline Day 1 visit, the Week 12 
visit, and at the Week 24 or early withdrawal and Follow-up visits, as well as if needed to 
evaluate any signs or symptoms.  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. 
6.7.2.6. 
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. 
The following will be assessed at each time point indicated for bone densitometry in the study 
Schedule of Activities (Section 1.1):  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, average bone 
mineral density of L1-L4, and T-score for average of L1-L4, total hip, and femoral neck. 
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.  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.  Investigators will be notified if a patient experiences a bone mineral 
density loss from baseline of 7% or more at any of the sties assessed during the study.  In this 
case, repeat scan may be required for confirmation of the results, and it is at the investigator’s 
discretion to consider the patient’s status and determine future management.  Detailed 
instructions for bone mineral density monitoring will be provided in the Study Reference 
Manual. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of blood collected for 
pharmacogenomics testing (see Section 6.7.1.11) will be stored frozen at an appropriate vendor 
facility identified by the sponsor. 
The need to conduct pharmacogenomic analysis may be identified after this study (or additional 
studies) has been completed.  For this reason, the collected samples will be retained for up to 
10 years after the last patient completes the study.  A patient may request the destruction of her 
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sample at any time.  The sponsor may destroy the samples sooner than 10 years after the study 
completes. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), ECGs, bone mineral density assessments, endometrial biopsy results, 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). 
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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 baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events which jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
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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 eDiary entries and answers to the UFS-QoL 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 will be collected from the time the first dose of study drug is administered until 
the Follow-up visit approximately 30 days after the last dose of 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).  Study procedure-related adverse 
events will be collected from the signing of the informed consent form. 
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Serious adverse events will be collected from the signing of the informed consent form until the 
safety follow-up visit approximately 30 days after the last dose of study drug.  Serious adverse 
events reported to the investigator after the safety reporting period should be reported to the 
sponsor if the investigator assesses the event as related to the study drug treatment. 
With the exception of adverse events that are considered related to study screening procedures, 
(which are to be recorded as adverse events), events occurring between signing of the informed 
consent form and the first dose of study drug will be recorded as medical history and in the 
patient’s clinical record for any patient who continues to meet eligibility criteria and proceeds to 
dosing with study drug. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
following definitions are to be used for the relationship of the adverse event to study drug: 
• Probably related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely attributed to concurrent 
disease or other drugs or chemicals, and that follows a clinically reasonable response on 
readministration (rechallenge) or withdrawal (dechallenge). 
• Possibly related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug but that could also be explained 
by concurrent disease or other drugs or chemicals.  Information on drug withdrawal may 
be lacking or unclear. 
• Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that makes a causal relationship improbable and/or in 
which other drugs, chemicals, or underlying disease provide a plausible explanation. 
All adverse events, whether or not related to study drug, must be fully and completely 
documented on the adverse event page of the eCRF and in the patient’s clinical record.  In the 
event a patient is withdrawn from the study because of an adverse event, it must be recorded on 
the eCRF as such. 
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 randomized treatment 
period or the Follow-up visit should be reported to the sponsor using the Serious Adverse Event 
Form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), 
even if the event does not meet SAE criteria.  Additional instructions for evaluating patients 
with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or the International Normalized 
Ratio (INR) > 1.5; or 
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
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Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge. 
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1. AST or ALT increases to ≥ 3 x ULN; AND 
2. Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3. Alkaline phosphatase value does not reach 2 x ULN; AND 
4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus) 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms 
• Alcoholic hepatitis 
• Nonalcoholic steatohepatitis  
• Autoimmune hepatitis  
If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
7.6. 
Serious Adverse Event Reporting 
Using a Safety Reporting Form, all serious adverse events must be reported within 24 hours of 
the study site personnel’s knowledge of the event, regardless of the investigator assessment of 
the relationship of the event to study drug. 
The contact information for submission of serious adverse events, adverse events of clinical 
interest, and events of overdose is available on the Serious Adverse Event report form and is as 
follows: 
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Send completed Safety Report Forms to PRA Safety & Risk Management: 
Site Location 
E-mail 
(Primary reporting method) 
Fax Number 
(Secondary reporting method) 
North/South American 
sites: 
 or 
 
Europe, Asia, Pacific and 
Africa sites: 
 
 
For questions on Serious Adverse Event (SAE)/Adverse Event of Clinical Interest (AECI) 
reporting, please call: 
• 
North/South America: 
 or 
  
• 
Europe, Asia, Pacific, and Africa: 
 
 
The initial report should include: 
• 
Study number (MVT-601-3001) 
• 
Site address and number 
• 
Investigator name 
• 
Patient ID number, sex, and age 
• 
Details of study drug administration 
• 
The date of the report 
• 
A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity) 
• 
Causal relationship to the study drug 
If the patient died, the report should include the cause of death as the event term (with death as 
outcome) and whether or not the event leading to death was related to study drug treatment, as 
well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
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PPD
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For this study, any dose of relugolix > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 x the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form according to Section 7.6, whether or not the overdose 
is associated with an adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); 
• 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.  The investigator 
must inform the patient of her right to receive treatment information.  If the patient chooses to 
receive unblinded treatment information, the individual blind should be broken and the treatment 
assignment provided to the patient.  The study team will remain blinded to the patient’s treatment 
assignment. 
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 (blinded or 
unblinded, as applicable). 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  The 
expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result, and neonatal data, etc, should be included in this 
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 6.7.2 details the requirements for measurement of safety parameters including vital 
signs, physical and gynecologic examinations, clinical laboratory tests, electrocardiograms and 
bone mineral density. 
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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 
(QTc prolongation), hepatic enzyme increases, PLD, reproductive toxicity, and metabolic and 
cardiovascular changes (insulin resistance, dyslipidemia, increased weight) with an increased 
risk of diabetes mellitus and possible increased risk of cardiovascular disease.  Additionally, 
there are potential risks associated with the addition of estradiol/norethindrone acetate.  
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
osteopenia, metabolic 
bone disease, and prior 
medical therapy for low 
bone mineral density. 
Bone mineral density will be 
monitored at the Baseline 
Day 1, Week 12, and End of 
Treatment visits and all 
fractures will be reported as 
adverse events. 
Drug Interactions 
Exclusion of co-
administration 
P-gp inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF  
> 470 msec. 
12-lead ECG at Baseline 
Day 1, Week 12 and End of 
Treatment 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 LFTs 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 LFTs (AST or 
ALT > 3 x ULN) that 
develop during the 
randomized 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; visual acuity will be 
checked at the beginning and 
end of the 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. 
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. 
Monthly pregnancy testing; 
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 are excluded.  
A mammogram, 
Papanicolaou test, 
physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed prior to 
enrollment. 
Clinical chemistries 
assessing LFTs, 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. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study.  The SAP will be prepared and finalized prior to unblinding of patients’ study 
treatment assignments. 
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All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%.  
Methodology to be used to maintain study-wide type I error rate of 5% across primary and 
secondary endpoint testing will be described in the SAP. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 1:1:1 to relugolix plus low-
dose hormonal add-back therapy (Group A), relugolix monotherapy plus placebo followed by 
relugolix plus low-dose hormonal add-back therapy (Group B), and placebo (Group C).  
Randomization will be stratified by the following factors: 
• Geographic Region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss using alkaline hematin method:  < 225 mL versus 
≥ 225 mL. 
Statistical analyses for all efficacy endpoints will incorporate these stratification factors unless 
otherwise specified. 
9.2. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis. 
The Per-Protocol Population will consist of those members of the ITT Population who have no 
major protocol violations.  The Per-Protocol Population will not be analyzed if this population 
comprises more than 95% or less than 50% of the ITT Population.  This population will be used 
for confirmatory analysis of the primary efficacy endpoint.  The Per-Protocol Population will be 
identified prior to breaking the study blind. 
The primary population for safety analyses will be the Safety Population, which will consist of 
all patients who are randomized and took at least one dose of study treatment. 
9.3. 
Efficacy Analyses 
Inferential efficacy assessments will be made between the following groups and 24 Weeks of 
placebo: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate; 
• Relugolix Group B:  12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone 
acetate. 
Descriptive characterization of treatment effect will be assessed between both relugolix groups. 
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9.3.1. 
Primary Endpoint Analysis 
The primary endpoint is the proportion of women in the relugolix Group A versus the placebo 
Group C who achieve both a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline in menstrual blood loss volume over the last 35 days of treatment 
as measured by the alkaline hematin method. 
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 as assessed by the alkaline hematin method.  The menstrual blood loss during the 
final study month is the total menstrual blood loss during the last 35 days on treatment as 
assessed by the alkaline hematin method.  The treatment comparison between the relugolix 
Group A and the placebo Group C will be analyzed using a Cochran-Mantel-Haenszel test 
statistic for stratified proportions.  The differences between the relugolix Group A and placebo 
Group C and 2-sided 95% confidence intervals will be estimated based on stratum-adjusted 
Mantel-Haenszel proportions. 
Patients who discontinue the study before Week 4 (28 days) will be considered as treatment 
failures for the primary endpoint.  The primary analyses will be based on the ITT Population.  In 
addition, analyses of the Per-Protocol Population will be used to support the primary efficacy 
analysis.  Details will be provided in the SAP.  Additional missing data imputations will be 
conducted as sensitivity analyses to support the primary analysis.  Details will be provided in the 
SAP. 
For the assessment of the superiority of relugolix Group A versus placebo Group C in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least 
a 50% reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size 
of ~130 patients in the relugolix Group A versus ~130 in the placebo Group C will provide 
greater than 99% power to detect a difference of greater than 30% using a 2-sided test at 
significance level of 0.05.  The study will enroll 3 groups with a targeted 130 patients in each 
group for a total sample size of 390. 
9.3.2. 
Secondary Endpoint Analyses 
The secondary endpoints are listed below: 
• Proportion of women in the relugolix Group B versus the placebo Group C who achieve a 
menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline 
menstrual blood loss volume over the last 35 days of treatment, as measured by the 
alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix treatment group to 
placebo inferentially and relugolix Group A to Group B descriptively: 
• Time to achieving a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss volume as measured by the alkaline 
hematin method; 
• Change from Baseline to Week 24 in menstrual blood loss; 
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• Proportion of women who achieve amenorrhea over the last 35 days of treatment as 
measured by the alkaline hematin method; 
• Time to amenorrhea as measured by the by the alkaline hematin method; 
• Proportion of women with a hemoglobin below the lower limit of normal at Baseline who 
achieve an increase of ≥ 1 g/dL from Baseline at Week 24; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
physical activities; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• Proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• Change from Baseline to Week 24 in uterine volume; and 
• Change from Baseline to Week 24 in uterine fibroid volume. 
The analysis methods used for the primary endpoint will be applied to the analyses of the 
secondary endpoints of proportion of patients who achieve both a menstrual blood loss volume 
of < 80 mL AND at least a 50% reduction in menstrual blood loss volume over the last 35 days 
of treatment compared between relugolix Group B and placebo Group C, the proportion of 
patients with amenorrhea over the last 35 days, the proportion of women with a hemoglobin 
below the lower limit of normal at Baseline who achieve an increase of at least 1 g/dL at Week 
24 and the proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction from 
Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days prior to 
randomization. 
For the secondary endpoints of time to achieving a menstrual blood loss volume of < 80 mL 
AND at least a 50% reduction from baseline menstrual blood loss volume and time to 
amenorrhea, time to event will be defined as weeks from randomization 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 and stratified log-rank test will be used to compare each relugolix 
arm to placebo.  Randomization stratification factors will be used to stratify inferential testing. 
Descriptive statistics will be provided for changes in menstrual blood loss, hemoglobin, 
Numerical Rating Scale score for uterine fibroid-associated pain, uterine volume, and uterine 
fibroid volume baseline.  The between treatment comparisons will be performed using model 
derived least squares means with treatment, stratification factors, baseline result accounted for in 
the model. 
Baseline Numerical Rating Scale score is defined as the average Numerical Rating Scale score 
from the 35 days of data collected prior to the date of first dose of study drug after 
randomization.  The Numerical Rating Scale score during the final study month is the average 
Numerical Rating Scale score during the last 35 days on treatment. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
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9.4. 
Safety Analyses 
Safety analyses will be conducted using the safety population and summarized by treatment 
group as treated.  The treatment emergent period will be defined as the period of time from the 
first dose date of study drug through approximately 30 days after the last dose of study drug, or 
the date of initiation of another investigational agent or hormonal therapy affecting the 
hypothalamic-pituitary-gonadal axis or surgical intervention for uterine fibroids, whichever 
occurs first.  Safety will be assessed through summaries of adverse events, the frequency of 
treatment discontinuations due to adverse events, laboratory evaluations, and bone densitometry 
results. 
The severity of all adverse events is to be evaluated by the investigator based on the National 
Cancer Institute’s CTCAE.  All adverse events will be coded to preferred term and system organ 
class using MedDRA 12.0 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 baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from baseline to each post-baseline study visit will be presented by treatment 
group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from baseline to each post-baseline study visit will be presented by 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 corrected QT interval will be summarized at each visit.  All data 
will be listed and summarized by visit.  The change from baseline to each post-baseline study 
visit will be presented by treatment group for each ECG parameter. 
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 average of L1-L4, total hip, and femoral neck.  All data will be listed 
and summarized by visit.  The change, percent change from Baseline to Weeks 12 and 24 and 
associated 95% confidence intervals will be presented by treatment group for each parameter. 
All data will be listed and summarized by visit.  The change, percent change from baseline to 
Weeks 12 and 24 and associated 95% confidence intervals will be presented by treatment group 
for each parameter. 
The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by treatment arm. 
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The number and percentage of patients meeting a bone mineral density decline of at least 4%, 
5%, 6%, or 7% by body area (lumbar, total hip, or femoral neck) will be estimated with 95% 
confidence intervals by 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. 
9.5. 
Pharmacokinetic Analyses 
The PK concentration data (relugolix, estradiol [PK lab], and norethindrone) and serum 
pharmacodynamic data (LH, FSH, estradiol [central lab] and progesterone) will be listed and 
summarized descriptively by treatment arm and visit. 
Plasma relugolix PK data will be combined with data from other phase 1 and phase 2 studies for 
population PK analysis.  Full details will be provided in a separate Population PK SAP and 
reported separately.  Plasma PK parameters of relugolix will be derived and summarized.  The 
relationship between efficacy, safety, and exposure will be explored. 
9.6. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed: 
• Change from Baseline to Week 24 in the Uterine Fibroid Scale – Quality of Life 
Symptom Severity and Health-related Quality of Life subscales comparing each relugolix 
treatment group to placebo inferentially and the two relugolix groups descriptively; 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-Dimension Five-
Level scale comparing each relugolix treatment group to placebo inferentially and the 
two relugolix groups descriptively. 
9.7. 
Interim Analyses 
There are no planned interim efficacy analyses. 
10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study participant.  For studies conducted under a United States investigational 
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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 one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures.  The 
investigator must utilize an IRB- or IEC-approved informed consent form for documenting 
written informed consent that contains all elements required by national, state, local, and 
institutional regulations or requirements.  Each informed consent form will be appropriately 
signed and dated by the patient. 
10.1.4. 
Confidentiality 
The investigator must assure that 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. 
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The investigator agrees that all information received from the sponsor, including but not limited 
to the IB, protocol, eCRFs and other study forms, the investigational drug, and any other study 
information, remain the sole and exclusive property of the sponsor during the conduct of the 
study and thereafter.  This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the sponsor.  The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
10.1.5. 
Study Committees and Communication 
There will be two formal committees for this study, a Steering Committee and a Data and Safety 
Monitoring Board. 
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.  Steering Committee 
members will remain blinded to patients’ treatment assignment and all unblinded data until the 
database is officially locked and unblinded. 
An independent Data and Safety Monitoring Board will be established consisting of experts in 
women’s health, clinical study safety monitoring, and statistics.  This committee will evaluate 
the safety of study participants on an ongoing basis.  Further details on the composition and 
responsibility of the Data and Safety Monitoring Board will be outlined in a separate charter. 
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 IB, 
protocol/amendments, IRB or IEC and governmental approval with correspondence, 
informed consent forms, drug records, staff curriculum vitae, authorization and training 
forms, and other appropriate documents and correspondence. 
2) Patient clinical source documents.  The required source data should include the following 
for each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
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• 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 IB, 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 the 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 (active and 
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placebos).  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. 
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. 
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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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REFERENCES 
ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of 
Leiomyomas. Obstetrics & Gynecology 2008;112(2 Part 1):387-400. 
Activella FDA Clinical Pharmacology Review. November 1998. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20907.cfm. Accessed: 16 August 
2016. 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 06 August 2016. 
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: 08 July 2016. 
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. 
Carr BR, Marshburn PB, Weatherall PT, Bradshaw KD, Breslau NA, Byrd W, Roark M, 
Steinkampf MP. An evaluation of the effect of gonadotropin-releasing hormone analogs 
and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance 
imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial. 
Journal of Clinical Endocrinology & Metabolism 1993;76(5):1217-23. 
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. 
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: 16 August 2016. 
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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: 
http://effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed: 16 August 2016. 
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. 
Lee DY, Park HG, Yoon BKoo, 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: 16 August 2016. 
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. 
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. 
Breast Imaging Reporting and Data System (BI-RADS) 
Category 
Assessment 
Follow-up 
0 
Need additional imaging evaluation:  means that more 
studies are necessary to gather more information. 
Additional imaging needed 
before a category can be 
assigned. 
1 
Negative:  means that there is no significant or 
noticeable abnormality to report. 
Continue annual screening 
mammography (for women 
over age 40). 
2 
Benign (noncancerous) finding:  means that there has 
been a finding, such as benign calcifications or 
fibroadenoma, which is not cancerous. 
Continue annual screening 
mammography (for women 
over age 40). 
3 
Probably benign:  means that there is a finding that is 
most likely benign, but should be followed in a shorter 
period of time to see if the area of concern changes. 
Receive a 6-month follow-up 
mammogram. 
4 
Suspicious abnormality:  means that there are 
suspicious findings that could turn out to be cancer. 
May require biopsy. 
5 
Highly suggestive of malignancy (cancer):  means that 
there are findings that look like and probably are 
cancer. 
Requires biopsy. 
6 
Known biopsy-proven malignancy (cancer):  means that 
any findings on the mammogram have already proven 
to be cancer through a biopsy. 
Biopsy confirms presence of 
cancer before treatment begins. 
 
 
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Appendix 2. 
Daily eDiary 
  
  
 
 
 
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Appendix 3. 
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 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 
Pt. lniliols: ----
Pt. ID: ___ 
_ 
Date: ------
UJERINE FIBROID 
!IE.>\L TH·REL\ TID QUALITY OF 
UF:E QUESTION!\AIRE (liFS-QOL) 
Liste-d bt:low an symptoms expe-rienced by wotoecn n:ho han u tuine 6broids. Please consider each 
.symp tom as it relates to your u terine fibroids or mmstru.al c,•C'Ie. Ea<'h question asks how mu<'h distress 
you han expe-rienced from ea<'h .symp tom during tM pre,ious 3 months. 
nH'e are no right or wrong aa'lttus. Please be sure to answer enry question by che-c-klng (.I) tM most 
appropriate box. If a question does not apply to you, please m.ark "not at all" as a response,. 
During the pretious 3 months, how did:ressed 
f\ot at 
A tittle 
A Cffi'l 
An·ry 
ttH'e you by ... 
all 
bit 
what 
d..U 
great 
d..U 
I. He.vy bleedmg during your menstnl.ll period 
Q 
Q 
Q 
Q 
Q 
2. PassU>g blood clots during your menstnl.1l period Q 
Q 
Q 
Q 
Q 
3. Fluctuation in the duration of your menstrual 
Q 
Q 
Q 
Q 
Q 
period cocq>ared to your previous cycles 
4. Fluctuation in the length of your monthly cycle 
Q 
Q 
Q 
Q 
Q 
compared to your previous cycles 
5. Feeling tightness or pre5SW'e in yOW' pel\'ic area 
Q 
Q 
0 
Q 
Q 
• 
6. Fnqumt urination during the daytime hours 
D 
D 
0 
D 
D 
' 
• 
. 
. 
. 
7. Frequent nighttime urinafioo 
Q 
Q 
Q 
Q 
Q 
8. Feelil!g farigued 
0 
0 
D 
0 
0 
' 
• 
. 
. 
. 
® Cq>yright 2001 CIRREF. All riglus resemd 
* 
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The foUoning que.'ition'> ask about your ff'f'lings and experiences regarding the impact of 
ute1ine fibroid symptoms on your life. Please con.'iidet· each question as it rebtes to your 
experiences uith uterine fi:broids during the prtlious 3 months. 
There are no right or UTong answers. Please be sure to answet· eYE:I'Y qut.'ition by chedting 
V ) the most appt'Opliate bo:t. If the question dot-' not apply to yo11, pltMt cbedt "none 
ol the time" as your option. 
During the pretious 3 months, how often 
your symptoms reb ted to ut erine fibroids. .. 
9. Made you tftl anxious abouttbe 
._-bw onset or cluntioo of your 
periods? 
10. Made you a:oxious about tnnling? 
12. Caused you to feel tUM 01' wom out? 
l l. Made you deere.,. the ......, oCrime you 
speot on exercise or other physical activities? 
14. Made you feel as if you are not in control of 
your life? 
15. Made you<ODOellll!d about soiling 
UDderclotbes? 
16. Made you fiH.IIess 
17. Caused you to li!el drowsy oc slftpy during 
the day? 
18. Made you feel 
of mrigbt 
. ? 
gam. 
19. Made you feel that it was diffi.cult to cany 
out your usual acti\'ities? 
20. Interfered with your social activities? 
21. Made you feel conscious about the size and 
appearmce of your stomach? 
22. Made you coocemed about soiling bed linen? 
® Cq>yright 2001 CIRREF. All rigllls resEmd 
'= -?1117JCIOI 
None of 
the 
time 
0 . 
Q 
Q 
Q 
0 . 
Q 
Q 
A tittlE 
of the 
time 
0 • 
0 • 
0 • 
0 • 
0 • 
0 • 
0 • 
0 • 
0 • 
Some 
of the 
time 
0 . 
0 • 
0 • 
0 • 
0 • 
Q 
Q 
0 . 
0 • 
0 • 
0 • 
Most 
of the 
time 
0 . 
Q 
Q 
Q 
Q 
Q 
0 . 
Q 
Q 
All of 
the 
time 
0 . 
Q 
Q 
Q 
0 . 
Q 
Q 
2 
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During the pre'riou1 3 months, how often 
None of A tittl• 
Some of Most of 
All of 
your symptoms reb ted to uterine fibroids. .. 
th• 
of the 
th• 
the time 
th• 
tim• 
time 
tim• 
tim• 
23. Made you feel 
or hopele>s? 
Q 
Q 
Q 
Q 
Q 
24. Made youfeeldownbeart.d.mdblue? 
Q 
D 
D 
Q 
Q 
• 
' 
25. Made you feel wiped out? 
Q 
Q 
Q 
Q 
Q 
26. Caused you to be coocemed or worried about 
Q 
Q 
Q 
Q 
Q 
your health? 
27. Caused you to plan acti\itie:s more carefully? 
Q 
Q 
Q 
Q 
Q 
28. Made you feel iDcon1.;'EDi.eoced about always 
caayiog -.,pads, tampoas, aDd clotbiog to 
Q 
D 
D 
Q 
Q 
n-oid accidents? 
• 
' 
29. Caused you embanassmeot? 
Q 
Q 
Q 
Q 
Q 
30. Made you feel tmcertain about your future? 
Q 
Q 
Q 
Q 
Q 
31. Made you feel initabw? 
Q 
Q 
Q 
Q 
Q 
32. Made you <ODCemed about soiling out... 
Q 
D 
D 
Q 
Q 
clothes? 
• 
' 
33. Affi!cted the SU. of clotbiog you wear duriDg 
Q 
D 
D 
Q 
Q 
yow' periods? 
• 
' 
34. Made you feel that you al'e not in control of 
Q 
Q 
Q 
Q 
Q 
your health? 
35. Made you feel \\oeak as ifeoergywas drained 
Q 
Q 
Q 
Q 
Q 
fromy .... body? 
36. Diminished your sexwl cleoirt? 
D 
D 
D 
D 
D 
' 
• 
• 
. 
. 
37. Caused you to avoid sexwlrelaU«os? 
Q 
Q 
Q 
Q 
Q 
® Cq>yright 2001 CIRREF. All rigbls resEmd 
3 
" 
'= -?1117JCIOI 
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Appendix 5. 
European Quality of Life Five-Dimension Five-Level Scale 
 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
I have slight problems walking 
I have moderate problems walking 
I have severe problems walking 
I am unable to walk 
SELF-CARE 
I have no problems washing or dressing myself 
I have slight problems washing or dressing myself 
I have moderate problems washing or dressing myself 
I have severe problems washing or dressing myself 
I am unable to wash or dress myself 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
I have no problems doing my usual activities 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
PAIN I DISCOMFORT 
I have no pain or discomfort 
I have slight pain or discomfort 
I have moderate pain or discomfort 
I have severe pain or discomfort 
I have extreme pain or discomfort 
ANXIETY I DEPRESSION 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed 
I am severely anxious or depressed 
I am extremely anxious or depressed 
2 
USA (English) © 2009 EuroQol Group EQ-50rM is a trade mark of the EuroQol Group 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
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Copyright ©, Stichting EuroQoL Research Foundation, all rights reserved. 
• 
We would like to know how good or bad your health is TODAY. 
• 
This scale is numbered from 0 to 100. 
• 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• 
Mark an X on the scale to indicate how your health is TODAY. 
• 
Now, please write the number you marked on the scale in the box 
below. 
YOUR HEALTH TODAY= D 
3 
USA (English) © 2009 EuroQol Group EQ-sorM is a trade mark of the EuroQol Group 
The best health 
you can imagine 
100 
95 
90 
85 
80 
75 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
The worst health 
you can imagine 
15 
10 
5 
0 
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Appendix 6. 
Assessment of Abnormal Liver Function Tests 
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) should be withheld for any liver test abnormality 
listed in Section 7.5.1, pending investigation of alternative causes of liver injury.  Follow-up 
should continue until the liver test abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations in 
Appendix Table 2.  If close monitoring is not possible, study drug should be withheld even if the 
results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]), Alkaline 
Phosphatase, and INR Tests 
If AST or ALT ≥ 3 × ULN and total 
bilirubin > 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities 
improve 
If ALT or AST ≥ 3 × ULN and total 
bilirubin and INR are normal  
Every 48 to 72 hours until laboratory 
abnormalities improve 
If the liver test abnormalities improve 
AND the patient is asymptomatic 
Frequency may decrease 
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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CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
 
Study Title: 
An International Phase 3 Randomized, Double-Blind, Placebo-
Controlled Efficacy and Safety Study to Evaluate Relugolix 
Co-Administered with and without Low-Dose Estradiol and 
Norethindrone Acetate in Women with Heavy Menstrual 
Bleeding Associated with Uterine Fibroids 
Investigational Product: 
Relugolix 
Protocol Number: 
MVT-601-3001 
Indication: 
Treatment of heavy menstrual bleeding associated with uterine 
fibroids 
Sponsor: 
Myovant Sciences GmbH 
c/o Vischer AG 
Aeschenvorstadt 4 
CH-4010 Basel 
Switzerland 
IND #: 
131161 
Version: 
Original 
Effective Date: 
10-NOV-2016 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Myovant Sciences GmbH, and is provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee.  The information is only to be 
used by you in connection with authorized clinical studies of the investigational drug described 
in the protocol.  You will not disclose any of the information to others without written 
authorization from Myovant Sciences GmbH, except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
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PPD

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CONFIDENTIAL 
INVESTIGATOR STATEMENT 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the conduct of 
the study understand their obligations and will comply with the study protocol.  
Mechanisms are in place to ensure that site staff receives the appropriate training and 
information throughout the study. 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
 
 
Date 
 
Site 
 
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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 .................................................................................................................................... 8 
List of Abbreviations .......................................................................................................................... 9 
1. 
Protocol Synopsis ................................................................................................................. 11 
1.1. 
Schedule of Activities ....................................................................................................... 21 
2. 
Introduction ......................................................................................................................... 25 
2.1. 
Uterine Fibroids with Heavy Menstrual Bleeding................................................................ 25 
2.2. 
Relugolix ......................................................................................................................... 26 
2.2.1. 
Indication ................................................................................................................. 26 
2.2.2. 
Pharmacology .......................................................................................................... 26 
2.2.3. 
Nonclinical Toxicology............................................................................................. 27 
2.2.4. 
Previous Human Experience...................................................................................... 28 
3. 
Study Objectives and Endpoints ............................................................................................ 32 
4. 
Investigational Plan .............................................................................................................. 34 
4.1. 
Overall Study Design ........................................................................................................ 34 
4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of Control Group......... 37 
4.3. 
Selection of Study Population ............................................................................................ 39 
4.3.1. Inclusion Criteria .............................................................................................................. 39 
4.3.2. 
Exclusion Criteria ..................................................................................................... 40 
4.4. 
Screening ......................................................................................................................... 43 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID Number ........................... 43 
4.6. 
Removal of Patients from Therapy ..................................................................................... 43 
4.7. 
Contraception/Pregnancy Avoidance.................................................................................. 44 
5. 
Treatments ........................................................................................................................... 45 
5.1. 
Treatments Administered .................................................................................................. 45 
5.2. 
Identity of Investigational Product ..................................................................................... 46 
5.2.1. 
Product Characteristics.............................................................................................. 46 
5.3. 
Randomization and Stratification ....................................................................................... 47 
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5.4. 
Directions for Administration ............................................................................................ 47 
5.5. 
Dose Reduction/Dose Administration ................................................................................ 47 
5.6. 
Storage, Packaging, and Labeling ...................................................................................... 48 
5.7. 
Blinding ........................................................................................................................... 48 
5.8. 
Study Drug Accountability and Treatment Compliance ....................................................... 49 
5.9. 
Treatment after the End of Study ....................................................................................... 49 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies.............................................. 49 
5.10.1. 
Prohibited Medications ............................................................................................. 49 
5.10.2. 
Permitted Medications .............................................................................................. 51 
5.10.3. 
Prohibited Non-Drug Therapies ................................................................................. 52 
6. 
Study Assessments and Procedures ........................................................................................ 52 
6.1. 
Schedule of Observations and Procedures........................................................................... 52 
6.2. 
Screening Period .............................................................................................................. 52 
6.3. 
Randomized Treatment Period (Baseline to Week 24) ......................................................... 54 
6.4. 
Continuation into Extension Study ..................................................................................... 54 
6.5. 
Follow-up Visit ................................................................................................................ 54 
6.6. 
Unscheduled Visits ........................................................................................................... 55 
6.7. 
Study Procedures .............................................................................................................. 55 
6.7.1. 
Efficacy-Related Procedures...................................................................................... 55 
6.7.2. 
Safety-Related Procedures......................................................................................... 58 
6.8. 
Biological Sample Retention and Destruction ..................................................................... 61 
7. 
Safety Considerations ........................................................................................................... 61 
7.1. 
Adverse Event Definitions................................................................................................. 61 
7.1.1. 
Adverse Event .......................................................................................................... 61 
7.1.2. 
Serious Adverse Event .............................................................................................. 62 
7.2. 
Adverse Event Reporting .................................................................................................. 63 
7.2.1. 
Adverse Event Reporting Period ................................................................................ 64 
7.3. 
Assigning Causal Relationship to Study Drug ..................................................................... 64 
7.4. 
Assigning Severity Rating for Adverse Events .................................................................... 65 
7.5. 
Adverse Events of Clinical Interest Reporting..................................................................... 65 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver Test 
Abnormalities .......................................................................................................................... 66 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with Liver Test 
Abnormalities .......................................................................................................................... 66 
7.6. 
Serious Adverse Event Reporting ...................................................................................... 67 
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7.7. 
Study Drug Overdose Management.................................................................................... 67 
7.8. 
Pregnancy Reporting......................................................................................................... 68 
7.9. 
Vital Signs, Physical Examinations, Clinical Laboratory Tests, Electrocardiograms, and Bone 
Mineral Density Measures ................................................................................................ 68 
7.10. 
Benefit/Risk Assessment ................................................................................................... 68 
8. 
Data Quality Assurance......................................................................................................... 71 
8.1. 
Clinical Procedures ........................................................................................................... 71 
8.2. 
Monitoring ....................................................................................................................... 71 
9. 
Statistical Considerations and Data Analyses .......................................................................... 71 
9.1. 
Randomization Methods ................................................................................................... 72 
9.2. 
Analysis Populations......................................................................................................... 72 
9.3. 
Efficacy Analyses ............................................................................................................. 72 
9.3.1. 
Primary Endpoint Analysis........................................................................................ 73 
9.3.2. 
Secondary Endpoint Analyses ................................................................................... 73 
9.4. 
Safety Analyses ................................................................................................................ 75 
9.5. 
Pharmacokinetic Analyses................................................................................................. 76 
9.6. 
Exploratory Analyses ........................................................................................................ 76 
9.7. 
Interim Analyses .............................................................................................................. 76 
10. 
Responsibilities .................................................................................................................... 77 
10.1. 
Investigator Responsibilities .............................................................................................. 77 
10.1.1. 
Good Clinical Practice .............................................................................................. 77 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ........................... 77 
10.1.3. 
Informed Consent ..................................................................................................... 77 
10.1.4. 
Confidentiality ......................................................................................................... 78 
10.1.5. 
Study Committees and Communication...................................................................... 78 
10.1.6. 
Study Files and Retention of Records ......................................................................... 78 
10.1.7. 
Electronic Case Report Forms ................................................................................... 80 
10.1.8. 
Investigational Product Accountability ....................................................................... 80 
10.1.9. 
Inspections ............................................................................................................... 80 
10.1.10. 
Protocol Compliance................................................................................................. 80 
10.2. 
Sponsor Responsibilities ................................................................................................... 81 
10.2.1. 
Protocol Modifications .............................................................................................. 81 
10.2.2. 
Study Report ............................................................................................................ 81 
10.2.3. 
Posting of Information on Publically Available Clinical Trial Registers........................ 81 
10.3. 
Joint Investigator/Sponsor Responsibilities......................................................................... 81 
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10.3.1. 
Access to Information Monitoring ............................................................................. 81 
10.3.2. 
Access to Information for Auditing or Inspections ...................................................... 82 
10.3.3. 
Study Discontinuation ............................................................................................... 82 
10.3.4. 
Publications ............................................................................................................. 82 
References ....................................................................................................................................... 83 
Appendices ...................................................................................................................................... 85 
Appendix 1. 
Breast Imaging Reporting and Data System (BI-RADS) .......................................... 85 
Appendix 2. 
Daily eDiary......................................................................................................... 86 
Appendix 3. 
Menorrhgia Impact Questionnaire .......................................................................... 88 
Appendix 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire ................................... 89 
Appendix 5. 
European Quality of Life Five-Dimension Five-Level Scale .................................... 91 
Appendix 6. 
Assessment of Abnormal Liver Function Tests ....................................................... 93 
 
LIST OF TABLES 
Table 1-1 
Schedule of Activities for Study MVT-601-3001 ........................................................ 21 
Table 5-1 
Description of MVT-601-3001 Study Drugs ............................................................... 46 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization ......................................... 47 
Table 5-3 
Prohibited Medications and Washout Periods ............................................................. 49 
Table 6-1 
Clinical Laboratory Tests .......................................................................................... 59 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE Version 5.0 ................................... 65 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies ................................................... 69 
 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury ..................... 93 
Appendix Table 2 
Investigations of Alternative Causes for Abnormal Liver Tests ............................ 94 
 
 
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LIST OF FIGURES 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001)........................ 29 
Figure 4-1 
MVT-601-3001 Study Schematic............................................................................... 36 
Figure 4-2 
Schematic of MVT-601-3001 Screening Visits and Feminine Product 
Dispensation and Collection during the Screening Period ............................................ 36 
 
 
 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
EQ-5D 
European Quality of Life Five-Dimension Five-Level 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-24 
area under the concentration-time curve from time 0 to 24 hours 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
di-22:6-BMP 
di-22:6-bis(monoacylglycerol)phosphate 
DXA 
dual-energy x-ray absorptiometry 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eDiary 
electronic diary 
EQ-5D 
European Quality of Life Five-Dimension Five-Level Scale 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GnRH 
gonadotropin-releasing hormone 
HDL 
high-density lipoprotein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
Intent-to-Treat (Population) 
IVRS/IWRS 
Interactive Voice/Web Recognition Service 
LFT 
liver function tests 
LH 
luteinizing hormone 
MBL 
menstrual blood loss 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIQ 
Menstrual Impact Questionnaire 
mmHg 
millimeters of mercury 
NOAEL 
no-observed-adverse-effect level 
NOEL 
no-observed-effect level 
PBAC 
Pictorial Blood Loss Assessment Chart 
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Term 
Explanation 
PD 
pharmacodynamics 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PLD 
phospholipidosis 
QTc 
corrected QT interval 
QTcF 
QT interval by the Fridericia correction 
SAP 
statistical analysis plan 
SD 
standard deviation 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
USP/NF 
United States Pharmacopeia and the National Formulary 
VAS 
visual analogue score 
WBC 
white blood cells 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
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1. 
PROTOCOL SYNOPSIS 
Study Title 
An International Phase 3 Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study to Evaluate Relugolix Co-Administered with and 
without Low-Dose Estradiol and Norethindrone Acetate in Women with 
Heavy Menstrual Bleeding Associated with Uterine Fibroids 
Protocol Number 
MVT-601-3001 
Location 
Multinational, including North and South America, Europe, and Australia 
Study Centers 
Approximately 120 sites 
Study Phase 
Phase 3 
Target Population 
Women aged 18 to 50 years diagnosed with heavy menstrual bleeding 
associated with uterine fibroids 
Number of Patients 
Planned 
Approximately 390 (~ 130 relugolix co-administered with low-dose estradiol 
and norethindrone acetate, ~ 130 relugolix monotherapy followed by relugolix 
co-administered with low-dose estradiol and norethindrone acetate, and ~ 
130 placebo) 
Study Objectives 
Primary Efficacy Objective 
• 
To determine the benefit of relugolix 40 mg once daily co-administered 
with low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding associated with uterine 
fibroids. 
 
Secondary Efficacy Objectives 
• 
To determine the benefit of relugolix 40 mg once daily for 12 weeks 
followed by 12 weeks of relugolix 40 mg once daily co-administered with 
low-dose estradiol and norethindrone acetate compared with placebo for 
24 weeks on heavy menstrual bleeding associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo for 24 weeks on the 
following: 
o Change in hemoglobin; 
o Impact of heavy menstrual bleeding on social, leisure, and physical 
activities; 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
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Safety Objectives 
• 
To determine the safety of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate in women with heavy menstrual bleeding associated 
with uterine fibroids compared with placebo for 24 weeks; 
• 
To determine the change in bone mineral density of women with heavy 
menstrual bleeding associated with uterine fibroids treated with 24 weeks 
of relugolix 40 mg once daily co-administered with either 12 or 24 weeks 
of low-dose estradiol and norethindrone acetate compared with placebo 
for 24 weeks. 
 
Pharmacokinetic and Pharmacodynamic Objectives 
• 
To evaluate the pharmacokinetic (PK) and pharmacodynamic effects of 
24 weeks of relugolix 40 mg once daily when co-administered with either 
12 or 24 weeks of low-dose estradiol and norethindrone acetate  
 
Exploratory Objectives 
• 
To determine the benefit of 24 weeks of relugolix 40 mg once daily co-
administered with either 12 or 24 weeks of low-dose estradiol and 
norethindrone acetate compared with placebo on patient-reported quality 
of life outcome measures. 
Study Design 
This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety 
study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-dose estradiol 
and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
compared with 24 weeks of placebo.  Approximately 390 women with heavy menstrual bleeding 
associated with uterine fibroids will be enrolled and randomized 1:1:1 to the relugolix plus low-dose 
hormonal add-back therapy group (Group A; N ≈ 130), the relugolix monotherapy followed by co-
administration with low-dose hormonal add-back therapy group (Group B; N ≈ 130), or placebo group 
(Group C; N ≈ 130).  Stratification variables will include:  geographic region (North America versus 
Rest of World) and mean screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the 
alkaline hematin method. 
The study consists of a screening period (~11 weeks), a randomized treatment period (24 weeks), and a 
follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) may be arranged for 
patients with study-related safety concerns as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by centrally-reviewed 
transvaginal and/or transabdominal ultrasound.  Heavy menstrual bleeding will be defined as menstrual 
blood loss of ≥ 80 mL each cycle for 2 cycles during the screening period.  During the randomized 
treatment period, study participants will take blinded study treatment orally once daily for 24 weeks.  
Women with iron-deficient microcytic anemia and hemoglobin ≥ 8 g/dL and ≤ 10 g/dL at Screening 
must be treated with oral or parenteral iron replacement therapy.  Between the Baseline Day 1 and 
Week 24 visits, patients will attend visits monthly (ie, every 4 weeks).  At the Screening, Week 12, and 
Week 24 visits, patients will have an assessment of bone mineral density with dual-energy x-ray 
absorptiometry (DXA).  An endometrial biopsy will also be performed at Screening.  A transvaginal 
and/or transabdominal ultrasound will be performed at Week 24, followed by a repeat endometrial 
biopsy.  Patients will have paired baseline and end-of-treatment endometrial biopsies, independent of 
ultrasound results.  Feminine products will be standardized and will be collected and assessed for blood 
loss by the alkaline hematin method.  Complete blood counts and chemistries will be collected monthly 
and uterine and uterine fibroid volumes will be assessed at the Screening and Week 24 visits.  Patients 
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will complete daily electronic diaries (eDiary) including compliance with study treatment, menstrual 
bleeding, use of feminine products for menstrual bleeding, uterine fibroid-associated pain by the 
Numerical Rating Scale, and use of pain medication to treat pain caused by uterine fibroids.  Quality of 
life questionnaires will be completed according to the Schedule of Activities. 
Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, endometrial 
biopsies, and assessments of bone mineral density.  Height will be measured at the Screening 1 visit 
and weight will be measured at specified intervals. 
Samples will be collected for PK assessment of relugolix, estradiol, and norethindrone and for the 
pharmacodynamic assessment of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
estradiol, and progesterone. 
All patients completing the Week 24 visit, including women randomized to placebo, will be offered the 
opportunity to enroll in an open-label extension study in which all eligible patients will receive 
relugolix co-administered with low-dose estradiol and norethindrone acetate.  Patients who do not 
enroll into the extension study will have a follow-up visit approximately 30 days after the end of 
treatment (ie, after the patient’s last dose of study medication). 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria (all inclusion criteria must have been met prior to randomization unless otherwise 
specified): 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening 
or study-specific procedures; 
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating 
the informed consent form; 
3. Has a body mass index (BMI) within the range of 18.0 to 40.0 kg/m2 (inclusive); 
4. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 38 days 
from the start of one menstrual period until the start of the next, by patient history for at least 
3 months prior to the Screening 1 visit; 
5. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal and/or transabdominal 
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ultrasound performed with saline or gel contrast during the screening period.  At least one 
uterine fibroid must be verified by a central reader to meet at least one of the following criteria: 
a. Subserosal, intramural, submucosal non-pedunculated fibroid with a diameter ≥ 2 cm 
(longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3; 
6. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a menstrual 
blood loss of ≥ 80 mL per cycle as measured by the alkaline hematin method for 2 menstrual 
cycles during the screening period; 
7. Patient does not desire and is not expected to be a candidate for gynecological surgery or 
ablation procedures within the 6 months following enrollment; 
8. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 visits; 
9. Agrees to use two forms of non-hormonal contraception (dual contraception, as described in 
Section 4.7) consistently during any required washout for excluded medications (if applicable), 
the screening period, and the randomized treatment period.  However, the patient is not 
required to use dual contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the screening 
period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the first screening visit (patients with Essure must 
have prior confirmation of tubal occlusion by hysterosalpingogram); 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires the 
use of dual non-hormonal contraception as noted above; or 
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; periodic 
abstinence is not acceptable; 
10. Has an adequate endometrial (aspiration) biopsy performed during the screening period, with 
results showing no clinically significant endometrial pathology (hyperplasia, polyp, 
endometritis, or endometrial cancer); 
11. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram (Breast 
Imaging Reporting and Data System category 1 to 3 or equivalent) during the screening period 
or within 3 months prior to the screening period; 
12. A randomization authorization form has been signed by a study medical monitor approving the 
patient for randomization into the trial. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating 
pathology other than uterine fibroids that could be responsible for or contributing to the 
patient’s heavy menstrual bleeding, such as uterine or cervical polyps, or any other clinically 
significant gynecological disorder determined by the investigator to require further evaluation 
and/or treatment; 
2. Has unexplained vaginal bleeding outside of the patient’s regular menstrual cycle; 
3. 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, as well as endometrial ablation for abnormal uterine bleeding 
within 6 months prior to the Screening 1 visit; 
4. Has a weight that exceeds the weight limit of the DXA scanner; 
5. Has a baseline bone mineral density z-score < -2.0 at spine or total hip; 
6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic 
(from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures 
are allowed).  A history of successfully treated hyperparathyroidism, hyperprolactinemia, or 
hyperthyroidism is allowed if the patient’s bone mineral density is within normal limits; 
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7. Has a history of the use of bisphosphonates, calcitonin/calcitriol, ipriflavone, teriparatide, 
denosumab, or any medication other than calcium and vitamin D preparations to treat bone 
mineral density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of more than 
5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, ophthalmic, 
intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
10. 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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A (HAV 
IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical glandular 
cells, atypical endocervical cells, atypical squamous cells favoring high grade.  Of note, 
patients with atypical squamous cells of undetermined significance and low-grade cervical 
neoplasia may be included in the study; 
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with initial screening hemoglobin results < 8 g/dL 
may be prescribed iron supplements and have their hemoglobin levels retested prior to 
the Baseline Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper limit of 
normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical laboratory testing 
at either the Screening 1 or Screening 2 visit (or > 2.0 x ULN if secondary to Gilbert 
syndrome or pattern consistent with Gilbert syndrome); 
c. Calculated creatinine clearance < 60 mL/min using the Modification of Diet in Renal 
Disease method; 
14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina; 
c. History of congestive heart failure; 
d. History of clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes, or history of permanent 
pacemaker, Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place or untreated supraventricular tachycardia (heart rate ≥ 120 beats 
per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury 
(mmHg) on 2 repeat measures at least 15 minutes apart, or treated ongoing 
symptomatic orthostatic hypotension with > 20 mmHg decrease in systolic blood 
pressure one minute or more after assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg on 2 
repeat measures at least 15 minutes apart or diastolic blood pressure > 100 mmHg at 
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any screening visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram; 
15. Has been a participant in an investigational drug or device study within the 1 month prior to 
Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the following: 
a. Untreated thyroid dysfunction or palpable thyroid abnormality (patients with 
adequately treated hypothyroidism who are stable on medication are not excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than 
curatively treated nonmelanoma skin cancer or surgically cured Stage 0 in situ 
melanoma; 
c. History of major depression or other major psychiatric disorder at any time including 
bipolar disorder, schizophrenia, or post-traumatic stress disorder (patients without a 
history of major depression treated with a selective serotonin-reuptake inhibitor 
antidepressant may be enrolled if stable for over 1 year); 
17. Is currently pregnant or lactating, or intends to become pregnant or to donate ova during the 
study period or within 1 month after the end of the study; 
18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable washout 
periods from these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or components 
thereof; or has a history of drug or other allergy that, in the opinion of the investigator or 
medical monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all patients 
must be questioned about their drug and alcohol use and this should be documented in the 
electronic case report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship with a 
study site employee who is involved in the conduct of this study (eg, spouse, parent, child, or 
sibling); 
23. Is inappropriate for participation in this study for other reasons, as determined by the 
investigator or sub-investigator or medical monitor. 
Dose and Route of 
Administration 
Test Product (Group A and Group B) 
• 
Group A:  Relugolix 40 mg tablet will be co-administered orally once 
daily with 1.0 mg estradiol/0.5 mg norethindrone acetate in a co-
formulated tablet.  The low-dose hormonal add-back therapy will be over-
encapsulated. 
• 
Group B:  Relugolix 40 mg tablet co-administered orally once daily with 
a placebo capsule designed to match the over-encapsulated active low-
dose hormonal add-back therapy in size, shape, color, and odor for 
12 weeks, followed by relugolix 40 mg tablet co-administered orally once 
daily with 1.0 mg estradiol/0.5 mg norethindrone acetate.  The active low-
dose hormonal add-back therapy will be over-encapsulated. 
Reference Product (Group C) 
• 
Group C:  Placebo relugolix manufactured to match relugolix in size, 
shape, color, and odor will be co-administered orally once daily with a 
placebo capsule designed to match the over-encapsulated active low-dose 
hormonal add-back therapy in size, shape, color, and odor. 
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Duration of 
Treatment 
Study treatment will be administered for 24 weeks (randomized treatment 
period).  For women who do not to enroll in an open-label extension study, 
there is a 30-day follow-up period after the end of treatment (ie, after the 
patient’s last dose of study medication). 
Criteria for 
Evaluation 
Inferential efficacy assessments will be made between the following groups 
and placebo after 24 weeks of study treatment: 
• 
Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-
administered with 1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• 
Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each 
relugolix group and placebo for safety outcomes and between each of the two 
relugolix groups for both efficacy and safety.  
 
Primary Efficacy Endpoint 
• 
Proportion of women in the relugolix Group A versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
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Secondary Efficacy Endpoints 
• 
Proportion of women in the relugolix Group B versus the placebo Group 
C who achieve a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline menstrual blood loss volume over the last 
35 days of treatment, as measured by the alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix 
treatment group to placebo inferentially and relugolix Group A to Group B 
descriptively: 
• 
Time to achieving a menstrual blood loss volume of < 80 mL AND at 
least a 50% reduction from baseline menstrual blood loss volume as 
measured by the alkaline hematin method; 
• 
Change from Baseline to Week 24 in menstrual blood loss;  
• 
Proportion of women who achieve amenorrhea over the last 35days of 
treatment as measured by the alkaline hematin method; 
• 
Time to amenorrhea as measured by the by the alkaline hematin method; 
• 
Proportion of women with a hemoglobin below the lower limit of normal 
at Baseline who achieve an increase of ≥ 1 g/dL from Baseline at Week 
24; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for physical activities; 
• 
Change from Baseline to Week 24 in the Menorrhagia Impact 
Questionnaire Score for social and leisure activities; 
• 
Proportion of women who achieve a mean Numerical Rating Scale score 
for uterine fibroid-associated pain over the last 35 days of treatment that 
is at least a 30% reduction from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days prior to randomization; 
• 
Change from Baseline to Week 24 in uterine volume; and 
• 
Change from Baseline to Week 24 in uterine fibroid volume. 
 
Safety Endpoints 
• 
Treatment-emergent adverse events, change in vital signs (including 
weight), clinical laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Weeks 12 and 24 in bone mineral 
density at the spine (average of L1-L4), total hip, and femoral neck as 
assessed by DXA; 
• 
Incidence of vasomotor symptoms. 
 
Pharmacokinetic and Pharmacodynamic Endpoints 
• 
Pre-dose trough concentrations (Cτ) of relugolix, estradiol, and 
norethindrone from Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-dose concentrations of LH, 
FSH, estradiol, and progesterone. 
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Exploratory Endpoints 
• 
Change from Baseline to Week 24 in the Uterine Fibroid Scale – Quality 
of Life Symptom Severity and Health-related Quality of Life subscales 
comparing each relugolix treatment group to placebo inferentially and the 
two relugolix groups descriptively; 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-
Dimension Five-Level scale comparing each relugolix treatment group to 
placebo inferentially and the two relugolix groups descriptively. 
Statistical Methods 
Efficacy 
The efficacy analyses will be conducted using an Intent-to-Treat (ITT) Population defined as all 
randomized patients, unless otherwise specified in the statistical analysis plan.  Randomization will be 
1:1:1 with the stratification variables of geographic region and mean screening menstrual blood loss 
volume (mL per alkaline hematin method) as follows: 
• 
Geographic Region:  North America versus Rest of World; 
• 
Mean screening menstrual blood loss volume:  < 225 mL versus ≥ 225 mL. 
The randomization stratification factors will be incorporated into inferential testing of all efficacy 
endpoints, unless otherwise specified. 
The primary hypothesis tested in this study is whether relugolix co-administered with 1.0 mg estradiol 
and 0.5 mg norethindrone acetate is superior to placebo in the percentage of women who achieve both 
a menstrual blood loss volume of < 80 mL AND at least a 50% reduction in menstrual blood loss 
volume over the last 35 days on treatment as compared with Baseline. 
The point estimate and 2-sided 95% confidence interval of the difference in the proportion will be 
calculated between the relugolix Group A and placebo Group C.  The between-treatment comparisons 
will be performed using the Cochran-Mantel-Haenszel method. 
The comparisons of the relugolix arms versus placebo will be performed for the secondary efficacy and 
safety endpoints using appropriate statistical methods.  Comparisons between the two relugolix arms 
will be descriptive.  A closed testing procedure will be used to control the overall type I error rate of 
5% across primary and secondary endpoint testing.  Details of this procedure will be provided in the 
statistical analysis plan. 
Sample Size 
Assuming a placebo control response rate of 25%, the assessment of the superiority of relugolix 40 mg 
co-administered with low-dose hormonal add-back therapy (Group A) versus placebo (Group C) in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size of 260 (130 
patients in each of the relugolix and placebo arms) will provide > 99% power to detect a difference of 
greater than 30 percentage points using a 2-sided test at significance level of 0.05.  The total sample 
size for the study will be approximately 390 patients (130 patients in each of the 3 arms). 
Safety 
Safety assessments will include treatment-emergent adverse events, vital signs, physical examinations, 
clinical laboratory tests, 12-lead electrocardiograms, endometrial biopsies, and assessments of bone 
mineral density.  Safety analyses will be based on all randomized patients who receive any amount of 
study drug (safety population).  Drug exposure will be summarized by descriptive statistics.  Severity 
of all treatment-emergent adverse events will be evaluated by the investigator based on the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 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 
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presented by MedDRA system organ class and preferred term, relationship to study drug, and severity.  
Descriptive statistics will be used rather than inferential statistics.  Laboratory values also will be 
classified by toxicity grade based on the National Cancer Institute’s CTCAE, version 5.0.  Laboratory 
shift tables of the 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),), total hip, and femoral neck at the 
Baseline, Week 12, and Week 24 visits and the absolute, percent, and standardized changes from 
baseline will be summarized.  Vasomotor adverse events will be separately summarized. 
A chartered independent Data and Safety Monitoring Board will monitor all available safety data, 
including bone density assessments, on an ongoing basis during this study. 
Pharmacokinetics and Pharmacodynamics 
The PK concentration data (relugolix, estradiol, and norethindrone pre-dose) and pharmacodynamics 
concentration data (LH, FSH, estradiol, and progesterone pre-dose) will be listed and summarized by 
treatment arm and visit.  In addition, the PK data from this study will be combined with PK data from 
other studies to define a population PK model, which will be reported separately.  Exposure-response 
analyses of the primary efficacy endpoint and safety will be conducted to assess the effect of relugolix 
exposure on outcomes. 
 
 
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1.1. 
Schedule of Activities 
Table 1-1 
Schedule of Activities for Study MVT-601-3001 
 
SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1b 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
Baseline 
Day 1d 
(if MBL is 
≥80 mL/cy
cle for 2 
cycles) 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upe 
(~30 days 
after last 
dose of 
study drug) 
Day of Study Drug 
Treatment 
 
 
 
 
1 
29 
57 
85 
113 
141 
169 
 
197 
Visit Window Timing (days)
Within 
4 days 
after com-
pletion of 
menses 
Within 
4 days 
after com-
pletion of 
Screening 
1 menses 
Within 
10 days of 
Screening 
2 visit 
Within 
4 days 
after com-
pletion of 
2nd 
Screening 
menses 
Within 
4 days of 
the start 
of menses 
± 7 
± 7 
± 7 
± 7 
± 7 
± 10 
 
-3 to + 10 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review Eligibility Criteria 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Temperature 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
 
Adverse Event Collectionf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical 
Examination, Including Visual 
Acuityg 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
Gynecologic Examination with 
Pap Test, if applicable 
 
 
Xh 
 
 
 
 
 
 
 
X 
 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1b 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
Baseline 
Day 1d 
(if MBL is 
≥80 mL/cy
cle for 2 
cycles) 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upe 
(~30 days 
after last 
dose of 
study drug) 
Signs and Symptoms-Directed 
Physical Exam 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
X 
12-Lead Electrocardiogram 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Clinical Laboratory Testsi 
X 
X 
 
 
Xi, j 
X 
X 
X 
X 
X 
Xi, k 
Xl 
X 
PK Samplem 
 
 
 
 
X 
X 
 
X 
 
 
X 
Xl 
 
PD Samplen and Administer 
Dose of Study Drug in Clinic 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
PGx Sampleo 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Test (Urine) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Mammogramp 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Transvaginal or 
Transabdominal Ultrasoundq 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Endometrial Biopsyr 
 
 
X 
 
 
 
 
 
 
 
Xs 
 
 
Bone Densitometryt 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Randomizationu 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Dispense Feminine Products 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense Study Treatment 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Patient eDiaryv 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Feminine Product Collection 
and Venous Blood Samplew 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
MIQ 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
UFS-QoL 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
EQ-5D 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Treatment Compliance 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
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SCREENING PERIODa 
RANDOMIZED TREATMENT PERIOD 
SAFETY 
FOLLOW-UP 
VISIT NAME Screening 
1b 
Screening 
2b 
Screening 
3c 
(if MBL is 
≥ 80 mL at 
1st 
Screening 
menses) 
Screening 
4b 
Baseline 
Day 1d 
(if MBL is 
≥80 mL/cy
cle for 2 
cycles) 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
(or Early 
Termin-
ation of 
Study 
Drug) 
Un-
scheduled 
Follow-
upe 
(~30 days 
after last 
dose of 
study drug) 
Status of Menstruation 
Recovery 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Notes: 
Abbreviations:  EQ-5D, European Quality of Life Five-Dimension Five-Level Scale; MBL, menstrual blood loss; MIQ, Menorrhagia Impact Questionnaire; Pap, 
Papanicolaou; PD, pharmacodynamics; PGx, pharmacogenomics; PK, pharmacokinetics; UFS-QoL, Uterine Fibroid Score – Quality of Life 
a. The screening period should be initiated after the informed consent form is signed and any required washout for excluded medications or devices is complete. 
b. Visit to occur within 4 days of the completion of menses. 
c. Visit to occur within 10 days after Screening 2 visit if the menstrual blood loss is determined to be ≥ 80 mL.  The Screening 1 or Screening 2 visits for alkaline 
hematin menstrual blood loss may be repeated at the discretion of the investigator if one menstrual cycle does not meet MBL criteria thought to be due to 
inadequate collection for a highly motivated patient. 
d. The Baseline Day 1 visit should occur within 4 days of the onset of menses.  Collect clinical laboratory, PK sample, pre-dose PD sample, pregnancy and 
urinalysis test samples prior to first dose of study drug.  The patient must complete MIQ, UFS-QoL, and EQ-5D questionnaires prior to first dose of study drug. 
e. Follow-up visit:  For women who do not continue into the open-label extension study (MVT-601-3003), a follow-up visit to assess safety will be scheduled 
approximately 30 days after the last dose of study drug, or the date of initiation of another investigational agent or hormonal therapy or surgical intervention, 
whichever occurs first (ie, ~Week 28 for patients who complete the study or ~4 weeks after an Early Termination visit). 
f. 
Collect serious adverse event information from the time of signed informed consent through approximately 30 days after the last dose of study drug, or the date 
of initiation of another investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  Collect nonserious adverse event information 
from the Baseline Day 1 visit through approximately 30 days after the last dose of study drug, or the date of initiation of another investigational agent or 
hormonal therapy or surgical intervention, whichever occurs first. 
g. Complete Physical Exam (not including a gynecological examination).  Visual acuity must be assessed with a standard eye chart.  The patient should wear any 
prescription glasses or contacts during the assessment. 
h. Papanicolaou test must be conducted for women without a test result 6 months prior to the Screening 1 visit.  Re-measurement should be performed for 
inadequate or false-positive results. 
i. 
Clinical laboratory tests at each visit include clinical chemistries and a complete blood count.   Samples should be obtained in the fasted state for the Baseline 
and Week 24 visit clinical laboratory tests. 
j. 
At the Baseline Day 1 visit (clinical laboratory tests in fasted state), in addition to clinical chemistries and a complete blood count, include a lipid profile, levels 
of parathyroid hormone, thyroid-stimulating hormone, prolactin, iron, ferritin, and hemoglobin A1c.  An additional sample will be collected at this visit and 
stored for possible future testing for presence of hepatitis A, B, and C if required per request from medical monitor to assess etiology of liver test abnormalities. 
k. At the Week 24 visit or Early Termination visit (clinical laboratory tests in fasted state), in addition to clinical chemistries and a complete blood count, include a 
lipid profile, thyroid-stimulating hormone, prolactin, and hemoglobin A1c. 
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l. 
For an Unscheduled visit, a central safety laboratory assessment or PK sample collection is performed as needed. 
m. Pharmacokinetics samples:  Samples should be obtained in the fasted since study drug is administered on an empty stomach.  Collect pre-dose samples for PK 
analysis of relugolix, estradiol (PK lab), and norethindrone.  Instruct the patient not to take her study treatment at home on these visit days and to record the time 
of her previous dose (ie, the dose taken the day before the visit).  Administer study drug after PK and pharmacodynamics sample collections are complete (with 
the exception of Week 24 when no dose is administered). 
n. Pharmacodynamic samples:  Samples should be obtained in the fasted since study drug is administered on an empty stomach, collect pre-dose samples for 
analysis of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations.  Instruct the patient not to take her study treatment at 
home on these visit days.  Administer study drug after PK and pharmacodynamic sample collections are complete (with the exception of Screening 1 visit, 
Week 24 and Follow Up visits when no dose is administered). 
o. Pharmacogenomics sample:  a separate pharmacogenomics consent is required before this sample may be collected.  If possible, the pharmacogenomic sample 
should be collected from consented patients at the Baseline Day 1 visit, but it may be collected at any time during the study through Week 24 (inclusive) 
p. Patients ≥ 39 years of age at the time of the Baseline Day 1 visit must have a normal mammogram (Breast Imaging Reporting and Data System category 1 to 3 
or equivalent) during the screening period or within 3 months prior to the screening period; if not, schedule at the Screening 3 visit. 
q. Transvaginal or transabdominal ultrasound with saline or gel contrast must be performed to confirm the presence of uterine fibroids and the absence of any other 
pathology that might be responsible for the increase in menstrual bleeding, such as uterine or cervical polyps.  Results must be submitted to and confirmed by a 
central reader prior to randomization into the study.  Note:  Transvaginal ultrasound is the preferred procedure.  A transabdominal ultrasound may also be 
obtained if indicated, for example, by extension of large masses outside the pelvis. 
r. 
Endometrial biopsy is performed at Screening after the first acceptable alkaline hematin sample collection. 
s. 
Endometrial biopsy is to be performed at the Week 24 visit and may be requested for central review if abnormal. 
t. 
Bone densitometry (L1-L4, total hip, femoral neck) will be assessed during the screening period and the central results available prior to randomization. 
u. Randomization:  After a patient is screened and the investigator determines that the patient is eligible for randomization the site staff will complete the 
Randomization Authorization Form and send it to the sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the Study Reference 
Manual.  The sponsor (or designee) will approve the patient’s randomization in writing.  Once the site has received approval, the patient may undergo her 
Baseline Day 1 visit. 
v. Patient electronic diary:  Patients enter diary information on a daily basis for their compliance with (study treatment starting at Baseline/Day 1), menstrual 
bleeding and use of feminine products for menstrual bleeding, uterine fibroid-associated pain by the Numerical Rating Scale, and use of pain medications 
(analgesics) starting at Screening visit 2 and compliance with study treatment starting at Baseline/Day 1 through Week 24 or early termination. 
w. Hemoglobin:  a venous blood sample must be collected each time feminine products are collected to be sent to the central laboratory conducting the alkaline 
hematin assessment. 
 
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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. 
Combined hormonal contraceptives and progestational agents are commonly prescribed to 
regulate abnormal uterine bleeding, but appear to have limited efficacy in the treatment of 
uterine fibroids [Carr, 1993].  Although no randomized studies evaluating the use of 
levonorgestrel-releasing intrauterine system devices for the treatment of heavy menstrual 
bleeding related to uterine fibroids have been conducted, observational studies have reported a 
reduction in uterine volume and bleeding and this system is approved for use by the United 
States (US) Food and Drug Administration (FDA). 
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 
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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, non-steroidal anti-inflammatory medications, and danazol. 
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 250,000 hysterectomies are performed in the US for uterine fibroids.  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 United States 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 
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 (also known as TAK-385) is an orally-active, potent, highly-selective high-affinity 
small molecule GnRH receptor antagonist with a novel structure.  Relugolix was discovered and 
initially studied by Takeda Pharmaceutical Company, Limited, before development rights 
outside of Japan and certain East Asian countries were licensed to Myovant Sciences GmbH. 
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Relugolix antagonizes the human GnRH receptors present on the gonadotrophin-secreting cells 
of the anterior pituitary by competitively inhibiting binding of the active ligand, GnRH, to the 
GnRH receptors.  In the absence of GnRH-stimulated secretion by the anterior pituitary, levels of 
LH and FSH fall rapidly, followed by a decline over a few days in 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. 
2.2.3. 
Nonclinical Toxicology 
A comprehensive package of nonclinical studies has been conducted to evaluate the toxicity of 
relugolix.  These include repeat-dose toxicity studies in mice of up to 13 weeks, in rats of up to 
26 weeks, and in monkeys of up to 39 weeks.  Oral administration of relugolix resulted in 
reversible liver toxicity (liver enzyme elevations with and without accompanying 
histopathological correlates) and changes related to reversible phospholipidosis (PLD) in several 
tissues/organs, most notably the lymph nodes, lungs, and testes in rats; and lymph nodes, parietal 
cells in the stomach, spleen, and intestines in monkeys.  PLD by itself is not adverse, and no 
significant adverse effects were associated with PLD in rats and monkeys except at doses that 
caused mortality in rats (≥ 1000 mg/kg/day), which were associated with extremely high 
systemic exposures.  The no-observed-effect level (NOEL) for liver findings in the 39-week 
monkey toxicity study was 5 mg/kg/day, and the no-observed-adverse-effect level (NOAEL) is 
considered to be 15 mg/kg/day.  The gender combined mean end of study area under the 
concentration-time curve from time 0 to 24 hours (AUC0-24) at the NOAEL of 15 mg/kg/day was 
5.2 μg⋅hr/mL, which is ~51 times higher than the estimated exposure (AUC) in women receiving 
40 mg once daily (0.101 μg⋅hr/mL), the dose of relugolix to be administered in this study.  Both 
the liver and PLD findings demonstrated evidence of reversibility following a 13-week recovery 
period in monkeys.  No evidence of PLD has been observed in clinical studies.  The relugolix 
toxicology program supports the conduct of clinical studies up to the NOAEL (15 mg/kg/day) 
exposure (5.2 μg⋅hr/mL) for liver toxicity in monkeys (most sensitive species). 
Relugolix is not mutagenic or clastogenic and was not carcinogenic in 2-year mouse and rat 
studies.  Embryo-fetal death was observed only in relugolix-treated pregnant rabbits, but no fetal 
malformation was observed in rat and rabbit embryo-fetal development studies.  While relugolix 
demonstrated phototoxic potential in an in vitro 3T3 neutral red uptake assay, in vivo data did 
not show phototoxicity in hairless mice, and no damage to the eye structure or function was 
evident in the 4- and 39-week monkey toxicity studies.  Prolongation of the corrected QT 
interval was observed in a study of cynomolgus monkeys at ≥100 mg/kg (estimated Cmax of 
4.0 µg/mL), but did not prolong the QT interval in a human thorough QT study at doses up to 
360 mg (Cmax of 0.181 µg/mL). 
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2.2.4. 
Previous Human Experience 
Nine phase 1 studies in healthy volunteers and three phase 2 studies (including one in women 
with uterine fibroids and two in women with endometriosis) have been completed.  In addition, 
six clinical studies evaluating relugolix are ongoing, including two phase 1 studies, two phase 2 
studies in men with prostate cancer (US and Europe), and two phase 3 studies in women with 
uterine fibroids in Japan.  More than 1380 patients and healthy volunteers have received at least 
one dose of relugolix, including 158 women receiving relugolix 40 mg once daily (the proposed 
phase 3 dose) for at least 28 days and at least 200 men receiving relugolix at doses of 80 mg or 
120 mg once daily for at least 24 weeks and for as long as 48 weeks.  Eighty-eight women have 
been treated with relugolix 40 mg once daily for 24 weeks. 
2.2.4.1. 
Clinical Pharmacology, Pharmacokinetics, and Metabolism 
Data from phase 1 studies demonstrate that relugolix treatment results in rapid, dose-dependent 
suppression of estradiol in female subjects and testosterone in male subjects.  After oral 
administration, the absolute bioavailability of relugolix was 12% (range 6 to 25%) with a 
predominant elimination half-life of 37 to 42 hours.  In a human radiolabeled study, there were 
no major circulating metabolites of relugolix.  The primary route of elimination of drug-related 
material was in the feces.  The pharmacokinetics (PK) and pharmacodynamics of relugolix have 
been evaluated, and appear to be similar in American and Japanese volunteers, despite the lower 
mean body mass index observed in Japanese volunteers. 
A phase 1 study (TAK-385_101) in healthy US premenopausal women demonstrated the 
tolerability of single doses of relugolix 1 to 80 mg, and once-daily dosing of relugolix at 10, 20, 
and 40 mg for 2 weeks.  Plasma concentrations of relugolix increased in a slightly greater than 
dose-proportional manner.  Suppression of serum estradiol was similar after single doses of 40 or 
80 mg once daily relugolix.  The serum concentrations of LH, FSH, estradiol, and progesterone 
rapidly decreased and remained at low levels with multiple doses of relugolix with the majority 
of women having estradiol levels < 10 pg/mL in the 40-mg dose group.  Based on these hormone 
reductions, oral relugolix 40 mg once daily was chosen as the high dose for further study in 
phase 2. 
A 6-week phase 1 study (MVT-601-1001) in healthy US premenopausal women was conducted 
to evaluate the safety, PK, and pharmacodynamics profile of oral relugolix 40 mg once daily and 
relugolix 40 mg once daily in combination with estradiol/norethindrone acetate (1 mg/0.5 mg 
once daily).  Median pre-dose trough concentrations in the relugolix alone arm were ~6 pg/mL; 
with the addition of 1 mg estradiol once daily, these were increased to ~26 pg/mL, and median 
peak concentrations were ~45 pg/mL.  This trough and peak concentration range is consistent 
with the estradiol range associated with reduced loss of bone mineral density [Barbieri, 1992].  
Relugolix PK and norethindrone acetate PK were similar to historic data.  The estrogenic 
metabolite of norethindrone, ethinyl estradiol, was below the limit of quantitation in almost all 
PK samples collected.  The adverse event profile was similar to prior phase 1 studies, with a 
marked reduction in hot flushes noted in the relugolix plus hormonal add-back therapy in 
comparison with the relugolix alone arm. 
Relugolix is to be administered in the fasted state, as food decreases the extent of relugolix 
absorption (AUC) by approximately 45%.  The exposure of relugolix is increased by inhibitors 
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of P-glycoprotein (P-gp) up to 6-fold, but relugolix does not significantly impact the exposure of 
cytochrome P450 1A2, 2C9, 2D6, or 3A4 substrates.  In a dedicated study, relugolix did not 
prolong the corrected (QTc) interval. 
2.2.4.2. 
Clinical Studies in Women with Uterine Fibroids or Endometriosis and Men with 
Prostate Cancer 
A phase 2 study (TAK-385/CCT-001) evaluated the efficacy, safety, PK, and pharmacodynamics 
of relugolix 10, 20, and 40 mg once daily for 12 weeks in 216 Japanese women with uterine 
fibroids and heavy menstrual bleeding.  Heavy menstrual bleeding was defined for enrollment 
into the study as a score on the Pictorial Blood Loss Assessment Chart (PBAC) of at least 120; 
uterine fibroids were confirmed by ultrasound, magnetic resonance imaging, computed 
tomography, or laparoscopy.  For the primary endpoint (proportion of patients with a total PBAC 
score of < 10 from Week 6 to 12), statistically significant dose-dependent differences were 
observed in all relugolix treatment groups compared to placebo (Figure 2-1).  The proportion 
was higher in the relugolix 40 mg group (83.6%) compared with 0% in the placebo group 
(p < 0.0001).  In the relugolix 20 mg group, 43.6% of women responded and in the 10 mg group 
20.8% responded, demonstrating a dose-response relationship.  Of the women in the relugolix 
40 mg group, 72.7% achieved amenorrhea from Week 6 to Week 12.  Similarly, improvement 
with increasing dose was also observed in the secondary endpoints including change in myoma 
and uterine volumes and blood concentration of hemoglobin. 
Figure 2-1 
Percent of Women with Markedly Decreased Blood Loss at End of Treatment 
Period after Once Daily Administration of Relugolix (Study CCT-001) 
 
Notes:  Data shown is Pictorial Blood Loss Assessment Chart (PBAC) method of assessing blood loss during Week 
6 to Week 12.  Primary endpoint is proportion of patients with PBAC score < 10. 
Statistically significant difference with p < 0.001 observed for each relugolix treatment arm versus placebo. 
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In the phase 2 uterine fibroid study, the most common treatment-emergent adverse events 
(occurring > 10% in any treatment group and more than placebo) were hot flush, metrorrhagia, 
menorrhagia, headache, genital hemorrhage, menstruation irregular and nasopharyngitis.  With 
the exception of the incidence of nasopharyngitis in all treatment groups, these common adverse 
events were thought to be caused by the pharmacological effect of relugolix.  The adverse events 
associated with menstruation were primarily reported in the first 28 days.  Most of the adverse 
events were mild or moderate, and no serious treatment-emergent adverse event considered 
related to study drug was observed.  Adverse events resulted in study drug discontinuation in 2 
patients (hemoglobin decreased in a placebo patient and tinnitus, libido decreased, menopausal 
depression and hyperhidrosis in one patient treated with relugolix 20 mg once daily).  Bone 
mineral density decreases appeared to correlate with increasing doses of relugolix.  Women 
treated with placebo for 12 weeks had a mild loss of bone mineral density (mean ± standard 
deviation [SD]) of -0.24 ± 2.218% compared with -0.75 ± 2.350%, -2.01 ± 2.334%, and -2.28 ± 
2.194% in the relugolix 10, 20, and 40 mg once daily groups, respectively.  One patient had a 
positive pregnancy test after receiving approximately 46 days of relugolix 10 mg once daily (a 
dose that does not fully suppress estradiol).  Study drug was discontinued.  An ultrasound 
determined that the patient was 7 weeks pregnant.  The patient subsequently had an uneventful 
pregnancy and delivered a healthy infant at 39 weeks. 
In a phase 2 study of women with endometriosis (TAK-385/CCT-101), 487 women were 
randomized to relugolix doses of 10, 20, or 40 mg or placebo, administered orally once daily 
over a 12-week period, or to leuprolide acetate (every 4-week injection) administered for 
12 weeks.  The study demonstrated dose-dependent decreases in pelvic pain as assessed by a 
100 mm visual analogue score (VAS).  The pain scores for pelvic pain were well-balanced across 
the groups at baseline and the means ranged from 14.6 to 15.6 mm.  The changes from baseline 
in the VAS score (mean ± SD) were -10.418 ± 11.0171 mm in the relugolix 40 mg group vs. -
3.753 ± 10.5018 mm in the placebo group (p < 0.0001).  All doses were better than placebo, with 
the greatest benefit observed at the highest dose evaluated, 40 mg once daily.  The decrease in 
mean VAS pain score for the leuprolide group (-10.460 ± 10.3013 mm) was similar to that of the 
relugolix 40 mg group.  The effects of relugolix on pain were maintained following an additional 
12 weeks of treatment in the extension study (total of 24 weeks).  Estradiol levels were 
suppressed for the duration of the study. 
In the 12-week phase 2 endometriosis study (CCT-101) and the companion 12-week extension 
study (OCT-101; total of 24 weeks of treatment), the safety profile of the relugolix 40 mg once 
daily dose was comparable to that of leuprolide treatment.  The most commonly reported 
treatment-emergent adverse events in the relugolix groups than in the placebo group included hot 
flush, metrorrhagia, and menstruation irregular, and were considered to be due to the 
pharmacological effects of relugolix.  The events of menstrual bleeding were primarily reported 
in the first 28 days.  Bone mineral density changes from baseline (mean ± standard deviation 
[SD]) observed after 24 weeks of treatment were -0.23 ± 1.986% in the placebo group, -1.61 ± 
2.338%, -2.58 ± 2.936%, and -4.90 ± 2.912% in the relugolix 10, 20, and 40 mg groups 
respectively, and -4.43 ± 2.157% in the leuprolide group.  Bone mineral density changes from 
baseline in the relugolix 40 mg group at 12 and 24 weeks were comparable to those in the 
leuprolide group for the same durations.  Two patients had liver function test abnormalities 
considered study drug-related by the investigator and that resulted in discontinuation of study 
drug. 
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Two phase 3 studies evaluating relugolix in women with uterine fibroids are ongoing in Japan.  
One study is assessing the effect of relugolix in women with moderate to severe pain associated 
with uterine fibroids, and the other is evaluating women with heavy menstrual bleeding 
associated with uterine fibroids.  Data from these ongoing studies are not available. 
Two phase 2 clinical studies of relugolix (C27002 and C27003) in men with advanced prostate 
cancer requiring androgen deprivation therapy were initiated in North America in 2014.  Study 
C27002, which remains ongoing, enrolled patients with advanced prostate cancer.  In this open-
label, parallel group study, men were randomized to receive oral relugolix at a dose of 80 mg or 
120 mg once daily after a single oral loading dose of 320 mg (N = 50 in each arm) or to the 
GnRH agonist therapy, leuprolide acetate, 22.5 mg administered subcutaneously every 12 weeks, 
(N = 25) for up to 48 weeks.  Study C27003, in which the last clinical study visits have been 
completed, enrolled men in North America or the United Kingdom requiring six months of 
androgen deprivation therapy as neoadjuvant and adjuvant therapy to external beam radiation 
therapy.  Patients were randomized to relugolix 120 mg once daily (after a single oral loading 
dose of 320 mg) (N = 65) or to degarelix 80 mg subcutaneously every four weeks (N = 38) for 
24 weeks (after a single loading dose of 240 mg).  Results from the C27002 interim analysis 
demonstrated that both doses of oral relugolix, 80 mg and 120 mg once daily, rapidly reduced 
testosterone levels below the castration threshold (≤50 ng/dL) and maintained these levels 
through at least 24 weeks.  These data are comparable to testosterone levels achieved by 
leuprolide 22.5 mg every 3 months.  Study C27003 demonstrated rapid and sustained 
suppression of testosterone levels for the 24-week treatment duration. 
In an interim analysis of the phase 2 prostate cancer study C27002, the most common treatment-
emergent adverse events occurring in at least 10% of men with advanced prostate cancer in the 
relugolix 80 mg or 120 mg once daily arms or leuprolide arm included hot flush, alanine 
aminotransferase increase, fatigue, aspartate aminotransferase, diabetes mellitus, hyperhidrosis, 
muscle spasm, injection site reaction, and frequent daytime urination.  The common adverse 
events observed with relugolix in men with prostate cancer were generally consistent with its 
mechanism of action and those observed with leuprolide.  A biomarker for PLD, di-22:6-
bis(monoacylglycerol)phosphate (di-22:6-BMP), was monitored in this study due to findings of 
PLD in nonclinical toxicity studies.  There were no systematic increases in post-baseline serum 
or urinary di-22:6-BMP levels and no changes exceeding 2-fold observed in any patients. 
No clinical evidence of relugolix-related PLD-associated toxicity has been observed regarding 
the heart, liver, central nervous system, or muscle in any clinical study. 
Relugolix has been generally well tolerated.  The serious identified risk associated with relugolix 
treatment is loss of bone mineral density in women.  Nonserious adverse events related to 
relugolix class effects include hot flush and headache in both sexes; reproductive system events 
(abnormal uterine bleeding, genital hemorrhage, menorrhagia or heavy menstrual bleeding, 
menstruation irregular, and oligomenorrhea), arthralgia, and hyperhidrosis in women with 
uterine fibroids or endometriosis; and vision blurred, hepatic enzyme increased, libido decreased, 
and anxiety in men. 
More detailed description of the results of phase 1 and phase 2 studies in women with uterine 
fibroids and endometriosis and in men with prostate cancer are provided in the relugolix 
Investigator Brochure, Version 9.0, dated 09 November 2016, along with a full discussion of the 
safety profile of relugolix. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
Inferential efficacy assessments will be made between the following groups and placebo 
Group C after 24 weeks of study treatment: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with 
1.0 mg estradiol and 0.5 mg norethindrone acetate; 
• Relugolix Group B:  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. 
Descriptive assessment of treatment effect will be made between each relugolix group (Group A 
and Group B) and placebo (Group C) for safety outcomes and between each of the two relugolix 
groups for both efficacy and safety. 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily co-administered with low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on heavy 
menstrual bleeding associated with uterine 
fibroids. 
• 
Proportion of women in the relugolix 
Group A versus the placebo Group C who 
achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
baseline menstrual blood loss volume over 
the last 35days of treatment, as measured by 
the alkaline hematin method. 
Secondary Efficacy 
• 
To determine the benefit of relugolix 40 mg 
once daily for 12 weeks followed by 12 
weeks of relugolix 40 mg once daily co-
administered with low-dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks on heavy menstrual bleeding 
associated with uterine fibroids; 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo for 24 weeks on the following: 
o Change in hemoglobin; 
o Impact of heavy menstrual bleeding on 
social, leisure, and physical activities; 
o Pain associated with uterine fibroids; 
o Uterine volume; and 
o Uterine fibroid volume. 
• 
Proportion of women in the relugolix 
Group B versus the placebo Group C who 
achieve a menstrual blood loss volume of 
< 80 mL AND at least a 50% reduction from 
baseline menstrual blood loss volume over 
the last 35 days of treatment, as measured by 
the alkaline hematin method. 
The following secondary endpoints will be 
assessed comparing each relugolix treatment 
group to placebo inferentially and relugolix 
Group A to Group B descriptively: 
• 
Time to achieving a menstrual blood loss 
volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss 
volume as measured by the alkaline hematin 
method; 
• 
Change from Baseline to Week 24 in 
menstrual blood loss;  
• 
Proportion of women who achieve 
amenorrhea over the last 35 days of treatment 
as measured by the alkaline hematin method; 
• 
Time to amenorrhea as measured by the by 
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Objective(s) 
Endpoint(s) 
the alkaline hematin method; 
• 
Proportion of women with a hemoglobin 
below the lower limit of normal at Baseline 
who achieve an increase of ≥ 1 g/dL from 
Baseline at Week 24; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
physical activities; 
• 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• 
Proportion of women who achieve a mean 
Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days 
of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a 
maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• 
Change from Baseline to Week 24 in uterine 
volume; and 
• 
Change from Baseline to Week 24 in uterine 
fibroid volume. 
Safety 
• 
To determine the safety of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate in women 
with heavy menstrual bleeding associated 
with uterine fibroids compared with placebo 
for 24 weeks; 
• 
To determine the change in bone mineral 
density of women with heavy menstrual 
bleeding associated with uterine fibroids 
treated with 24 weeks of relugolix 40 mg 
once daily co-administered with either 12 or 
24 weeks of low dose estradiol and 
norethindrone acetate compared with placebo 
for 24 weeks. 
• 
Treatment-emergent adverse events, change 
in vital signs (including weight), clinical 
laboratory tests, and electrocardiograms; 
• 
Percent change from Baseline to Weeks 12 
and 24 in bone mineral density at the spine 
(average of L1-L4), total hip, and femoral 
neck as assessed by DXA; 
• 
Incidence of vasomotor symptoms. 
 
 
Pharmacokinetic and Pharmacodynamic 
• 
To evaluate the pharmacokinetic (PK) and 
pharmacodynamic effects of 24 weeks of 
relugolix 40 mg once daily when co-
administered with either 12 or 24 weeks of 
• 
Pre-dose trough concentrations (Cτ) of 
relugolix, estradiol, and norethindrone from 
Baseline through Week 24; 
• 
Changes from Baseline to Week 24 in pre-
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Objective(s) 
Endpoint(s) 
low-dose estradiol and norethindrone acetate. 
dose concentrations of LH, FSH, estradiol, 
and progesterone. 
Exploratory 
• 
To determine the benefit of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of low-dose 
estradiol and norethindrone acetate compared 
with placebo on patient-reported quality of 
life outcome measures. 
• 
Change from Baseline to Week 24 in the 
Uterine Fibroid Scale – Quality of Life 
Symptom Severity and Health-related 
Quality of Life subscales comparing each 
relugolix treatment group to placebo 
inferentially and the two relugolix groups 
descriptively; 
• 
Change from Baseline to Week 24 in the 
European Quality of Life Five-Dimension 
Five-Level scale comparing each relugolix 
treatment group to placebo inferentially and 
the two relugolix groups descriptively. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and 
safety study to evaluate 24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate and 12 weeks of oral relugolix 40 mg once daily 
followed by 12 weeks of oral relugolix 40 mg once daily co-administered with low-dose 
estradiol and norethindrone acetate compared with 24 weeks of placebo.  Approximately 
390 women with heavy menstrual bleeding associated with uterine fibroids will be enrolled and 
randomized 1:1:1 to the relugolix plus low-dose hormonal add-back therapy group (Group A; 
N ≈ 130), the relugolix monotherapy followed by co-administration with low-dose hormonal 
add-back therapy group (Group B; N ≈ 130), or the placebo group (Group C; N ≈ 130).  
Stratification variables will include:  geographic region (North America versus Rest of World) 
and mean screening menstrual blood loss volume (< 225 mL versus ≥ 225 mL) by the alkaline 
hematin method. 
The study consists of a screening period (~11 weeks), a randomized treatment period (24 weeks), 
and a follow-up period (~30 days).  Additionally, unscheduled follow-up visit(s) may be 
arranged for patients with study-related safety concerns as needed. 
A diagnosis of uterine fibroids will be confirmed during the screening period by a centrally-
reviewed transvaginal and/or transabdominal ultrasound.  Heavy menstrual bleeding will be 
defined as menstrual blood loss of ≥ 80 mL per cycle for each of 2 cycles during the screening 
period.  During the randomized treatment period, study participants will take blinded study drug 
orally once daily for 24 weeks.  Women with iron-deficient microcytic anemia with a 
hemoglobin ≤ 10 g/dL at Screening must be treated with oral or parenteral iron replacement 
therapy.  Between the Baseline and Week 24 visits, patients will attend visits monthly (ie, every 
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4 weeks).  At the Screening, Week 12, and Week 24 visits, patients will have an assessment of 
bone mineral density with dual-energy x-ray absorptiometry (DXA).  An endometrial biopsy will 
also be performed at Screening.  A transvaginal and/or transabdominal ultrasound will be 
performed at Week 24, followed by a repeat endometrial biopsy.  Feminine products will be 
standardized and will be collected and assessed for blood loss by the alkaline hematin method.  
Complete blood counts and chemistries will be collected monthly and uterine and uterine fibroid 
volumes will be assessed at the Screening and Week 24 visits.  Patients will complete daily 
electronic diaries (eDiary) including compliance with study treatment, menstrual bleeding, use of 
feminine products for menstrual bleeding, uterine fibroid-associated pain by the Numerical 
Rating Scale, and use of pain medication to treat pain caused by uterine fibroids.  Quality of life 
questionnaires will be completed according to the Schedule of Activities. 
Safety assessments will include treatment-emergent adverse events, vital signs, physical 
examinations including visual acuity, clinical laboratory tests, 12-lead electrocardiograms, 
endometrial biopsies, and assessments of bone mineral density.  Samples will also be collected 
for PK assessment of relugolix, estradiol, and norethindrone, and for the pharmacodynamic 
assessment of LH, FSH, estradiol, and progesterone. 
All patients completing the Week 24 visit, including women randomized to placebo, will be 
offered the opportunity to enroll in an open-label extension study in which all eligible patients 
will receive relugolix co-administered with low-dose estradiol and norethindrone acetate.  
Patients who do not enroll into the extension study will have a follow-up visit to assess safety 
approximately 30 days after the end of treatment (ie, after the patient’s last dose of study 
medication). 
A schematic of the overall study design is provided as Figure 4-1.  Details of the screening 
period visits and dispensation and collection of feminine products during this time are provided 
in Figure 4-2. 
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Figure 4-1 
MVT-601-3001 Study Schematic 
 
 
Figure 4-2 
Schematic of MVT-601-3001 Screening Visits and Feminine Product Dispensation 
and Collection during the Screening Period 
 
 
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4.2. 
Discussion of Study Design, Including Dosing Rationale and Choice of 
Control Group 
This phase 3 study is one of two replicate studies designed to establish the efficacy and safety of 
relugolix 40 mg once daily in women with heavy menstrual bleeding associated with uterine 
fibroids.  This study will focus on the primary objective of demonstrating a reduction in heavy 
menstrual bleeding, the most common and burdensome symptom of uterine fibroids.  The study 
is designed to demonstrate the benefit and safety of relugolix co-administered with low-dose 
estradiol (1 mg) and norethindrone acetate (0.5 mg) for 24 weeks.  An additional relugolix arm 
dosed with 12 weeks of relugolix monotherapy 40 mg once daily followed by 12 weeks of 
relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone acetate 
will be used to provide an assessment of the requirement for the low-dose hormonal add-back 
therapy to mitigate the adverse effects of relugolix monotherapy on bone mineral density loss 
and vasomotor symptoms.  An extension study is planned to provide additional safety and 
efficacy data through 48 weeks. 
Women with uterine fibroids and heavy menstrual blood loss by the alkaline hematin method of 
≥ 80 mL/cycle as assessed during two cycles will be enrolled in this study.  Randomization will 
be 1:1:1.  Placebo was selected as the appropriate control for the study because there is no 
standard of care medical therapy for the long-term treatment of women with uterine fibroids and 
heavy menstrual bleeding.  Commonly-used treatment options range from combined oral 
contraceptive pills, which are not effective in many cases, levonorgestrel-containing intrauterine 
devices, and leuprolide therapy indicated for 3 months in the preoperative setting. 
The dose of relugolix for phase 3 evaluation is 40 mg once daily.  This dose was selected for 
evaluation in phase 2 clinical studies based upon phase 1 data demonstrating similar estradiol 
and progesterone suppression in women treated with single doses of relugolix 40 mg or 80 mg, 
and data demonstrating that premenopausal women treated with multiple doses of 40 mg once 
daily relugolix over 14 days had estradiol levels suppressed to a median value of 3.68 pg/mL. 
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, as described above, a phase 
2 study of doses of relugolix 10, 20 and 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 
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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 48 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 48 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, 1992; 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 has demonstrated that this dose of add-back therapy maintains serum 
estradiol in the 25-50 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 PK 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) 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 is not included as a control arm as 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 
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density loss unacceptable for long-term treatment.  This phase 3 study will primarily assess the 
efficacy and safety of relugolix 40 mg co-administered with a low-dose of estradiol and 
norethindrone acetate compared with placebo at 24 weeks 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.  An additional arm with 
monotherapy relugolix administered for 12 weeks followed by 12 weeks of relugolix co-
administered with low-dose hormonal add-back therapy is included to provide data on the 
requirement for hormonal therapy to mitigate the adverse relugolix side effects of bone mineral 
density loss and hot flushes. 
All eligible women who complete the 24-week study will be offered the opportunity to enroll in 
an open-label extension study to obtain long-term safety and efficacy data over an additional 
24 weeks of treatment, providing approximately 1 year of safety data on the women originally 
randomized to relugolix. 
4.3. 
Selection of Study Population 
The study population will include approximately 390 premenopausal women aged 18 to 50 years 
with heavy menstrual bleeding (≥ 80 mL over 2 cycles by the alkaline hematin method) 
associated with uterine fibroids demonstrated over two cycles 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. 
4.3.1. 
Inclusion Criteria 
A woman will be eligible for randomization and enrollment in this study only if all of the 
following inclusion criteria apply and have been met at the time of the Baseline Day 1 visit, 
unless otherwise specified: 
1. Has voluntarily signed and dated the informed consent form prior to initiation of any 
screening or study-specific procedures; 
2. Is a premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and 
dating the informed consent form; 
3. Has a body mass index (BMI) within the range of 18.0 to 40.0 kg/m2 (inclusive); 
4. Has regularly-occurring menstrual periods of ≤ 14 days duration with a cycle of 21 to 
38 days from the start of one menstrual period until the start of the next, by patient 
history for at least 3 months prior to the Screening 1 visit; 
5. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal and/or 
transabdominal ultrasound performed with saline or gel contrast during the screening 
period.  At least one uterine fibroid must be verified by a central reader to meet at least 
one of the following criteria: 
a. Subserosal, intramural, submucosal non-pedunculated fibroid with a diameter 
≥ 2 cm (longest diameter), or 
b. Multiple small fibroids with a total uterine volume of ≥ 130 cm3; 
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6. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by a 
menstrual blood loss of ≥ 80 mL per cycle as measured by the alkaline hematin method 
for 2 menstrual cycles during the screening period; 
7. Patient does not desire and is not expected to be a candidate for gynecological surgery or 
ablation procedures within the 6 months following enrollment; 
8. Has a negative urine pregnancy test at the Screening 1, Screening 3, and Baseline Day 1 
visits; 
9. Agrees to use two forms of non-hormonal contraception (dual contraception, as described 
in Section 4.7) consistently during any required washout for excluded medications (if 
applicable), the screening period, and the randomized treatment period.  However, the 
patient is not required to use dual contraception if she: 
a. Has a sexual partner(s) who was vasectomized at least 6 months prior to the 
screening period; 
b. Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the first screening visit (patients with Essure 
must have prior confirmation of tubal occlusion by hysterosalpingogram); 
c. Is not sexually active with men; periodic sexual relationship(s) with men requires 
the use of dual non-hormonal contraception as noted above; or 
d. Practices total abstinence from sexual intercourse as her preferred lifestyle; 
periodic abstinence is not acceptable; 
10. Has an adequate endometrial (aspiration) biopsy performed during the screening period, 
with results showing no clinically significant endometrial pathology (hyperplasia, polyp, 
endometritis, or endometrial cancer); 
11. If ≥ 39 years of age at the time of the Baseline Day 1 visit, has a normal mammogram 
(Breast Imaging Reporting and Data System category 1 to 3 or equivalent) during the 
screening period or within 3 months prior to the screening period; 
12. A randomization authorization form has been signed by a study medical monitor 
approving the patient for randomization into the trial. 
4.3.2. 
Exclusion Criteria 
1. Has transvaginal and/or transabdominal ultrasound during the screening period 
demonstrating pathology other than uterine fibroids that could be responsible for or 
contributing to the patient’s heavy menstrual bleeding, such as uterine or cervical polyps, 
or any other clinically significant gynecological disorder determined by the investigator 
to require further evaluation and/or treatment; 
2. Has unexplained vaginal bleeding outside of the patient’s regular menstrual cycle; 
3. 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, as well as endometrial ablation for 
abnormal uterine bleeding within 6 months prior to the Screening 1 visit; 
4. Has a weight that exceeds the weight limit of the DXA scanner; 
5. Has a baseline bone mineral density z-score < -2.0 at spine or total hip; 
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6. Has a history of or currently has osteoporosis, or other metabolic bone disease, 
hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low 
traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and 
ankle fractures are allowed).  A history of successfully treated hyperparathyroidism, 
hyperprolactinemia, or hyperthyroidism is allowed if the patient’s bone mineral density is 
within normal limits; 
7. Has a history of the use of bisphosphonates, calcitonin/calcitriol, ipriflavone, teriparatide, 
denosumab, or any medication other than calcium and vitamin D preparations to treat 
bone mineral density loss; 
8. Anticipated use of systemic glucocorticoids at an oral prednisone-equivalent dose of 
more than 5 mg every other day during the study.  Note:  topical, inhaled, intranasal, otic, 
ophthalmic, intraarticular, or intralesional subcutaneous are permitted without restriction;  
9. Gastrointestinal disorder affecting absorption or gastrointestinal motility; 
10. 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 Baseline Day 1 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; 
11. Has jaundice or known current active liver disease from any cause, including hepatitis A 
(HAV IgM), hepatitis B (HBsAg), or hepatitis C (HCV Ab positive, confirmed by HCV 
RNA); 
12. Has any of the following cervical pathology:  high grade cervical neoplasia, atypical 
glandular cells, atypical endocervical cells, atypical squamous cells favoring high grade.  
Of note, patients with atypical squamous cells of undetermined significance and low-
grade cervical neoplasia may be included in the study; 
13. Has any of the following clinical laboratory abnormalities at any screening visit: 
a. Hemoglobin < 8.0 g/dL (patients with initial screening hemoglobin results 
< 8 g/dL may be prescribed iron supplements and have their hemoglobin levels 
retested prior to the Baseline Day 1 visit); 
b. Alanine aminotransferase or aspartate aminotransferase > 2.0 times the upper 
limit of normal (ULN), or bilirubin (total bilirubin) > 1.5 x ULN on clinical 
laboratory testing at either the Screening 1 or Screening 2 visit (or > 2.0 x ULN if 
secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome); 
c. Calculated creatinine clearance < 60 mL/min using the Modification of Diet in 
Renal Disease method; 
14. Has clinically significant cardiovascular disease including: 
a. Prior history of myocardial infarction; 
b. History of angina; 
c. History of congestive heart failure; 
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d. History of clinically significant ventricular arrhythmias such as ventricular 
tachycardia, ventricular fibrillation, or torsades de pointes, or history of 
permanent pacemaker, Mobitz II second degree or third degree heart block 
without a permanent pacemaker in place or untreated supraventricular tachycardia 
(heart rate ≥ 120 beats per minute); 
e. QT interval by the Fridericia correction formula (QTcF) of > 470 msec; 
f. Hypotension, as indicated by systolic blood pressure < 84 millimeters of mercury 
(mmHg) on 2 repeat measures at least 15 minutes apart, or treated ongoing 
symptomatic orthostatic hypotension with > 20 mmHg decrease in systolic blood 
pressure one minute or more after assuming an upright position; 
g. Uncontrolled hypertension, as indicated by systolic blood pressure > 160 mmHg 
on 2 repeat measures at least 15 minutes apart or diastolic blood pressure > 100 
mmHg at any screening visit or the Baseline Day 1 visit; 
h. Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram; 
15. Has been a participant in an investigational drug or device study within the 1 month prior 
to Screening 1 visit; 
16. Has a history of clinically significant condition(s) including, but not limited to the 
following: 
a. Untreated thyroid dysfunction or palpable thyroid abnormality (patients with 
adequately treated hypothyroidism who are stable on medication are not 
excluded); 
b. History of malignancy within the past 5 years or ongoing malignancy other than 
curatively treated nonmelanoma skin cancer or surgically cured Stage 0 in situ 
melanoma; 
c. History of major depression or other major psychiatric disorder at any time 
including bipolar disorder, schizophrenia, or post-traumatic stress disorder 
(patients without a history of major depression treated with a selective serotonin-
reuptake inhibitor antidepressant may be enrolled if stable for over 1 year); 
17. Is currently pregnant or lactating, or intends to become pregnant or to donate ova during 
the study period or within 1 month after the end of the study; 
18. Is currently using any prohibited medications as detailed in Section 5.10.1 (suitable 
washout periods from these medications are also described therein); 
19. Has a contraindication or history of sensitivity to any of the study treatments or 
components thereof; or has a history of drug or other allergy that, in the opinion of the 
investigator or medical monitor, contraindicates study participation; 
20. Has a prior (within 1 year of Screening 1 visit) or current history of drug or alcohol abuse 
disorder according to Diagnostic and Statistical Manual of Mental Disorders V (all 
patients must be questioned about their drug and alcohol use and this should be 
documented in the electronic case report form); 
21. Has participated in a previous clinical study that included the use of relugolix; 
22. Is an immediate family member, study site employee, or is in a dependent relationship 
with a study site employee who is involved in the conduct of this study (eg, spouse, 
parent, child, or sibling); 
23. Is inappropriate for participation in this study for other reasons, as determined by the 
investigator or sub-investigator or medical monitor. 
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4.4. 
Screening 
Screening numbers will be assigned to each patient who signs an informed consent form and 
begins the screening period.  Screening failures are patients who consent to participate in the 
clinical study but are never randomized. 
4.5. 
Method of Assigning Patients to Treatment Group and Patient ID 
Number 
After a patient is screened and the investigator determines that the patient is eligible for 
enrollment, the site staff will complete the Randomization Authorization Form and send it to the 
sponsor (Myovant Sciences GmbH) or sponsor designee per the instructions in the Study 
Reference Manual.  The sponsor (or designee) will approve the patient’s enrollment in writing.  
Once the site has received approval, the patient may undergo her Baseline Day 1 visit.  After 
confirming that all inclusion criteria and no exclusion criteria are met, the site will randomize the 
patient to treatment by using the Interactive Voice/Web Recognition Service (IVRS/IWRS) 
during the patient’s Baseline Day 1visit.  The IWRS will assign the patient a study treatment kit 
number available at the site according to the randomization code.  The IVRS/IWRS will also 
assign the Patient Identification Number. 
4.6. 
Removal of Patients from Therapy 
Patients may withdraw consent to participate in the study and discontinue treatment at any time 
for any reason.  Investigators or the medical monitor may remove patients from therapy under 
this protocol for reasons of safety and/or lack of compliance as discussed below.  Patients 
removed from therapy for any reason will undergo the assessments for the Early Termination 
visit (Week 24 visit) on the Schedule of Activities 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 randomization 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%); 
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• Patients who have percent change from Baseline in bone mineral density at either the 
Week 12 or Week 24 visit (or any unscheduled visit) at the lumbar spine (average L1-
L4), total hip, or femoral neck of < -4.0 that is repeated and confirmed (ie, both values 
are < -4.0); 
• Corrected QTcF prolongation of more than 500 msec as read by a cardiologist; 
• Patients who have a clinically significant decrease in visual acuity as evaluated by an 
ophthalmologist; 
• Patients who are, in the opinion of the investigator or the medical monitor, grossly non-
compliant with the protocol’s requirements; 
• If the patient becomes pregnant at any time after providing a signed informed consent 
form, the patient must be withdrawn immediately (see Section 7.6 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 non-compliance.  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.” 
4.7. 
Contraception/Pregnancy Avoidance 
In this study, medications and devices containing hormones are excluded, and patients must 
agree to use two forms of non-hormonal contraception (dual contraception), unless any of the 
following apply: 
• Has a sexual partner(s) who was vasectomized at least 6 months prior to the Screening 
visit; 
• Had a bilateral tubal occlusion (including ligation and blockage methods such as 
Essure™), at least 4 months prior to the first Screening visit (patients with Essure must 
have prior confirmation of tubal occlusion by hysterosalpingogram); 
• Is not sexually active with men; periodic sexual relationship(s) with men requires the use 
of dual non-hormonal contraception as noted above; 
• Practices total abstinence from sexual intercourse, as her preferred lifestyle; periodic 
abstinence is not acceptable. 
The only acceptable methods of dual contraception are: 
• Condom with 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 when they sign a consent form they understand the 
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requirements for avoidance of pregnancy during the course of the study.  Patients may not donate 
ova during the course of the study and for 1 month following the last study visit. 
A patient may start hormonal contraception 4 weeks after her last study visit provided her 
menstrual cycle has returned. 
Urine pregnancy tests will be performed at monthly intervals during the study (including just 
prior to receiving 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). 
5. 
TREATMENTS 
5.1. 
Treatments Administered 
In this study, patients will be randomized to receive one of the following blinded oral study 
treatments: 
• 24 weeks of relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol 
and 0.5 mg norethindrone acetate; OR 
• 12 weeks of relugolix 40 mg tablet plus a placebo capsule followed by 12 weeks of 
relugolix 40 mg tablet plus a capsule containing a tablet of 1.0 mg estradiol and 0.5 mg 
norethindrone acetate; OR 
• 24 weeks of relugolix placebo tablet plus a placebo capsule. 
Each patient will be instructed to take one tablet and one capsule per day. 
The placebo relugolix tablet is manufactured to match the relugolix tablet in size, shape, color, 
and odor.  The placebo capsule is designed to match the over-encapsulated 
estradiol/norethindrone acetate active product in size, shape, color, and odor. 
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Table 5-1 
Description of MVT-601-3001 Study Drugs 
Name of 
Investigational 
Product 
Relugolix 
Relugolix Placebo 
Estradiol / 
Norethindrone 
Acetate 
Estradiol / 
Norethindrone 
Acetate Placebo 
Formulation 
Description 
Round film-coated 
pink tablet 
Round film-coated 
pink tablet 
An over-
encapsulated 
round film-coated 
white tablet with 
placebo back-fill 
material 
Capsule with 
placebo back-fill 
material 
Dosage Form 
Tablet 
Tablet 
Capsule 
Capsule 
Unit Dose 
Strength 
40 mg 
0 mg 
Estradiol 1.0 mg / 
norethindrone 
acetate 0.5 mg 
0 mg 
Route of 
Administration / 
Duration 
Oral once daily/ 
12 or 24 weeks 
Oral once daily/ 
24 weeks 
Oral once daily/ 
12 or 24 weeks 
Oral once daily/ 
12 or 24 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 
(Activella™). 
5.2.1. 
Product Characteristics 
Relugolix has no chiral centers.  The compound is slightly to partially soluble in acidic solutions 
but essentially insoluble at neutral pH (pH 7) and above.  It is partially soluble in polar organic 
solvents.  The compound is provided as an immediate-release pink tablet using the United States 
Pharmacopeia and the National Formulary (USP/NF) excipients. 
Placebo to match relugolix is a pink tablet using USP/NF 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 USP/NF grade back-fill material. 
Placebo to match the over-encapsulated estradiol/norethindrone acetate combination product is a 
capsule containing back-fill material only. 
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5.3. 
Randomization and Stratification 
At the Baseline Day 1 visit, patients will be randomized in a 1:1:1 ratio to one of the following 
treatment arms: 
Table 5-2 
Protocol MVT-601-3001 Treatment Group Randomization 
Treatment 
Group 
Randomized Treatment 
Approximate 
Number of Patients 
Group A 
Relugolix 40 mg tablet co-administered with 1.0 mg estradiol / 
0.5 mg norethindrone acetate capsule for 24 weeks 
130 
Group B 
Relugolix 40 mg tablet co-administered with relugolix placebo 
tablet for 12 weeks followed by relugolix 40 mg tablet co-
administered with 1.0 mg estradiol / 0.5 mg norethindrone 
acetate capsule for 12 weeks 
130 
Group C 
Relugolix placebo tablet co-administered with 
estradiol/norethindrone acetate placebo capsule 24 weeks 
130 
 
Randomization will be stratified by geographic region and mean screening menstrual blood loss 
as follows: 
• Geographic region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss by the alkaline hematin method: < 225 mL versus ≥ 
225 mL. 
Patients are assigned to one of the three treatment arms in accordance with the randomization 
schedule (see additional information on randomization in Section 4.5). 
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 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. 
Patients should take any oral iron supplementation with meals. 
Patients will hold their study treatment on clinic visit days and record the time of their previous 
dose (ie, the time that they took their dose on the day before the clinic visit); they will be 
instructed to take their study treatment in the clinic after PK/PD samples are collected. 
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 
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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 1°C to 30°C until it is used or returned to the sponsor (or designee).  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, medication or kit number, contents, 
directions for use, storage directions, clinical study statement, and any other labeling required by 
regulatory bodies in the study locations and will list Myovant Sciences GmbH as the sponsor.  
Patients will be instructed to store study drug at room temperature out of the reach of children. 
All labels for relugolix, the estradiol/norethindrone acetate combination, relugolix placebo, and 
the estradiol/norethindrone acetate placebo to be distributed will meet all applicable 
requirements of the US 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 and relugolix placebo will be supplied to the study site in blister cards co-
packaged with the estradiol/norethindrone acetate or estradiol/norethindrone acetate placebo. 
5.7. 
Blinding 
All patients, investigators, and sponsor staff or representatives involved in the conduct of the 
study will be blinded to treatment assignment, with the exception of an unblinded statistician(s) 
who is responsible for developing the randomization codes and presenting unblinded data to the 
Data and Safety Monitoring Board if requested.  The blind will be maintained during assessment 
of PK and pharmacodynamic testing; PK concentrations will be reported to the sponsor in a 
blinded fashion, or only after database lock and unblinding, or provisions will be made to 
provide data only to personnel approved for unblinding. 
Unblinding for a given patient will occur only if the knowledge of treatment assignment will 
materially change the planned management of a medical emergency.  Investigators will have 
direct access to a given patient’s individual study treatment, however, the Investigator should 
make every effort to first contact the medical monitor or appropriate study personnel to discuss 
options before unblinding the patient’s treatment assignment.  If unblinding occurs before 
sponsor personnel can be consulted or notified, the Investigator must notify the sponsor as soon 
as possible after unblinding, but without revealing the treatment assignment of the unblinded 
patient, unless that information is important for the safety of patients currently in the study.  
Patients whose treatment assignment has been unblinded will be permanently discontinued from 
treatment. 
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The sponsor (or designee) may unblind the treatment assignment for any patient with a serious 
adverse event. 
5.8. 
Study Drug Accountability and Treatment Compliance 
Patients should complete their eDiary each day on study and prior to each visit, and should bring 
all unused and used study drug to each study visit.  At the week 12 visit all unused stud drug 
should be retained at the site and new study drug dispensed.  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. 
Treatment after the End of Study 
Patients who complete 24 weeks of treatment on this study and wish to continue therapy may be 
eligible to continue treatment in the extension study MVT-601-3003.  Eligibility criteria are set 
forth in that protocol. 
5.10. 
Prior and Concomitant Medications and Non-Drug Therapies 
5.10.1. 
Prohibited Medications 
This table provides examples of prohibited drug categories; however, it is not a comprehensive 
list of all restricted medications.  Consult the medical monitor if there is any uncertainty 
regarding patient use of a particular drug or drug class. 
Table 5-3 
Prohibited Medications and Washout Periods 
Drug Class 
Examples 
Washout Period/Comments 
Bisphosphonates 
alendronate 
etidronate 
No prior use permitted 
GnRH Analogues 
leuprolide acetate injection, also 
known as leuprorelin 
goserelin acetate injection 
3 months 
(6 months for sustained 3-monthly 
injections) 
Anti-Androgens 
danazol 
4 months 
Anti-convulsant drugs 
(specified) 
phenobarbital, carbamazepine, 
phenytoin, valproic acid, and 
primidone 
1 month 
Aromatase Inhibitors 
anastrozole 
4 months 
letrozole 
Progestins 
dienogest 
norethindrone 
medroxyprogesterone 
2 months 
(6 months for depot subcutaneous 
or intramusclar injections) 
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Drug Class 
Examples 
Washout Period/Comments 
Estrogens 
estradiol valerate 
conjugated estrogens 
2 months  
(6 months for depot subcutaneous 
or intramusclar injections) 
Oral Contraceptives 
combined or progestin only 
2 months 
Selective Estrogen 
Receptor Modulators 
raloxifene 
lasofoxifene 
clomifene 
tamoxifen 
2 months 
Selective Progesterone 
Receptor Modulators  
mifepristone 
ulipristal acetate 
2 months 
Intrauterine Devices 
levonorgestrel 
copper 
2 months 
Bone Agents 
calcitonin, calcitriol 
ipriflavone 
teriparatide 
denosumab 
abaloparatide 
odanacatib 
romosozumab 
2 months 
Anti-Coagulants/ 
Platelets/Fibrinolytics 
warfarin 
tranexamic acid 
vitamin k preparations 
1 month 
Glucocorticoids 
prednisolone or prednisone 
dexamethasone 
No washout 
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. 
P-glycoprotein Inducers 
carbamazepine 
rifampin 
St John’s wort 
2 weeks 
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Drug Class 
Examples 
Washout Period/Comments 
Moderate and Strong P-
glycoprotein Inhibitors 
amiodarone 
azithromycin 
captopril 
carvedilol 
clarithromycin 
conivaptan 
cyclosporin 
diltiazem 
dronedarone 
erythromycin 
felodipine 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
quercetin 
quinidine 
ranolazine 
ticagrelort 
verapamil 
2 weeks 
(6 months for amiodarone) 
Abbreviation:  GnRH, gonadotropin-releasing hormone 
5.10.2. 
Permitted Medications 
All concomitant medications used during the study will be recorded, including the drug generic 
name, dose amount, route of administration, start date, and stop date. 
5.10.2.1. 
Analgesics 
Use of analgesics is ONLY permitted under the following conditions from the Screening 1 
visit to the Week 24 (or Early Termination) visit: 
• Ibuprofen or other non-steroidal anti-inflammatory medications can be used as the first 
choice medicine for pain associated with uterine fibroids.  Narcotic analgesics should 
be used for severe pain that cannot otherwise be controlled. 
• Acetaminophen can be used as the first choice medicine for treatment of an adverse event 
or other pain NOT associated with uterine fibroids such as headache or a common 
cold. 
• Analgesics for topical/external use are also permitted. 
• Codeine that is not intended to relieve pain associated with uterine fibroids (eg, codeine 
phosphate in a combination cold remedy) is permitted. 
This restriction was set because analgesic medications are likely to have an impact on the 
evaluation of a secondary endpoint regarding pain.  Analgesics refer to drugs containing 
compounds that have indications for pain symptoms in the package inserts and antispasmodic 
drugs that possess indications for gynecological or urological disease in the package inserts. 
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Patients should be instructed not to use analgesics for prophylactic purposes.  Patients should 
also be instructed to record in the eDiary their worst pain symptoms during the past 24 hours 
before taking analgesics. 
5.10.2.2. 
Iron Therapy 
Women with a hemoglobin < 8.0 g/dL are excluded from participating in the study.  Women 
identified during the screening period to have a microcytic iron deficiency anemia defined as a 
hemoglobin ≥ 8 g/dL but ≤ 10 g/dL, a mean corpuscular volume below normal, and a low serum 
iron and ferritin, must be started on iron therapy, either oral or parenteral and then continued on 
treatment during the study.  Women who enter the screening period 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 
normal, and a low serum iron and ferritin, must also be started on iron therapy, either oral or 
parenteral. 
5.10.3. 
Prohibited Non-Drug Therapies 
Surgical treatment of uterine fibroids and use of intrauterine devices are prohibited from the 
Screening 1 visit until the patient’s final study visit unless urgently needed for patient safety. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
The timing of each study assessment and procedure is provided in the Schedule of Activities in 
the study synopsis (see Section 1.1).  Study procedures are briefly described within Section 6.7.  
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 in the study synopsis (see Section 1.1).  The study is divided into three periods:  
screening period, randomized treatment period, and Safety Follow-Up (to assess safety for 
patients who do not enroll in an open-label extension study; unscheduled visits may also occur as 
needed to evaluate patients). 
6.2. 
Screening Period 
Pre-screening evaluation, not including any study procedures or tests, may be conducted prior to 
the initial formal screening evaluation at the Screening 1 visit in an effort to identify patients 
unlikely to meet study-related entry criteria.  Review of medical history, menstrual history, and 
prior uterine imaging assessments is permitted.  Patients should have a diagnosis of uterine 
fibroids and a history of heavy menstrual bleeding with or without associated pain on a 
background of generally regular menses (ie, regularly occurring menstrual periods of ≤ 14 days 
duration with a cycle of 21 to 38 days from the start of one menstrual period until the start of the 
next cycle) as reported by the patient for at least 3 months prior to the Screening 1 visit. 
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The screening period consists of the Screening 1, 2, 3, and 4 visits.  See Figure 4-2 for details of 
the timing of the screening period visits as well as details of the feminine product dispensation 
and collection during screening. 
The Screening 1 visit will be conducted following the signing of the informed consent form and 
should occur within 4 days after completion of menses.  The Screening 1 visit will include a full 
medical history (including menstrual history for 3 months prior to Screening and prior uterine 
imaging assessments), review of inclusion and exclusion  criteria, collection of concomitant 
medications and SAEs, obtaining of clinical evaluations including vital signs, height, weight, 
temperature, a complete physical examination including visual acuity (not including a 
gynecological examination), clinical laboratory tests, urinalysis, and a urine pregnancy test will 
be conducted.  Feminine product will be dispensed with instructions to collect and return all 
product used during the next menses. 
Screening 2 visit is scheduled to occur within 4 days after cessation of the patient’s first menses 
following the Screening 1 visit.  Patients will return at Screening 2 visit to return their feminine 
product to determine if their menstrual blood loss is ≥ 80 mL.  At this visit, clinical laboratory 
tests will be drawn, including a venous blood sample for use in the quantitation of menstrual 
blood loss.  Additional feminine product will be dispensed for collection of menstrual blood loss 
during the next menses. 
The patient will return for the Screening 3 visit within 10 days of Screening 2 visit if her 
menstrual blood loss from cycle 1 is ≥ 80 mL.  At the Screening 3 visit 3, review of inclusion 
and exclusion criteria will be conducted confirmation of continued eligibility.  Concomitant 
medication and adverse events will be assessed and vital signs taken.  In addition, the patient will 
undergo a gynecological examination (a Papanicolaou test must be conducted for women without 
a test result 6 months prior to the Screening 1 visit).  Re-measurement should be performed for 
inadequate or false-positive results.  A signs and symptoms directed physical examination, a 12-
lead ECG and a urine pregnancy test will be performed.   A transvaginal and/or transabdominal 
pelvic ultrasound with saline or gel contrast will be performed to assess for uterine fibroids.  The 
anatomic location and size of the fibroid disease will be estimated.  The ultrasound images will 
be submitted to the central reader for confirmation that the patient meets the inclusion criteria for 
a diagnosis of uterine fibroids (this confirmation must be received prior to randomization).  An 
endometrial biopsy will be obtained.  Bone densitometry by DXA of the lumbar spine, total hip, 
and femoral neck will be scheduled to be completed prior to randomization for submission to 
central reader.  Patients who will be ≥ 39 years of age at the time of the Baseline Day 1 visit 
must have a normal mammogram (Breast Imaging Reporting and Data System category 1 to 3 or 
equivalent) within 3 months prior to the Screening 1 visit.  If not, a mammogram will also be 
scheduled as a part of Screening 3 visit. 
Patients will be provided with the eDiary instructions at this Screening 3 visit and will be 
dispensed feminine products to be gathered for the second cycle.  Each patient will begin 
recording information into the eDiary including menstrual bleeding and use of feminine products 
for menstrual bleeding (ie, on the day of Screening 3 visit).  The eDiary will be maintained on a 
daily basis for the duration of the study up until the day before the Week 24 (or Early 
Termination) visit. 
The Screening 4 visit is scheduled to occur within 4 days after cessation of the patient’s menses 
following Screening 3 visit.  At the Screening 4 visit, the patient’s feminine products will be 
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collected to submit for the quantitation of menstrual blood loss, and a blood sample will be 
drawn for hemoglobin assessment.  The patient’s eDiary data collection will be reviewed.  
Laboratory and imaging evaluations will be reviewed to ensure eligibility for randomization. 
At the discretion of the investigator, the Screening 1 or 2 visits can be repeated if one menstrual 
cycle does not meet the heavy menstrual bleeding alkaline hematin criteria and it is thought to be 
due to an inadequate collection by a highly motivated patient.  A Randomization Authorization 
Form must be submitted to the sponsor for approval prior to conducting the Baseline Day 1 visit.  
The Baseline Day 1 visit should be scheduled to coincide as closely as possible to when the 
patient will be finished with her next menses. 
6.3. 
Randomized Treatment Period (Baseline to Week 24) 
At the Baseline Day 1 visit, patients will be randomized to one of the three study treatment arms 
(see Section 5.3).  Patients will take their randomized study treatment once daily, beginning on 
the day of the Baseline Day 1 visit and continuing through the Week 24 visit.  Patients will 
continue recording daily in their eDiary.  On-treatment study visits will occur every 4 weeks 
through the end of Week 24.  At each post-baseline visit, patients will return their feminine 
products for alkaline hematin testing.  Safety monitoring including signs and symptoms directed 
physical examination, ECGs, clinical laboratory tests, pregnancy tests, and adverse event 
collection will occur at each visit.  Bone densitometry will occur at the Week 12 and 24 visits.  A 
repeat transabdominal and/or transabdominal ultrasound and endometrial biopsy will be 
performed at the Week 24 visit.  The endometrial biopsy will be read locally.  Study drug and 
eDiary compliance will be reviewed at each visit.  Refer to the Schedule of Activities in the 
synopsis (see Section 1.1) for information about study procedures during the randomized 
treatment period. 
Sites should try to schedule patient visits during the morning, instructing patients to arrive before 
taking their study drug to allow for pre-dose PK/PD sampling.  Patients should come to the clinic 
in the fasted state (eg, nothing to eat or drink after midnight the day before the clinic visit). 
6.4. 
Continuation into Extension Study 
It is expected that most patients will enter the 24-week extension study (MVT-601-3003), which 
will be conducted under a separate protocol.  Patients will provide separate informed consent to 
participate in the extension study during which all patients will receive relugolix 40 mg co-
administered with 1.0 mg estradiol / 0.5 mg norethindrone acetate. 
6.5. 
Follow-up Visit 
All patients who do not wish to or who are not eligible to enroll in the extension study 
(MVT-601-3003), will have a 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 or surgical 
intervention, whichever occurs first.  This visit will be used to assess safety after discontinuation 
of study treatment including adverse events, clinical safety laboratories, 12-lead ECG, and return 
of menstruation.  Patients who withdraw early from this study will also undergo the Follow-up 
visit approximately 30 days after the last dose of study drug, or the date of initiation of another 
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investigational agent or hormonal therapy or surgical intervention, whichever occurs first.  Refer 
to the Schedule of Activities at the end of the synopsis (see Section 1.1) for individual study visit 
procedures during the Follow-up visit. 
6.6. 
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 conducted to 
evaluate adverse events:  vital signs, weight, symptom-directed brief physical examination, 
central safety laboratory assessment and PK sample if indicated, 12-lead ECG, recording of 
concomitant medications, and study drug compliance. 
6.7. 
Study Procedures 
6.7.1. 
Efficacy-Related Procedures 
6.7.1.1. 
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.  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. 
6.7.1.2. 
Transvaginal and/or Transabdominal Ultrasound 
Transvaginal and/or transabdominal ultrasound with saline or gel contrast is performed for the 
diagnosis of uterine fibroids, 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 
physician (investigator or sub-investigator) will be assigned to a patient and will perform each of 
the ultrasound scans using the same device as far as possible.  Transvaginal ultrasound is 
preferred, but transabdominal ultrasound may be used as necessary for full visualization of the 
uterus.  The ultrasound method used at screening should be repeated for the ultrasound at the 
Week 24 visit. 
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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.  
At the Screening 1 visit, the longest diameter (D1) of the largest myoma will be noted and 
recorded.  Only the largest myoma among those measurable at the Screening 1 visit will be 
measured throughout the study. 
6.7.1.3. 
Endometrial Biopsy 
An endometrial biopsy is to be performed during the pelvic examination at the Screening 3 visit.  
A second biopsy is to be performed at the Week 24.  The biopsies will be read locally, but 
biopsies may be requested for central review. 
6.7.1.4. 
Pharmacodynamics Sample Collection 
Blood samples for the pharmacodynamic analysis of serum LH, FSH, estradiol, and progesterone 
will be collected pre-dose at the visits indicated in the study Schedule of Activities in the 
protocol synopsis (see Section 1.1).  These pharmacodynamic samples will be analyzed at a 
central laboratory.  For PK analysis of estradiol, a separate PK sample will be obtained to be 
analyzed at a PK laboratory (see Section 6.7.1.5).  To maintain blinding, concentrations of these 
hormones should be reported to the investigator, other vendors, and sponsor personnel only after 
database lock and unblinding. 
6.7.1.5. 
Pharmacokinetics Sample Collection 
Blood samples for PK analysis of relugolix, estradiol, and norethindrone will be collected pre-
dose at the visits indicated in the study Schedule of Activities in the protocol synopsis (see 
Section 1.1).  The actual date and time of each blood sample collection will be recorded. 
Patients will be instructed to hold their dose of study drug on clinic visit days and record the time 
of their previous dose (ie, the time they took their dose on the day before the clinic visit).  If the 
study patient inadvertently took drug at home on the morning of the clinic visit, the dosing 
history should be accurately recorded and a PK sample collected (which may be used for 
population PK modeling). 
To maintain blinding, PK concentrations will be reported to the sponsor in a blinded fashion, or 
only after database lock and unblinding.  Collection, processing, storage, and shipping 
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procedures are provided in the Study Reference Manual.  Plasma and serum analysis will be 
performed by the sponsor (or designee). 
Plasma concentrations of relugolix and norethindrone and serum concentrations of estradiol will 
be determined in samples using a validated bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site.  Once a sample has been analyzed for relugolix, estradiol, or 
norethindrone, any remaining plasma may be analyzed for other compound-related metabolites 
and the results reported under a separate protocol. 
6.7.1.6. 
Patient eDiary 
All women enrolled in the study will be provided with a device with an application for a patient 
eDiary, along with detailed instructions for its use.  During menstruation, patients will complete 
daily diaries including compliance with study treatment, menstrual bleeding, use of feminine 
products, uterine fibroid-associated pain, and use of pain medication (analgesics) to treat uterine 
fibroid pain (see Appendix 2). 
Queries will be handled by the vendor managing the eDiary data through the clinical site.  The 
eDiary data will act as its own source data and these data will be reviewed by the investigator to 
identify any potential adverse events. 
6.7.1.7. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire (MIQ) 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 3).  The MIQ has undergone psychometric 
validation.  Patients will complete the MIQ at each study visit during the randomized 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. 
6.7.1.8. 
Uterine Fibroid Symptom – Quality of Life 
The Uterine Fibroid Symptom – Quality of Life (UFS-QoL) score is used to evaluate the 
symptom severity and the quality of life of patients with uterine fibroids (see Appendix 4).  
Patients will complete the UFS-QoL questionnaire at the site at the Baseline Day 1 visit, Week 
12 visit, and Week 24 visit before other study procedures, such as blood draws and physical 
examinations, are performed. 
6.7.1.9. 
European Quality of Life Five-Dimension Five-Level Scale 
The European Quality of Life Five-Dimension Five-Level Scale (EQ-5D) is a standardized 
instrument for use as a measure of health outcomes (see Appendix 5).  Mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression are each assessed on 3-point categorical scales 
ranging from “no problem” to “severe problem.” 
Patients will complete the EQ-5D questionnaire at the site at the Baseline Day 1 visit and the 
Week 24 visit before other study procedures, such as blood draws and physical examinations, are 
performed. 
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6.7.1.10. 
Status of Menstruation Recovery 
If the patient does not continue into the extension study (MVT-601-3003), and the first 
menstruation after the end of study treatment administration is observed before the Follow-up 
visit, the date of onset of the first menstruation is recorded in the eCRF.  After the Follow-up 
visit, additional follow-up for the status of menstruation recovery will not be continued, 
6.7.1.11. 
Pharmacogenomics Sample Collection 
For possible exploratory investigation of markers enabling the prediction of drug response, one 
5-mL sample of whole blood will be collected and stored for future pharmacogenomic analyses.  
All patients will be eligible for collection of the pharmacogenomic sample, however, the sample 
may only be obtained and stored from patients who provide a separate informed consent form for 
pharmacogenomic sample collection.  Patient participation in the pharmacogenomic research is 
voluntary and refusal to participate will not preclude entry into the study or indicate withdrawal 
from the study. 
If possible, the pharmacogenomic sample should be drawn from consented patients at the 
Baseline Day 1 visit, but it may be drawn at any time during the study through Week 24 
(inclusive).  Patients can request their sample to be destroyed at any time.  A pharmacogenomic 
sample should not be collected from any patient who has received comparable bone marrow 
transplant or whole blood transfusion within 6 months before sample collection.  Refer to the 
Study Reference Manual for directions on collecting, handling, and storage of pharmacogenomic 
samples. 
6.7.2. 
Safety-Related Procedures 
6.7.2.1. 
Weight, Height, and Body Mass Index 
Patients should have weight and height measured while wearing indoor clothing and with shoes 
removed. 
6.7.2.2. 
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. 
6.7.2.3. 
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 the Baseline assessment.  Visual acuity will be 
checked at the beginning and end of the study by a standard visual eye chart.  The patient should 
wear any prescribed glasses or contacts during the visual acuity assessment.  The gynecologic 
examinations will include breast and pelvic exams.  A Papanicolaou test must be conducted for 
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women without an available test result from within 6 months prior to the Screening 1 visit.  Re-
measurement should be performed for inadequate or false-positive results. 
6.7.2.4. 
Clinical Laboratory Samples 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual and the protocol Schedule of Activities in the synopsis (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. 
Table 6-1 
Clinical Laboratory Tests 
Chemistry 
Hematology 
Urinalysis 
Potassium 
White Blood Cell (WBC) Count 
Qualitative 
Chloride 
WBC Differential 
Protein 
Bicarbonate 
Red Blood Cell Count 
Glucose 
Blood Urea Nitrogen 
Hemoglobin 
Occult blood 
Creatinine 
Hematocrit 
Urobilinogen 
Glucose 
Mean Corpuscular Volume  
Bilirubin 
Calcium 
Platelet Count 
Pregnancy test 
Phosphate 
 
(human chorionic gonadotropin) 
Magnesium 
 
 
Albumin 
 
 
Total Protein 
 
 
Alkaline Phosphatase 
 
 
Lactate Dehydrogenase 
 
 
Creatine Kinase 
 
 
Liver Function Tests including: 
Bilirubin Total 
Alanine Aminotransferase 
Aspartate Aminotransferase  
Gamma-Glutamyl Transferase 
 
 
Lipid Profile including: 
Total Cholesterol 
Low Density Lipoprotein 
High Density Lipoprotein 
Triglycerides 
 
 
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Specialized Hormonal 
Assessments: 
Thyroid-Stimulating 
Hormone 
Parathyroid Hormone 
Prolactin 
Luteinizing Hormone 
Follicle-Stimulating 
Hormone 
Estradiol 
Progesterone 
Iron (Baseline only) 
Ferritin ((Baseline only) 
Hemoglobin A1c (Baseline 
and Week 24 only) 
 
 
 
A separate sample will be collected at the Day 1 visit and will be banked and tested for presence 
of hepatitis A, B, and C  (hepatitis A antibody, IgM, hepatitis B core antibody, IgM, hepatitis B 
surface antigen, and hepatitis C antibody) if requested by the medical monitor for evaluation of 
abnormal liver function tests. 
The central laboratory will perform laboratory tests for chemistry, hematology, urinalysis, and 
plasma and serum hormone levels.  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. 
6.7.2.5. 
Electrocardiograms 
ECGs (12-lead) will be obtained at the Screening 3 visit, the Baseline Day 1 visit, the Week 12 
visit, and at the Week 24 or early withdrawal and Follow-up visits, as well as if needed to 
evaluate any signs or symptoms.  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. 
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6.7.2.6. 
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). 
The following will be assessed at each time point indicated for bone densitometry in the study 
Schedule of Activities (Section 1.1):  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, average bone 
mineral density of L1-L4, and T-score for average of L1-L4, total hip, and femoral neck. 
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.  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.  Detailed 
instructions for bone mineral density monitoring will be provided in the Study Reference 
Manual. 
6.8. 
Biological Sample Retention and Destruction 
Biological samples present at the conclusion of this study may be retained in storage by the 
sponsor for a period up to 10 years for purposes of this study.  Samples of 5 mL of whole blood 
collected for pharmacogenomics testing (see Section 6.7.1.11) will be stored frozen at an 
appropriate vendor facility identified by the sponsor. 
The need to conduct pharmacogenomic analysis may be identified after this study (or additional 
studies) has been completed.  For this reason, the collected samples will be retained for up to 
10 years after the last patient completes the study.  A patient may request the destruction of her 
sample at any time.  The sponsor may destroy the samples sooner than 10 years after the study 
completes. 
7. 
SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, physical examinations, vital signs (and 
weight), ECGs, bone mineral density assessments, endometrial biopsy results, 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: 
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• 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). 
Adverse events that occur during the study should be evaluated by the investigator and graded 
according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.  
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, 
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drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
c. 
Requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the patient has been detained at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during hospitalization 
are adverse events.  If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event should be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not considered an 
adverse event. 
d. Results in persistent or significant disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect; 
f. 
Important medical events which jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such events are 
invasive or malignant cancers, intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
7.2. 
Adverse Event Reporting 
The reporting of serious adverse events by the sponsor (Myovant Sciences GmbH) to regulatory 
authorities is a requirement and each authority has a timetable for reporting these events based 
upon established criteria.  Likewise, it is the responsibility of the investigator to report serious 
adverse events to their local Institutional Review Board (IRB) or 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 eDiary entries and answers to the UFS-QoL 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 
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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 or partner will be reported as described in Section 7.7 and 
Section 7.8, respectively. 
7.2.1. 
Adverse Event Reporting Period 
Adverse events will be collected from the time the first dose of study drug is administered until 
the Follow-up visit approximately 30 days after the last dose of study drug or the date of 
initiation of another investigational agent or hormonal therapy or surgical intervention, 
whichever occurs first, as also specified in the study Schedule of Activities (Section 1.1). 
Serious adverse events will be collected from the signing of the informed consent form until the 
safety follow-up visit approximately 30 days after the last dose of study drug.  Serious adverse 
events reported to the investigator after the safety reporting period should be reported to the 
sponsor if the investigator assesses the event as related to the study drug treatment. 
Any event occurring between signing of the informed consent form and the first dose of study 
drug will be recorded as medical history and in the patient’s clinical record for any patient who 
continues to meet eligibility criteria and proceeds to dosing with study drug. 
Reporting instructions for serious adverse events are provided in Section 7.6. 
7.3. 
Assigning Causal Relationship to Study Drug 
The reasonable possibility of the relationship of an adverse event to study drug(s) is to be 
assessed with careful medical consideration at the time of evaluation of an adverse event.  The 
following definitions are to be used for the relationship of the adverse event to study drug: 
• Probably related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely attributed to concurrent 
disease or other drugs or chemicals, and that follows a clinically reasonable response on 
readministration (rechallenge) or withdrawal (dechallenge). 
• Possibly related:  A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug but that could also be explained 
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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, version 5.0.  For terms not specified with the CTCAE, the criteria in 
Table 7-1 should be used to determine the grade severity. 
Table 7-1 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not Specified 
by the National Cancer Institute CTCAE Version 5.0 
Grade 
Criteria 
1/Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2/Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3/Severe or medically significant 
Not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4/Life-threatening 
Life threatening consequences; urgent intervention indicated 
5/Death 
Death related to adverse event 
 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form and in the patient’s source documents. 
7.5. 
Adverse Events of Clinical Interest Reporting 
Adverse events of clinical interest in this study are defined as any increase in ALT or AST ≥ 3 x 
ULN. 
Any ALT or AST elevation of this degree or greater occurring during the randomized treatment 
period or the Follow-up visit should be reported to the sponsor using the Serious Adverse Event 
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Form within 24 hours of the study site personnel’s knowledge of the event (see Section 7.6), 
even if the event does not meet SAE criteria.  Additional instructions for evaluating patients 
with an increase in ALT or AST ≥ 3 x ULN may be found in Appendix 6. 
7.5.1. 
Criteria for Temporary Withholding of Study Drug in Association with Liver 
Test Abnormalities 
Hepatic enzymes will be monitored in accordance with FDA drug-induced liver injury guidelines 
[FDA, 2009]. 
If the following liver test abnormalities develop, study drug should be withheld immediately with 
appropriate clinical follow-up (including repeat laboratory tests, until a patient’s laboratory 
profile has returned to normal/baseline status), and the event reported as a serious adverse event: 
• ALT or AST > 8 x ULN; or 
• ALT or AST > 5 x ULN and persists for more than 2 weeks; or 
• ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or the International Normalized 
Ratio (INR) >1.5  
• ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is discovered and the laboratory abnormalities resolve to normal or baseline 
values.  The investigator and sponsor must discuss and agree with any decision to rechallenge.  
Rechallenge should not occur when the etiology of the liver test abnormalities is considered 
possibly drug induced. 
7.5.2. 
Criteria for Permanent Discontinuation of Study Drug in Association with 
Liver Test Abnormalities 
Study drug treatment should be discontinued permanently if all of the following 4 criteria are 
met (ie, potential severe drug-induced liver injury/Hy’s law case): 
1. AST or ALT increases to ≥ 3 x ULN; AND 
2. Total bilirubin increases to > 2 x ULN or INR > 1.5; AND 
3. Alkaline phosphatase value does not reach 2 x ULN; AND 
4. No alternative cause explains the combination of the above laboratory abnormalities; 
important alternative causes include, but are not limited to the following: 
• Hepatobiliary tract disease 
• Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus) 
• Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants, and mushrooms 
• Alcoholic hepatitis 
• Nonalcoholic steatohepatitis  
• Autoimmune hepatitis  
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If an alternative cause for hepatotoxicity is identified, then it should be determined (based on the 
severity of the hepatotoxicity or event) whether study drug treatment should be withheld or 
permanently discontinued as appropriate for the safety of the patient. 
7.6. 
Serious Adverse Event Reporting 
Using a serious adverse event report form, all serious adverse events must be reported within 
24 hours of the study site personnel’s knowledge of the event, regardless of the investigator 
assessment of the relationship of the event to study drug. 
The contact information for submission of serious adverse events and events of overdose or 
pregnancy is available on the Serious Adverse Event report form.  Information may also be 
provided to 
 
The initial report should include: 
• 
Study number (MVT-601-3001) 
• 
Site name and number 
• 
Investigator name 
• 
Patient ID number, sex, and age 
• 
Details of study drug administration 
• 
The date of the report 
• 
A description of the serious adverse event (event term, seriousness of the event, date of 
onset, intensity) 
• 
Causal relationship to the study drug 
If the patient died, the report should include the cause of death and whether or not the cause of 
death was related to study drug, as well as the autopsy findings if available. 
Do not delay reporting a suspected serious adverse event in order to obtain additional 
information.  Any additional information, if collected, can be reported as a follow-up to the 
initial report.  All serious adverse events will be followed until resolution, until the event has 
stabilized, and/or reached a new baseline.  All serious adverse events continuing at the 
completion of the study must be assessed or followed to determine outcome. 
7.7. 
Study Drug Overdose Management 
The medical monitor must be contacted in the event of any study drug overdose. 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by 
a study patient, at a dose above that assigned to that individual patient according to the study 
protocol. 
For this study, any dose of relugolix > 80 mg within a 24-hour window is an overdose and any 
dose of estradiol/norethindrone acetate > 2 x the protocol dose is an overdose (ie, more than 
2 capsules taken within a 24-hour window).  There is no known antidote for an overdose. 
In the event of an overdose, the investigator or treating physician should: 
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• Contact the medical monitor immediately; 
• Closely monitor the patient for adverse events and laboratory abnormalities; 
• All overdose events are to be reported within 24 hours of awareness by the study site, 
using a serious adverse event form according to Section 7.6, whether or not the overdose 
is associated with an adverse event; 
• If possible, obtain a plasma sample for PK analysis within 2 days from the date of the last 
dose of study drug if requested by the medical monitor (determined on a case-by-case 
basis); 
• 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.  The investigator 
must inform the patient of her right to receive treatment information.  If the patient chooses to 
receive unblinded treatment information, the individual blind should be broken and the treatment 
assignment provided to the patient.  The study team will remain blinded to the patient’s treatment 
assignment. 
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 (blinded or 
unblinded, as applicable). 
A pregnancy is to be reported to the sponsor within 24 hours of awareness by the study site 
personnel, using the Pregnancy reporting forms and contact information in Section 7.6.  The 
expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result, and neonatal data, etc, should be included in this 
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 6.7.2 details the requirements for measurement of safety parameters including vital 
signs, physical and gynecologic examinations, clinical laboratory tests, electrocardiograms 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 
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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 
(QTc prolongation), hepatic enzyme increases, PLD, reproductive toxicity, and metabolic and 
cardiovascular changes (insulin resistance, dyslipidemia, increased weight) with an increased 
risk of diabetes mellitus and possible increased risk of cardiovascular disease.  Additionally, 
there are potential risks associated with the addition of estradiol/norethindrone acetate.  
Summaries of findings from both nonclinical and clinical studies conducted with relugolix can 
be found in the current version of the Investigator Brochure. 
The risk assessment and mitigation strategy for this protocol are outlined in Table 7-2. 
Table 7-2 
Protocol Risk Assessment and Mitigation Strategies 
Potential Risk of Clinical Significance 
Mitigation Strategy 
Impact on Eligibility 
Monitoring and 
Withdrawal Criteria 
Bone Mineral Density 
Reversible loss of bone mineral density is 
a risk of the hypoestrogenic state induced 
by relugolix.  This risk is mitigated by the 
co-administration of low-dose estradiol 
and norethindrone acetate hormonal add-
back therapy. 
Exclusion criteria for a 
history of osteoporosis, 
osteopenia, metabolic 
bone disease, and prior 
medical therapy for low 
bone mineral density. 
Bone mineral density will be 
monitored at the Baseline 
Day 1, Week 12, and End of 
Treatment visits and all 
fractures will be reported as 
adverse events.   
Drug Interactions 
Exclusion of co-
administration 
P-gp inhibitors/inducers. 
Collection of adverse events. 
QTc Prolongation 
Negative Thorough QT/QTc clinical study. 
Empiric exclusion of 
baseline QTcF  
> 470 msec. 
12-lead ECG at Baseline 
Day 1, Week 12 and End of 
Treatment 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 LFTs 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 LFTs (AST or 
ALT > 3 x ULN) that 
develop during the 
randomized 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; visual acuity will be 
checked at the beginning and 
end of the 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. 
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. 
Monthly pregnancy testing; 
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, and 
pregnancy are excluded.  
A mammogram, 
Papanicolaou test, 
physical examination, 
clinical chemistries, and 
12-lead ECG will be 
performed prior to 
enrollment. 
Clinical chemistries 
assessing LFTs, 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. 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
A statistical analysis plan (SAP) will describe the detailed statistical methods and analyses for 
this study.  The SAP will be prepared and finalized prior to unblinding of patients’ study 
treatment assignments. 
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All hypothesis tests and confidence intervals will be 2-sided at an alpha level of 5%.  
Methodology to be used to maintain study-wide type I error rate of 5% across primary and 
secondary endpoint testing will be described in the SAP. 
All efficacy and safety measures over the course of the study will be presented.  Continuous data 
will be summarized by means, standard deviations, medians, maximum, minimum, and number 
of patients.  Categorical data will be summarized by counts and percentages. 
9.1. 
Randomization Methods 
Central randomization will be used and treatment allocation will be 1:1:1 to relugolix plus low-
dose hormonal add-back therapy (Group A), relugolix monotherapy plus placebo followed by 
relugolix plus low-dose hormonal add-back therapy (Group B), and placebo (Group C).  
Randomization will be stratified by the following factors: 
• Geographic Region:  North America versus Rest of World; and 
• Mean screening menstrual blood loss using alkaline hematin method:   < 225 mL versus 
≥225 mL. 
Statistical analyses for all efficacy endpoints will incorporate these stratification factors unless 
otherwise specified. 
9.2. 
Analysis Populations 
The Intent-to-Treat (ITT) Population will consist of all patients randomized to treatment who 
have taken at least one dose of study treatment.  This will be the primary population used for the 
efficacy analysis. 
The Per-Protocol Population will consist of those members of the ITT Population who have no 
major protocol violations.  The Per-Protocol Population will not be analyzed if this population 
comprises more than 95% or less than 50% of the ITT Population.  This population will be used 
for confirmatory analysis of the primary efficacy endpoint.  The Per-Protocol Population will be 
identified prior to breaking the study blind. 
The primary population for safety analyses will be the Safety Population, which will consist of 
all patients who are randomized and took at least one dose of study treatment. 
9.3. 
Efficacy Analyses 
Inferential efficacy assessments will be made between the following groups and 24 Weeks of 
placebo: 
• Relugolix Group A:  24 weeks of oral relugolix 40 mg once daily co-administered with low-
dose estradiol and norethindrone acetate; 
• Relugolix Group B:  12 weeks of oral relugolix 40 mg once daily followed by 12 weeks of 
oral relugolix 40 mg once daily co-administered with low-dose estradiol and norethindrone 
acetate. 
Descriptive characterization of treatment effect will be assessed between both relugolix groups. 
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9.3.1. 
Primary Endpoint Analysis 
The primary endpoint is the proportion of women in the relugolix Group A versus the placebo 
Group C who achieve both a menstrual blood loss volume of < 80 mL AND at least a 
50% reduction from baseline in menstrual blood loss volume over the last 35 days of treatment 
as measured by the alkaline hematin method. 
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 as assessed by the alkaline hematin method.  The menstrual blood loss during the 
final study month is the total menstrual blood loss during the last 35 days on treatment as 
assessed by the alkaline hematin method.  The treatment comparison between the relugolix 
Group A and the placebo Group C will be analyzed using a Cochran-Mantel-Haenszel test 
statistic for stratified proportions.  The differences between the relugolix Group A and placebo 
Group C and 2-sided 95% confidence intervals will be estimated based on stratum-adjusted 
Mantel-Haenszel proportions. 
Patients who discontinue the study before Week 4 (28 days) will be considered as treatment 
failures for the primary endpoint.  The primary analyses will be based on the ITT Population.  In 
addition, analyses of the Per-Protocol Population will be used to support the primary efficacy 
analysis.  Details will be provided in the SAP.  Additional missing data imputations will be 
conducted as sensitivity analyses to support the primary analysis.  Details will be provided in the 
SAP. 
For the assessment of the superiority of relugolix Group A versus placebo Group C in the 
proportion of patients who achieve both a menstrual blood loss volume of < 80 mL AND at least 
a 50% reduction in menstrual blood loss volume over the last 35 days of treatment, a sample size 
of ~130 patients in the relugolix Group A versus ~130 in the placebo Group C will provide 
greater than 99% power to detect a difference of greater than 30% using a 2-sided test at 
significance level of 0.05.  The study will enroll 3 groups with a targeted 130 patients in each 
group for a total sample size of 390. 
9.3.2. 
Secondary Endpoint Analyses 
The secondary endpoints are listed below: 
• Proportion of women in the relugolix Group B versus the placebo Group C who achieve a 
menstrual blood loss volume of < 80 mL AND at least a 50% reduction from baseline 
menstrual blood loss volume over the last 35 days of treatment, as measured by the 
alkaline hematin method. 
The following secondary endpoints will be assessed comparing each relugolix treatment group to 
placebo inferentially and relugolix Group A to Group B descriptively: 
• Time to achieving a menstrual blood loss volume of < 80 mL AND at least a 50% 
reduction from baseline menstrual blood loss volume as measured by the alkaline 
hematin method; 
• Change from Baseline to Week 24 in menstrual blood loss; 
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• Proportion of women who achieve amenorrhea over the last 35 days of treatment as 
measured by the alkaline hematin method; 
• Time to amenorrhea as measured by the by the alkaline hematin method; 
• Proportion of women with a hemoglobin below the lower limit of normal at Baseline who 
achieve an increase of ≥ 1 g/dL from Baseline at Week 24; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
physical activities; 
• Change from Baseline to Week 24 in the Menorrhagia Impact Questionnaire Score for 
social and leisure activities; 
• Proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction 
from Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days 
prior to randomization; 
• Change from Baseline to Week 24 in uterine volume; and 
• Change from Baseline to Week 24 in uterine fibroid volume. 
The analysis methods used for the primary endpoint will be applied to the analyses of the 
secondary endpoints of proportion of patients who achieve both a menstrual blood loss volume 
of < 80 mL AND at least a 50% reduction in menstrual blood loss volume over the last 35 days 
of treatment compared between relugolix Group B and placebo Group C, the proportion of 
patients with amenorrhea over the last 35 days, the proportion of women with a hemoglobin 
below the lower limit of normal at Baseline who achieve an increase of at least 1 g/dL at Week 
24 and the proportion of women who achieve a mean Numerical Rating Scale score for uterine 
fibroid-associated pain over the last 35 days of treatment that is at least a 30% reduction from 
Baseline in the subset of women with a maximum pain score ≥ 4 during the 35 days prior to 
randomization. 
For the secondary endpoints of time to achieving a menstrual blood loss volume of < 80 mL 
AND at least a 50% reduction from baseline menstrual blood loss volume and time to 
amenorrhea, time to event will be defined as weeks from randomization 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 and stratified log-rank test will be used to compare each relugolix 
arm to placebo.  Randomization stratification factors will be used to stratify inferential testing. 
Descriptive statistics will be provided for changes in menstrual blood loss, hemoglobin, the 
Numerical Rating Scale score for uterine fibroid-associated pain, uterine volume, and uterine 
fibroid volume baseline.  The between treatment comparisons will be performed using model 
derived least squares means with treatment, stratification factors, baseline result accounted for in 
the model. 
Baseline Numerical Rating Scale score is defined as the average Numerical Rating Scale score 
from the 35 days of data collected prior to the date of first dose of study drug after 
randomization.  The Numerical Rating Scale score during the final study month is the average 
Numerical Rating Scale score during the last 35 days on treatment. 
Details on the endpoint analyses including derivations, handling of missing data, and statistical 
methods will be provided in the SAP. 
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9.4. 
Safety Analyses 
Safety analyses will be conducted using the safety population and summarized by treatment 
group as treated.  The treatment emergent period will be defined as the period of time from the 
first dose date of study drug through approximately 30 days after the last dose of study drug, or 
the date of initiation of another investigational agent or hormonal therapy or surgical 
intervention, 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, version 5.0.  All adverse events will be coded to preferred term and 
system organ class using MedDRA 12.0 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, v. 
5.0 will be used to categorize toxicity grade for the laboratory parameters.  Shift tables will be 
provided for each gradable parameter to summarize baseline toxicity grade versus post-baseline 
toxicity grade.  For laboratory parameters that are not gradable by the CTCAE, a shift table 
based upon the normal range (low, normal, and high) will be provided for each parameter to 
summarize the baseline versus post-baseline results.  All data will be listed and summarized by 
visit.  The change from baseline to each post-baseline study visit will be presented by treatment 
group for each laboratory test. 
For vital signs parameters, including temperature, all data will be listed and summarized by visit.  
The change from baseline to each post-baseline study visit will be presented by 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 corrected QT interval will be summarized at each visit.  All data 
will be listed and summarized by visit.  The change from baseline to each post-baseline study 
visit will be presented by treatment group for each ECG parameter. 
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), T-score for average of L1-L4, total hip, and femoral neck.  All data will be listed 
and summarized by visit.  The change, percent change from Baseline to Weeks 12 and 24 and 
associated 95% confidence intervals will be presented by treatment group for each parameter. 
All data will be listed and summarized by visit.  The change, percent change from baseline to 
Weeks 12 and 24 and associated 95% confidence intervals will be presented by treatment group 
for each parameter. 
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The incidence of vasomotor symptoms as assessed through adverse event reporting will be 
summarized by treatment arm. 
The number and percentage of patients meeting a bone mineral density decline of at least 4%, 
5% or 6% by body area (lumbar, total hip, and femoral neck) will be estimated with 95% 
confidence intervals by treatment group.  The number and percentage of patients meeting a T-
score of < -2.5 by body area will also be estimated with 95% confidence interval by 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. 
9.5. 
Pharmacokinetic Analyses 
The PK concentration data (relugolix, estradiol [PK lab], and norethindrone) and serum 
pharmacodynamic data (LH, FSH, estradiol [central lab] and progesterone) will be listed and 
summarized descriptively by treatment arm and visit. 
Plasma relugolix PK data will be combined with data from other phase 1 and phase 2 studies for 
population PK analysis.  Full details will be provided in a separate Population PK SAP and 
reported separately.  Plasma PK parameters of relugolix will be derived and summarized.  The 
relationship between efficacy, safety, and exposure will be explored. 
9.6. 
Exploratory Analyses 
Descriptive summaries by treatment group and between treatment group comparisons (when 
applicable) will be provided for the following exploratory endpoints.  Details on the endpoint 
analyses including deviations, handling of missing data, and statistical methods will be provided 
in the SAP.  The following exploratory endpoints will be assessed: 
• Change from Baseline to Week 24 in the Uterine Fibroid Scale – Quality of Life 
Symptom Severity and Health-related Quality of Life subscales comparing each relugolix 
treatment group to placebo inferentially and the two relugolix groups descriptively; 
• 
Change from Baseline to Week 24 in the European Quality of Life Five-Dimension Five-
Level scale comparing each relugolix treatment group to placebo inferentially and the 
two relugolix groups descriptively. 
9.7. 
Interim Analyses 
There are no planned interim efficacy analyses. 
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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 United States 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 one year following completion of the study. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the patient (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB or IEC.  Approval from the IRB or IEC 
must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
10.1.3. 
Informed Consent 
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 or the patient’s legally authorized representative and the person 
obtaining consent. 
10.1.4. 
Confidentiality 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only patient number, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the sponsor, IRB or IEC, or laboratory.  The investigator must keep a screening log 
showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from the sponsor, including but not limited 
to the IB, protocol, eCRFs and other study forms, the investigational drug, and any other study 
information, remain the sole and exclusive property of the sponsor during the conduct of the 
study and thereafter.  This information is not to be disclosed to any third party (except employees 
or agents directly involved in the conduct of the study or as required by law) without prior 
written consent from the sponsor.  The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
10.1.5. 
Study Committees and Communication 
There will be two formal committees for this study, a Steering Committee and a Data and Safety 
Monitoring Board. 
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.  Steering Committee 
members will remain blinded to patients’ treatment assignment and all unblinded data until the 
database is officially locked and unblinded. 
An independent Data and Safety Monitoring Board will be established consisting of experts in 
women’s health, clinical study safety monitoring, and statistics.  This committee will evaluate 
the safety of study participants on an ongoing basis.  Further details on the composition and 
responsibility of the Data and Safety Monitoring Board will be outlined in a separate charter. 
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 IB, 
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. 
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2) Patient clinical source documents.  The required source data should include the following 
for each patient: 
• Patient identification (name, date of birth, gender); 
• Documentation that the patient meets eligibility criteria, (eg, history, physical 
examination, and confirmation of diagnosis to support inclusion and exclusion 
criteria); 
• Participation in the study (including study number); 
• Study discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end date (including dose regimen) of study medication (drug dispensing and 
return should be documented as well); 
• Record of all adverse events and other safety parameters (start and end date, and 
causality and intensity as assigned by the investigator); 
• Concomitant medication (including start and end date); and 
• Date of study completion and reason for early discontinuation, if applicable. 
All clinical study documentation must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, 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 IB, 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. 
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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 the 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 (active and 
placebos).  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. 
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10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to patients, may be made 
only by the sponsor.  All protocol modifications must be submitted to the IRB or IEC in 
accordance with local requirements.  Approval must be obtained before changes can be 
implemented.  The investigator must not deviate from the protocol without first obtaining 
approval from the sponsor and the IRB or IEC, if required.  In medical emergencies, the 
investigator will use medical judgment and will remove the patient from immediate hazard, then 
notify the sponsor (or designee) and the IRB or IEC immediately regarding the type of 
emergency and the course of action taken.  The investigator must notify the sponsor (or 
designee) of any inadvertent protocol deviations upon their discovery, and document the 
deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the informed consent form will be amended and approved by the IRB or IEC, and all 
patients on treatment will again provide informed consent. 
10.2.2. 
Study Report 
A clinical study report will be prepared and provided to the regulatory authority(ies).  The 
sponsor will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be 
prepared in certain cases. 
10.2.3. 
Posting of Information on 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. 
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10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits of 
the clinical study.  If the investigator is notified of an inspection by a regulatory authority, the 
investigator agrees to notify the sponsor’s medical monitor immediately.  The investigator agrees 
to provide to representatives of a regulatory agency or the sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
10.3.3. 
Study Discontinuation 
The sponsor reserves the right to terminate the study at any time.  Should this be necessary, the 
sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies) and IRBs/IECs.  In terminating the study, the sponsor and the investigator will 
assure that adequate consideration is given to the protection of the study participants’ interests. 
10.3.4. 
Publications 
After conclusion of the study and without prior written approval from the sponsor, investigators 
in this study may communicate, orally present, or publish in scientific journals or other scholarly 
media only after the following conditions have been met: 
• The results of the study in their entirety have been publicly disclosed by or with the 
consent of the sponsor in an abstract, manuscript, or presentation form; or 
• The study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Myovant Sciences GmbH 
confidential information (see Section 10.1.4). 
The investigator will submit to the sponsor any proposed publication or presentation along with 
the respective target scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation.  The investigator will comply with sponsor requests to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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REFERENCES 
ACOG Practice Bulletin No. 96: Alternatives to Hysterectomy in the Management of 
Leiomyomas. Obstetrics & Gynecology 2008;112(2 Part 1):387-400. 
Activella FDA Clinical Pharmacology Review. November 1998. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20907.cfm. Accessed: 16 August 
2016. 
Activella US Prescribing Information. Revised 10/2013. Available at: http://www.novo-
pi.com/activella.pdf. Accessed: 06 August 2016. 
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: 08 July 2016. 
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. 
Carr BR, Marshburn PB, Weatherall PT, Bradshaw KD, Breslau NA, Byrd W, Roark M, 
Steinkampf MP. An evaluation of the effect of gonadotropin-releasing hormone analogs 
and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance 
imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial. 
Journal of Clinical Endocrinology & Metabolism 1993;76(5):1217-23. 
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. 
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: 16 August 2016. 
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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: 
http://effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed: 16 August 2016. 
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. 
Lee DY, Park HG, Yoon BKoo, 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: 16 August 2016. 
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. 
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. 
Breast Imaging Reporting and Data System (BI-RADS) 
Category 
Assessment 
Follow-up 
0 
Need additional imaging evaluation:  means that more 
studies are necessary to gather more information. 
Additional imaging needed 
before a category can be 
assigned. 
1 
Negative:  means that there is no significant or 
noticeable abnormality to report. 
Continue annual screening 
mammography (for women 
over age 40). 
2 
Benign (noncancerous) finding:  means that there has 
been a finding, such as benign calcifications or 
fibroadenoma, which is not cancerous. 
Continue annual screening 
mammography (for women 
over age 40). 
3 
Probably benign:  means that there is a finding that is 
most likely benign, but should be followed in a shorter 
period of time to see if the area of concern changes. 
Receive a 6-month follow-up 
mammogram. 
4 
Suspicious abnormality:  means that there are 
suspicious findings that could turn out to be cancer. 
May require biopsy. 
5 
Highly suggestive of malignancy (cancer):  means that 
there are findings that look like and probably are 
cancer. 
Requires biopsy. 
6 
Known biopsy-proven malignancy (cancer):  means that 
any findings on the mammogram have already proven 
to be cancer through a biopsy. 
Biopsy confirms presence of 
cancer before treatment begins. 
 
 
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Appendix 2. 
Daily eDiary 
Clinical Study Medication 
1. Did you take your dose of study treatment today? 
□ Yes 
If Yes, please provide  
Date:   dd – MMM - yyyy 
Time:   HH:MM  [AM/PM] 
□ No 
 
2. Did you take your dose of study treatment while on an empty stomach? (i.e., at least 1 
hour before a meal) 
□ Yes 
□ No 
□ Not applicable, I did not take a dose today 
 
Uterine Fibroid Pain 
Please rate your pain caused by your uterine fibroids by indicating the number that best 
describes your pain at its worst in the last 24 hours: 
 
 
  0         1          2         3          4         5        6         7         8          9        10 
No Pain                                                                            Pain As Bad As You Can Imagine 
 
Menstrual Bleeding 
1. Did you experience any menstrual bleeding today? 
□ Yes (this includes spotting as well as bleeding) 
□ No 
 
2. Did you use a menstrual product today for bleeding (i.e., pads, tampons, panty liners)? 
□ Yes 
□ No 
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Use of Pain Medication (Analgesics) and Supplements 
1. Did you take any medication today to treat pain caused by your uterine fibroids? 
□ Yes 
If yes, record medication:_______________________________________ 
□ No 
 
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Appendix 3. 
Menorrhgia 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 4. 
Uterine Fibroid Symptom and Quality of Life Questionnaire 
 
During the previous month, how distressed were 
you by... 
Not at 
all 
A little 
bit 
Somewha
t 
A great 
deal 
A very 
great 
deal 
1 
Heavy bleeding during your menstrual period 
□ 
□ 
□ 
□ 
□ 
2 
Passing blood clots during your menstrual period 
□ 
□ 
□ 
□ 
□ 
3 
Fluctuation in the duration of your menstrual period 
compared to your previous cycle 
□ 
□ 
□ 
□ 
□ 
4 
Fluctuation in the length of your monthly cycle 
compared to your previous cycle 
□ 
□ 
□ 
□ 
□ 
5 
Feeling tightness or pressure in your pelvic area 
□ 
□ 
□ 
□ 
□ 
6 
Frequent urination during the daytime hours 
□ 
□ 
□ 
□ 
□ 
7 
Frequent nighttime urination 
□ 
□ 
□ 
□ 
□ 
8 
Feeling fatigued 
□ 
□ 
□ 
□ 
□ 
 
 
During the previous month, how often have your 
symptoms related to uterine fibroids... 
None of 
the time 
A little 
of the 
time 
Some of 
the time 
Most of 
the time 
All of 
the time 
9 
Made you feel anxious about the unpredictable onset 
or duration of your periods? 
□ 
□ 
□ 
□ 
□ 
10 Made you anxious about traveling? 
□ 
□ 
□ 
□ 
□ 
11 Interfered with your physical activities? 
□ 
□ 
□ 
□ 
□ 
12 Caused you to feel tired or worn out? 
□ 
□ 
□ 
□ 
□ 
13 Made you decrease the amount of time you spent on 
exercise or other physical activities? 
□ 
□ 
□ 
□ 
□ 
14 Made you feel as if you are not in control of your 
life? 
□ 
□ 
□ 
□ 
□ 
15 Made you concerned about soiling underclothes? 
□ 
□ 
□ 
□ 
□ 
16 Made you feel less productive? 
□ 
□ 
□ 
□ 
□ 
17 Caused you to feel drowsy or sleepy during the day? □ 
□ 
□ 
□ 
□ 
18 Made you feel self-conscious of weight gain? 
□ 
□ 
□ 
□ 
□ 
19 Made you feel that it was difficult to carry out your 
usual activities? 
□ 
□ 
□ 
□ 
□ 
20 Interfered with your social activities? 
□ 
□ 
□ 
□ 
□ 
21 Made you feel conscious about the size and 
appearance of your stomach? 
□ 
□ 
□ 
□ 
□ 
22 Made you concerned about soiling bed linen? 
□ 
□ 
□ 
□ 
□ 
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During the previous month, how often have your 
symptoms related to uterine fibroids... 
None of 
the time 
A little 
of the 
time 
Some of 
the time 
Most of 
the time 
All of 
the time 
23 Made you feel sad, discouraged, or hopeless? 
□ 
□ 
□ 
□ 
□ 
24 Made you feel down hearted and blue? 
□ 
□ 
□ 
□ 
□ 
25 Made you feel wiped out? 
□ 
□ 
□ 
□ 
□ 
26 Caused you to be concerned or worried about your 
health? 
□ 
□ 
□ 
□ 
□ 
27 Caused you to plan activities more carefully? 
□ 
□ 
□ 
□ 
□ 
28 Made you feel inconvenienced about always 
carrying extra pads, tampons, and clothing to avoid 
accidents? 
□ 
□ 
□ 
□ 
□ 
29 Caused you embarrassment? 
□ 
□ 
□ 
□ 
□ 
30 Made you feel uncertain about your future? 
□ 
□ 
□ 
□ 
□ 
31 Made you feel irritable? 
□ 
□ 
□ 
□ 
□ 
32 Made you concerned about soiling outer clothes? 
□ 
□ 
□ 
□ 
□ 
33 Affected the size of clothing you wear during your 
periods? 
□ 
□ 
□ 
□ 
□ 
34 Made you feel that you are not in control of your 
health? 
□ 
□ 
□ 
□ 
□ 
35 Made you feel weak as if energy was drained from 
your body? 
□ 
□ 
□ 
□ 
□ 
36 Diminished your sexual desire? 
□ 
□ 
□ 
□ 
□ 
37 Caused you to avoid sexual relations? 
□ 
□ 
□ 
□ 
□ 
Copyright ©, SIR Foundation, all rights reserved. 
 
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Appendix 5. 
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 6. 
Assessment of Abnormal Liver Function Tests  
Study drug treatment (blinded relugolix monotherapy or relugolix co-administered with low-dose 
estradiol and norethindrone acetate or placebo) should be withheld for any liver test abnormality 
listed in Section 7.5.1, pending investigation of alternative causes of liver injury.  Follow-up 
should continue until the liver test abnormalities resolve to baseline. 
Monitor liver tests per the applicable schedule in Appendix Table 1, and per the investigations in 
Appendix Table 2.  If close monitoring is not possible, study drug should be withheld even if the 
results do not meet the criteria for withholding in Section 7.5.1. 
The medical monitor should be contacted for questions regarding adequate follow-up tests and 
frequency of follow-up tests for a patient. 
Appendix Table 1 
Monitoringa of Liver Tests for Potential Drug-Induced Liver Injury 
Results 
Frequency for Repeating Liver (AST, ALT, Bilirubin 
[Total and Direct]), Alkaline Phosphatase, and INR 
Tests  
If AST or ALT ≥ 3 × ULN and total bilirubin 
> 2 × ULN or INR > 1.5 
Every 24 hours until laboratory abnormalities 
improve 
If ALT or AST ≥ 3 × ULN and total bilirubin 
and INR are normal  
Every 48 to 72 hours until laboratory abnormalities 
improve 
If the liver test abnormalities improve AND the 
patient is asymptomatic 
Frequency may decrease 
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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