Conditions: Heavy Menstrual Bleeding Uterine Fibroid
Keywords: Uterine Fibroid Heavy Menstrual Bleeding Menstrual Blood Volume
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 388
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the benefit of relugolix 40 milligrams (mg) once a day co-administered with estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg compared with placebo for 24 weeks on heavy menstrual bleeding associated with uterine fibroids.

Detailed description:
This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety study to evaluate 24 weeks of oral daily relugolix 40 mg co-administered with low-dose E2 and NETA (Group A) and 12 weeks of daily oral relugolix 40 mg alone followed by 12 weeks of daily oral relugolix 40 mg co-administered with low-dose E2 and NETA (Group B) compared with 24 weeks of placebo (Group C).

All participants completing the Week 24 visit, including women randomized to placebo, were offered the opportunity to enroll in an open-label extension study in which all eligible participants will receive relugolix co-administered with low-dose E2 and NETA. Participants who did not enroll into the extension study had a follow-up visit approximately 30 days after the end of treatment (that is, after the participant's last dose of study medication).

Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and assessments of bone mineral density.

Arms:
arm 1: Relugolix co-administered with E2/NETA for 24 weeks. arm 2: Relugolix co-administered with E2/NETA placebo for 12 weeks, followed by relugolix co-administered with E2/NETA for 12 weeks. arm 3: Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.

Interventions: intervention 1: Relugolix intervention 2: Estradiol/norethindrone acetate intervention 3: Estradiol/norethindrone acetate placebo intervention 4: Relugolix placebo
Intervention descriptions: intervention 1: Relugolix (40 mg) tablet administered orally once daily. intervention 2: E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily. intervention 3: E2 (0 mg)/NETA (0 mg) placebo capsule administered orally once daily and designed to match the capsule containing E2/NETA in size, shape, color, and odor. intervention 4: Relugolix (0 mg) placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor.

Protocol document:
Prot_000.pdf: 
 
 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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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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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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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
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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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
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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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
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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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
Item; 
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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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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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 
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 
 
Amendment 2, Effective:  18-SEP-2017 
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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Clinical Study Protocol:  MVT-601-3001 
 
Amendment 2, Effective:  18-SEP-2017 
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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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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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) 
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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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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Clinical Study Protocol:  MVT-601-3001 
 
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Clinical Study Protocol:  MVT-601-3001 
 
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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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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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Amendment 1, Effective:  08-FEB-2017 
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7 
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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CONFIDENTIAL 
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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Clinical Study Protocol:  MVT-601-3001 
 
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CONFIDENTIAL 
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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CONFIDENTIAL 
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) 
 
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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 
 
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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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Clinical Study Protocol:  MVT-601-3001 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................................ 1 
SPONSOR SIGNATURE PAGE ............................................................................................................... 2 
INVESTIGATOR STATEMENT ............................................................................................................. 3 
TABLE OF CONTENTS ........................................................................................................................... 4 
LIST OF TABLES ...................................................................................................................................... 7 
LIST OF FIGURES .................................................................................................................................... 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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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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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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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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SAP_001.pdf: 
 
 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 
 
LIBERTY 2: 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: 
Statistical Analysis Plan Amendment 1: 14-Jun-2019 
  
 
 
 
 
 


 
Statistical Analysis Plan 
MVT-601-3001 and 3002 
Amendment 1: Effective June 14, 2019 
 
Myovant Sciences GmbH 
1 
CONFIDENTIAL 
STATISTICAL ANALYSIS PLAN 
 
Study Titles: 
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 
 
LIBERTY 2:  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 and MVT-601-3002 
 
Indication: 
Heavy menstrual bleeding associated with uterine fibroids 
 
Sponsor: 
Myovant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel 
Switzerland 
 
Regulatory 
Identifier(s): 
IND # 131161 
EudraCT # 2016-003727-27 
 
Version/Effective Date: 
Original: 07-May-2019 
Amendment 1: 14-Jun-2019 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property or under control of Myovant Sciences GmbH 
and cannot be disclosed without written authorization from Myovant Sciences GmbH. 


Statistical Analysis Plan 
MVT-601-3001 and 3002 
Amendment I: Effective June 14,2019 
ST ATISTICAL ANALYSIS PLAN APPROVAL SHEET 
MVT-601-3001 (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 
MVT-601-3002 (LIBERTY 2): 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 
This statistical analysis plan has been approved by Myovant Sciences GmbH ("Myovant"), with 
Myovant Sciences, Inc., acting as agent of Myovant. The foHowing signatures document this 
approval. 
Date 
. I 
Date 
Date 
Date 
Date 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL SHEET ............................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
INTRODUCTION ......................................................................................................11 
1.1. 
Study Objectives and Endpoints .................................................................................11 
2. 
STUDY DESIGN .......................................................................................................16 
2.1. 
Summary of Study Design ..........................................................................................16 
2.2. 
Sample Size Considerations .......................................................................................18 
2.2.1. 
Sample Size Justifications for Primary Efficacy Endpoint .........................................18 
2.2.2. 
Sample Size Justifications for Percent Change in Bone Mineral Density at 
12 Weeks ....................................................................................................................18 
3. 
PLANNED ANALYSES ............................................................................................19 
3.1. 
Interim Analyses .........................................................................................................19 
3.2. 
Final Analyses ............................................................................................................19 
3.3. 
Safety Follow-Up Analyses ........................................................................................19 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA ............................................................................20 
4.1. 
Data Presentation Conventions ...................................................................................20 
4.2. 
Analysis Populations ..................................................................................................21 
4.2.1. 
Modified Intent-to-Treat Population ...........................................................................21 
4.2.2. 
Per-Protocol Population ..............................................................................................21 
4.2.3. 
Safety Population ........................................................................................................21 
4.3. 
Definitions, Computation, and Convention ................................................................21 
4.3.1. 
Definition of Date of First Dose and Date of Last Dose of Study Drug ....................21 
4.3.2. 
Study Day ...................................................................................................................22 
4.3.3. 
Definition of Treatment Duration ...............................................................................22 
4.3.4. 
Definition of Baseline Value and Post-Baseline Value ..............................................22 
4.3.5. 
Visit Windows ............................................................................................................22 
4.4. 
General Rules for Missing Data .................................................................................25 
4.4.1. 
By-Visit Endpoints .....................................................................................................25 
4.4.2. 
Adverse Events and Concomitant Medications ..........................................................25 
5. 
STUDY POPULATION .............................................................................................27 
5.1. 
Subjects Disposition ...................................................................................................27 


 
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5.2. 
Screen Failure .............................................................................................................27 
5.3. 
Protocol Deviations ....................................................................................................27 
5.4. 
Demographic and Baseline Characteristics ................................................................28 
5.5. 
Medical History ..........................................................................................................30 
5.6. 
Prior Medications and Concomitant Medications ......................................................30 
6. 
STUDY DRUG EXPOSURE AND COMPLIANCE ................................................31 
7. 
EFFICACY ANALYSES ...........................................................................................32 
7.1. 
General Considerations ...............................................................................................32 
7.1.1. 
Analyses for Binary Data and Other Categorical Data ...............................................32 
7.1.2. 
Analyses for Categorical Data ....................................................................................32 
7.1.3. 
Analyses for Continuous Data ....................................................................................32 
7.1.4. 
Analyses for Time to Event Data ................................................................................32 
7.2. 
Multiplicity Adjustment..............................................................................................33 
7.3. 
Primary Efficacy Endpoint .........................................................................................33 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................34 
7.3.2. 
Data Sources Supporting Derivation of Responder Status .........................................34 
7.3.3. 
Definitions Related to Menstrual Blood Loss ............................................................35 
7.3.4. 
Definition of Responder at Week 24/EOT .................................................................37 
7.3.5. 
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules ...........................................................................................................................38 
7.3.6. 
Mixed-Effects Model for Imputing Missing or Partially Missing MBL 
Volume at Week 24/EOT ...........................................................................................41 
7.3.7. 
Sensitivity Analyses ....................................................................................................42 
7.3.7.1. 
Sensitivity Analysis 1 .................................................................................................42 
7.3.7.2. 
Sensitivity Analysis 2 .................................................................................................42 
7.3.7.3. 
Sensitivity Analysis 3 .................................................................................................44 
7.3.7.4. 
Sensitivity Analysis 4 .................................................................................................44 
7.3.7.5. 
Sensitivity Analysis 5 .................................................................................................44 
7.3.7.6. 
Sensitivity Analysis 6 .................................................................................................44 
7.3.8. 
Subgroup Analyses .....................................................................................................45 
7.4. 
Secondary Efficacy Endpoints ....................................................................................46 
7.4.1. 
Key Secondary Efficacy Endpoints with Alpha-Protection .......................................46 
7.4.2. 
Other Secondary Efficacy and Exploratory Endpoints ...............................................50 


 
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7.4.3. 
Derivation of Amenorrhea-Related Endpoints ...........................................................51 
7.4.4. 
Derivation of Patient-Reported Outcome ...................................................................54 
7.4.4.1. 
Numerical Rating Scale Score for Pain Associated with Uterine Fibroids ................54 
7.4.4.2. 
UFS-QoL Score ..........................................................................................................54 
7.4.4.3. 
Patient Global Assessment .........................................................................................56 
7.4.4.4. 
Menorrhagia Impact Questionnaire ............................................................................57 
7.5. 
Exploratory Efficacy Endpoints .................................................................................57 
7.5.1. 
Exploratory Efficacy Analyses ...................................................................................57 
8. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ...................58 
9. 
SAFETY ANALYSES ...............................................................................................59 
9.1. 
Adverse Events ...........................................................................................................59 
9.1.1. 
Relationship to Study Drug ........................................................................................60 
9.1.2. 
Severity of Adverse Event ..........................................................................................60 
9.1.3. 
Serious Adverse Event ................................................................................................60 
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug ...............................................61 
9.1.5. 
Adverse Events Leading to Dose Interruption ............................................................61 
9.1.6. 
Adverse Events Resulting to Fatal Outcome ..............................................................61 
9.1.7. 
Adverse Event Categories ...........................................................................................61 
9.2. 
Laboratory Data ..........................................................................................................62 
9.3. 
Other Safety Analyses ................................................................................................63 
9.3.1. 
Electrocardiograms .....................................................................................................63 
9.3.2. 
Visual Acuity ..............................................................................................................63 
9.3.3. 
Vital Signs ..................................................................................................................64 
9.3.4. 
Endometrial Biopsy ....................................................................................................64 
9.3.5. 
Bone Mineral Density .................................................................................................65 
9.3.6. 
Bleeding Pattern ..........................................................................................................66 
10. 
REFERENCES ...........................................................................................................68 
APPENDICES ...............................................................................................................................69 
2.1. 
Development of the Bleeding and Pelvic Discomfort Scale Using Phase 2 
and Phase 3 Data .........................................................................................................74 
2.2. 
Psychometric Analyses Based on Phase 3 Data .........................................................75 
2.3. 
References ...................................................................................................................76 


 
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3.1. 
Development of the Bleeding and Pelvic Discomfort Scale Using 
Exploratory and Confirmatory Factor Analysis .........................................................77 
3.1.1. 
Exploratory Factor Analysis Using Phase 2 Data.......................................................77 
3.2. 
Development of the Bleeding and Pelvic Discomfort Scale Using 
Confirmatory Factor Analysis Based on Phase 3 Data ...............................................79 
3.2.1. 
Confirmatory Factor Analysis using Phase 3 Data .....................................................79 
3.3. 
Classical Test Theory Psychometric Analyses of the Bleeding and Pelvic 
Discomfort Scale Based on Phase 3 Data ...................................................................81 
3.3.1. 
Item Level Analysis of the UFS-QoL Symptom Severity Scale ................................81 
3.3.2. 
Scale Level Analysis of the BPD Scale ......................................................................84 
3.3.2.1. 
Internal Consistency ...................................................................................................84 
3.3.2.2. 
Item-to-Total Correlations ..........................................................................................84 
3.3.2.3. 
Item Discrimination Indices .......................................................................................84 
3.3.2.4. 
Known-Groups Validity .............................................................................................85 
3.3.2.5. 
Ability to Detect Change ............................................................................................85 
3.4. 
Conclusions.................................................................................................................87 
4.2. 
Statistical Analyses Plan for Estimation of the Responder Threshold .......................89 
4.2.1. 
Anchor and Its Correlation with UFS-QoL Endpoint.................................................89 
4.2.2. 
Target Anchor Category .............................................................................................89 
4.2.3. 
Anchor-Based Methods ..............................................................................................90 
4.2.3.1. 
Correlation with Anchor .............................................................................................90 
4.2.3.2. 
Within-Group Meaningful Change .............................................................................90 
4.2.3.3. 
Supportive Analysis of Between Group Meaningful Change Using Analysis 
of Variance ..................................................................................................................90 
4.2.3.4. 
Visualizing Cumulative Distribution Function and Probability Distribution 
Function Plots by Anchor Category Group ................................................................91 
4.2.4. 
Determining a Meaningful Change Threshold Using the Totality-of-
Evidence Approach .....................................................................................................91 
4.3. 
Results from Anchor-Based Analyses ........................................................................91 
4.3.1. 
Correlation of Change in BPD with PGA of Symptom Severity ...............................91 
4.3.2. 
Improvement on BPD Scale by PGA Change Category ............................................92 
4.3.3. 
Estimation of Responder Threshold ...........................................................................93 
4.4 
Exit Interview Study Synthesis ...................................................................................96 
4.4.1 
Objectives ...................................................................................................................96 


 
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4.4.2 
Methodology – Qualitative Interviews .......................................................................97 
4.4.3 
Results.........................................................................................................................98 
UFS-QoL Bleeding and Pelvic Discomfort Scale .......................................................................100 
Patient Global Assessment of Symptom Severity .......................................................................101 
4.4.4 
Discussion .................................................................................................................102 
4.5. 
Determination of Responder Threshold via Triangulation of Findings ....................102 
4.6. 
References .................................................................................................................103 
5.1. 
Approach to Estimating the Responder Threshold of the Revised Activities 
Scale ..........................................................................................................................104 
5.2. 
Statistical Analysis Plan for Estimation of the Responder Threshold ......................105 
5.2.1. 
Anchor and Its Correlation with UFS-QoL Endpoint...............................................105 
5.2.2. 
Target Anchor Category ...........................................................................................105 
5.2.3. 
Anchor-Based Methods ............................................................................................106 
5.2.3.1. 
Correlation with Anchor ...........................................................................................106 
5.2.3.2. 
Within-Group Meaningful Change ...........................................................................106 
5.2.3.3. 
Supportive Analysis of Between Group Meaningful Change Using Analysis 
of Variance ................................................................................................................107 
5.2.3.4. 
Visualizing Cumulative Distribution Function and Probability Distribution 
Function Plots by Anchor Category Group ..............................................................107 
5.2.4. 
Determining a Meaningful Change Threshold Using Totality-of-Evidence 
Approach ...................................................................................................................107 
5.3. 
Results from Anchor-Based Analyses ......................................................................108 
5.3.1. 
Correlation of Change in Revised Activities Scale Score with PGA of 
Function ....................................................................................................................108 
5.3.2. 
Improvement on Revised Activities Scale by PGA Change Category .....................109 
5.3.3. 
Estimation of Responder Threshold .........................................................................110 
5.4. 
Exit Interview Study Synthesis .................................................................................112 
5.4.1 
Objectives .................................................................................................................112 
5.4.2 
Methodology – Qualitative Interviews .....................................................................113 
5.4.3 
Results.......................................................................................................................114 
5.4.3.1 
PGA of Function .......................................................................................................114 
5.4.3.2 
UFS-QoL Revised Activities Subscale .....................................................................115 
5.5. 
Determination of Responder Threshold via Triangulation of Findings ....................117 
5.6. 
References .................................................................................................................117 


 
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LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................12 
Table 2: 
Visit Windows for Monthly Assessments ..................................................................23 
Table 3: 
Visit Windows for Week 12/Week 24 Assessments (ECG, BMD, UFS-QoL) ..........24 
Table 4: 
Visit Windows for Week 24 Assessments (Transvaginal Ultrasound, 
Endometrial Biopsy, EQ-5D-5L) ................................................................................24 
Table 5: 
Time Window for eDiary and Feminine Product Collection ......................................24 
Table 6: 
Categories for Demographic and Baseline Characteristics ........................................29 
Table 7: 
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules – for Primary Analysis ......................................................................................40 
Table 8:  
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules – for Sensitivity Analysis .................................................................................43 
Table 9: 
Planned Subgroup Analyses .......................................................................................46 
Table 10: Rules for Determining Amenorrhea by Visit ..............................................................52 
Table 11: Sustained Amenorrhea Rate by Visit ..........................................................................53 
Table 12: Constitution of Adverse Event Categories .................................................................62 
Table 13: Categories of Liver Test Elevations ...........................................................................63 
Table 14: Categories of Potentially Clinically Significant Abnormalities in Vital Signs ..........64 
Table 15: Categories of Primary Diagnosis in Endometrial Biopsies ........................................65 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................17 
Figure 2: 
Data Sources Supporting Derivation of Primary Endpoint ........................................35 
Figure 3: 
Mixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints in LIBERTY 1 ...........................................................................................47 
Figure 4: 
Mixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints in LIBERTY 2 ...........................................................................................48 
 
 


 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS 
 
Term 
Definition/Explanation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMD 
bone mineral density 
BMI 
body mass index 
Cτ 
predose trough concentrations 
CDF 
cumulative distribution function 
CFI 
comparative fit index 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
DSMB 
data safety monitoring board 
DXA 
dual-energy x-ray absorptiometry 
E2 
estradiol 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end-of-treatment 
EQ-5D-5L 
European Quality of Life Five-Domain Five-Level 
FP 
feminine product 
FPRR 
feminine product return rate 
FSH 
follicle-stimulating hormone 
GFI 
goodness of fit index 
Hgb 
hemoglobin 
ICH 
International Council on Harmonisation 
ITT 
intent-to-treat 
KM 
Kaplan Meier 
LH 
luteinizing hormone 
LLN 
lower limit of normal 
LS 
least squares 
max 
maximum 
MBL 
menstrual blood loss 
min 
minimum 
mITT 
modified intent to treat 


 
Statistical Analysis Plan 
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Term 
Definition/Explanation 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
M-vol 
myoma volume 
NET 
norethindrone 
NETA 
norethindrone acetate 
NRS 
Numerical Rating Scale 
PBO 
placebo 
PDF 
probability density function 
PGA 
patient global assessment 
PK 
pharmacokinetic 
PT 
Preferred Term 
QD 
once daily 
QTcF 
corrected QT interval Fridericia 
RMSEA 
root mean square error of approximation 
SAP 
statistical analysis plan 
SD 
standard deviation 
SES 
standardized effect size 
SMQ 
standard MedDRA query 
SOC 
System Organ Class 
UFS-QoL 
Uterine Fibroid Symptom and Health-Related Quality of Life (Questionnaire) 
ULN 
upper limit of normal 
U-vol 
uterine volume 
WHO 
World Health Organization 
Wks 
weeks 
 


 
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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the analyses planned for phase 3 
studies MVT-601-3001 (LIBERTY 1) and MVT-601-3002 (LIBERTY 2), both entitled “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.”  In these 
studies, patients are randomized to one of three treatment arms:  relugolix 40 mg + 
estradiol/norethindrone acetate (E2/NETA) 1 mg/0.5 mg for 24 weeks (Group A, also referred to 
as the relugolix + E2/NETA group), relugolix 40 mg for 12 weeks followed by 12 weeks of 
relugolix 40 mg + E2/NETA 1 mg/0.5 mg (Group B, also referred to as the relugolix + delayed 
E2/NETA group ), or placebo for 24 weeks (Group C, also referred to as the placebo group). 
The 2 phase 3 studies are replicative; the only difference between the two protocols is the Week 24 
endometrial biopsies, which in MVT-601-3001 are done in all patients and in MVT-601-3002 
depend on the results of the Week 24 ultrasound.   
This SAP was developed in accordance with the International Council on Harmonisation (ICH) 
E9 guidelines.  All decisions regarding statistical analysis of the study, as defined in this SAP, 
will be made prior to unblinding of the study data.   
The SAP is based on: 
• Protocol MVT-601-3001, Amendment 2, dated 18 Sept 2017; 
• Protocol MVT-601-3002, Amendment 2, dated 25 Sept 2017; 
• ICH guidelines E3 (Clinical Study Reports) and E9 (Statistical Principles for Clinical 
Trials). 
This document may evolve over time (eg, to reflect the requirements of protocol amendments or 
regulatory requests).  However, the SAP is to be finalized, approved by the sponsor, and placed 
on file before the database is locked.  Changes to the final approved plan will be noted in the 
clinical study report (CSR).  Unless otherwise specified, the objectives, definitions of endpoints, 
and pre-specification of analyses presented in this document apply to both studies.   
1.1. 
Study Objectives and Endpoints 
The study objectives and corresponding endpoints are listed in the following table.  The 
endpoints in italics are not listed in the protocol, but they have been identified as important for 
assessment of treatment effect on the basis of emerging data and clinical relevance to the study 
objectives and therefore are included in this SAP. 
 
 


 
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Table 1: 
Study Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary Efficacy 
To determine the benefit of relugolix 40 mg 
once daily co-administered with E2 1 mg and 
NETA 0.5 mg compared with placebo for 
24 weeks on heavy menstrual bleeding 
associated with uterine fibroids 
Proportion of women in the relugolix + E2/NETA 
group versus the placebo group who achieve an MBL 
volume of < 80 mL AND at least a 50% reduction 
from Baseline MBL volume over the last 35 days of 
treatment, as measured by the alkaline hematin 
method 
Key Secondary Efficacy  
(Alpha-Protected for Hierarchical Hypothesis Testing — relugolix + E2/NETA versus placebo) 
Achievement of amenorrhea 
Proportion of women who achieve amenorrhea over 
the last 35 days of treatment 
Heavy menstrual bleeding associated with 
uterine fibroids 
Percent change from Baseline to Week 24 in MBL 
volume 
Impact of uterine fibroids on symptoms, 
activities, and health-related quality of life as 
measured by components of the UFS-QoL 
Change from Baseline to Week 24 in the UFS-QoL 
Bleeding and Pelvic Discomfort Scale score, a sub-
scale of the UFS-QoL Symptom Severity scale  
Change in hemoglobin 
Proportion of women with a hemoglobin ≤ 10.5 g/dL 
at Baseline who achieve an increase of > 2 g/dL from 
Baseline to Week 24 
Pain associated with uterine fibroids 
Proportion of patients with a maximum NRS score 
≤ 1 during the last 35 days before the last dose of 
study drug in the subset of women with a maximum 
NRS score ≥ 4 for pain associated with uterine 
fibroids during the last 35 days prior to 
randomization  
Uterine fibroid volume 
Percent change from Baseline to Week 24 in uterine 
fibroid volume  
Uterine volume 
Percent change from Baseline to Week 24 in uterine 
volume 
Other Secondary Efficacy 
(Not for Hierarchical Hypothesis Testing) a 
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 E2 1 mg and NETA 
0.5 mg compared with placebo for 24 weeks 
on heavy menstrual bleeding associated with 
uterine fibroids 
Proportion of women in the relugolix + delayed 
E2/NETA group versus the placebo group who 
achieve an MBL volume of < 80 mL AND at least a 
50% reduction from Baseline MBL volume over the 
last 35 days of treatment, as measured by the alkaline 
hematin method 
Heavy menstrual bleeding associated with 
uterine fibroids 
• 
Percent change from Baseline in MBL volume by 
visit 
• 
Change from Baseline in MBL volume by visit 


 
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Objective(s) 
Endpoint(s) 
• 
Time to achieve an MBL volume of < 80 mL 
AND at least a 50% reduction from Baseline 
MBL volume as measured by the alkaline 
hematin method 
• 
Proportion of women in the relugolix + E2/NETA 
group versus the placebo group who achieve an 
MBL volume of < 80 mL AND at least a 50% 
reduction from Baseline MBL volume by visit 
Achievement of amenorrhea 
• 
Sustained amenorrhea rate by visit 
• 
Time to achieving sustained amenorrhea 
• 
Time to achieving amenorrhea 
Change in hemoglobin 
• 
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 hemoglobin 
for women with a hemoglobin ≤ 10.5g/dL at 
Baseline 
Impact of uterine fibroids on symptoms, 
activities and health-related quality of life as 
measured by components of the UFS-QoL 
• 
Change from Baseline to Week 24 in the 
UFS-QoL Symptom Severity Scale score 
• 
Change from Baseline to Week 24 in the 
UFS-QoL Activities Scale score 
• 
Change from Baseline to Week 24 in the 
UFS-QoL Revised Activities Scale score 
• 
Proportion of responders who achieved a 
meaningful increase of at least 20 points from 
Baseline to Week 24 in UFS-QoL Revised 
Activities Scale score  
• 
Proportion of responders who achieved a 
meaningful reduction of at least 20 points from 
Baseline to Week 24 in UFS-QoL Bleeding and 
Pelvic Discomfort Scale score  
• 
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 


 
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Objective(s) 
Endpoint(s) 
• 
Change from Baseline to Week 24 in 
embarrassment caused by uterine fibroids based 
on UFS-QoL Question 29 
Patient global assessment for function and 
symptoms as measured by the PGA for 
function and symptoms 
• 
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 
• 
Proportion of patients achieving improvement 
from Baseline in PGA for uterine fibroid 
symptoms from Baseline to Week 24 
• 
Proportion of patients achieving improvement 
from Baseline in PGA for uterine fibroid related 
function from Baseline to Week 24 
Impact of heavy menstrual bleeding on 
social, leisure, and physical activities as 
measured by the Menorrhagia Impact 
Questionnaire 
• 
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 
Pain associated with uterine fibroidsb 
Proportion of women who achieve a maximum NRS 
score for pain associated with uterine fibroids 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 
Safety 
To determine the safety of 24 weeks of 
relugolix 40 mg once daily co-administered 
with either 12 or 24 weeks of E2 1 mg and 
NETA 0.5 mg in women with heavy 
menstrual bleeding associated with uterine 
fibroids compared with placebo for 24 weeks 
Treatment-emergent adverse events, change in vital 
signs (including weight), clinical laboratory tests, and 
electrocardiograms 
To determine the percent change from 
Baseline to Week 12 in bone mineral density 
at the lumbar spine (L1-L4) in the 
relugolix + E2/NETA group compared with 
the relugolix + delayed E2/NETA group in 
women with heavy menstrual bleeding 
associated with uterine fibroids 
Percent change from Baseline to Week 12 in bone 
mineral density at the lumbar spine (L1-L4) in the 
relugolix + E2/NETA group compared with 
relugolix + delayed E2/NETA group as assessed by 
DXA 


 
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Objective(s) 
Endpoint(s) 
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 E2 1 mg and NETA 0.5 mg 
compared with placebo for 24 weeks 
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 
To determine the incidence of vasomotor 
symptoms with relugolix 40 mg once daily 
co-administered with either 12 or 24 weeks 
of E2 1 mg and NETA 0.5 mg in women 
with heavy menstrual bleeding associated 
with uterine fibroids 
Incidence of vasomotor symptoms 
Pharmacokinetic and Pharmacodynamic 
To evaluate the pharmacokinetic and 
pharmacodynamic effects of 24 weeks of 
relugolix 40 mg once daily when 
co-administered with either 12 or 24 weeks 
of E2 1 mg and NETA 0.5 mg 
• 
Predose trough concentrations (Cτ) of relugolix, 
and NET and Baseline-adjusted E2 concentration 
• 
Absolute and changes from Baseline to Week 24 
in predose concentrations of LH, FSH, E2, 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 E2 1 mg and 
NETA 0.5 mg compared with placebo on 
patient-reported quality of life outcome 
measures (EQ-5D-5L) 
Change from Baseline to Week 24 in the EQ-5D-5L 
Scale score 
Abbreviations:  DXA, dual energy x-ray absorptiometry; E2, estradiol; EQ-5D-5L, European Quality of Life Five-
Domain Five-Level; FSH, follicle-stimulating hormone; LH, luteinizing hormone; MBL, menstrual blood loss; 
NET, norethindrone; NETA, norethindrone acetate; NRS, numerical rating scale; PGA, Patient Global Assessment; 
UFS-QoL, Uterine Fibroid Symptom and Health-Related Quality of Life.   
a The secondary endpoints below will be assessed comparing the relugolix + E2/NETA group with the placebo 
group inferentially; the relugolix + E2/NETA group to the relugolix + delayed E2/NETA group and the relugolix + 
delayed E2/NETA group to the placebo group descriptively, unless otherwise specified. 
b Changed from mean NRS score (in the protocol) to maximum NRS score.  Since pain associated with uterine 
fibroids is mostly during menstrual days, mean NRS scores over the last 35 days is very low (< 1) for most 
patients, hence, not appropriate to define percent reduction from Baseline.   
 


 
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2. 
STUDY DESIGN 
2.1. 
Summary of Study Design 
The LIBERTY 1 and LIBERTY 2 studies are two replicate, randomized, double-blind, placebo-
controlled phase 3 studies evaluating the efficacy and safety of relugolix 40 mg in combination 
with E2 1 mg/NETA 0.5 mg in women with heavy menstrual bleeding associated with uterine 
fibroids (MVT-601-3001, MVT-601-3002).  Patients with heavy menstrual bleeding associated 
with uterine fibroids — as evidenced by a menstrual blood loss (MBL) volume of ≥ 80 mL per 
cycle for 2 cycles or ≥ 160 mL during one cycle, as measured by the alkaline hematin method 
during the screening period — who met other eligibility criteria were randomly assigned (1:1:1) 
to 1 of the 3 treatment arms: 
• Group A (relugolix + E2/NETA):  relugolix 40 mg once daily co-administered with 
E2 1 mg/NETA 0.5 mg for 24 weeks; 
• Group B (relugolix + delayed E2/NETA):  relugolix 40 mg once daily for 12 weeks 
followed by relugolix 40 mg once daily co-administered with E2 1 mg/NETA 0.5 mg 
for 12 weeks; 
• Group C (placebo):  placebo for 24 weeks 
Randomization was stratified as follows:  
• Geographic Region:  North America versus Rest of World;  
• Mean screening MBL volume using alkaline hematin method:  < 225 mL versus 
≥ 225 mL. 
The primary endpoint for both trials is the proportion of women receiving relugolix + E2/NETA 
(Group A) versus placebo (Group C) who achieve BOTH a MBL volume of < 80 mL AND at 
least a 50% reduction from Baseline in MBL volume over the last 35 days of treatment, as 
measured by the alkaline hematin method. 
This study includes a screening period (up to ~13 weeks), a randomized treatment period 
(24 weeks), and a safety follow-up period (~30 days).  During the screening period, diagnoses of 
uterine fibroids are confirmed by centrally reviewed transvaginal ultrasound.  Women with iron-
deficient microcytic anemia and hemoglobin ≥ 8 g/dL and ≤ 10 g/dL during the screening period 
are treated with oral or parenteral iron replacement therapy.  After randomization, patients begin 
double-blinded study drug treatment for 24 weeks. 
Patients who complete LIBERTY 1 or LIBERTY 2, including those randomized to placebo, and 
who meet other eligibility criteria are offered the opportunity to enroll in a 28-week open-label 
extension study, in which all patients will receive relugolix 40 mg co-administered with E2 1 mg 
and NETA 0.5 mg.  Patients who do not enroll into the extension study have a safety follow-up 
visit approximately 30 days after their last doses of study medication. 
Additional safety follow-up may be performed after the safety follow-up visit.  Data collected 
during the additional safety follow-up period will be summarized and reported in an addendum 
to the respective clinical study report.  Patients who are not proceeding into the extension study 
and who have endometrial hyperplasia or endometrial cancer on the endometrial biopsy should 
be treated as per standard of care and additional follow-up should be evaluated and managed, as 


 
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needed, by a gynecologist.  In addition, they should 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.  
Patients who are not proceeding into the extension study and who have a bone mineral density 
(BMD) loss of > 2% at the lumbar spine (L1–L4) or total hip relative to the Baseline 
measurement at their Week 24/Early Termination visit will undergo a follow-up DXA scan 
6 months (± 1 month) after discontinuation of study drug and will be contacted to obtain 
information about medications and conditions (eg, pregnancy, hyperparathyroidism, 
hypothyroidism, etc.) that might affect BMD through the time of the repeat DXA scan.  If the 
DXA scan 6 months post-treatment continues to show BMD loss of > 1.5% at the lumbar spine 
and/or > 2.5% at the total hip compared with Baseline, patients will have an additional scan at 12 
months post-treatment.  All follow-up DXA scans will be submitted for central reading.  Patients 
whose menses had not resumed as of the safety follow-up visit for unexplained reasons will be 
contacted by telephone to determine if menses have resumed.  Patients with reductions in visual 
acuity will be referred for ophthalmology consultation. 
An external independent data and safety monitoring board (DSMB) was established to review 
periodic safety analyses, including BMD assessments.  The roles and responsibilities of the 
independent DSMB are described in a separate charter.  A separate SAP was created to 
document the specific safety data analyses that would be performed by an independent data 
coordinating center for the DSMB on an ongoing basis during the study. 
A schematic of the study is presented in Figure 1. 
Figure 1: 
Study Schematic 
 
Abbreviations:  E2, estradiol; NETA, norethindrone; PBO, placebo; QD, once daily; Wks, weeks. 
 


 
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2.2. 
Sample Size Considerations 
2.2.1. 
Sample Size Justifications for Primary Efficacy Endpoint 
The following assumptions were used to determine the sample size for this study: 
• 2-sided type I error rate:  0.05 
• Randomization:  1:1:1 
• Responder rate for placebo group:  25% 
• Difference in responder rates between the relugolix + E2/NETA group and the 
placebo group:  30% 
• Dropout rate:  ~20% 
With the assumption of a dropout rate of 20%, approximately 130 women in the relugolix + 
E2/NETA group and 130 women in the placebo group will provide at least 99% power at a 2-
sided 0.05 significance level to detect a 30% difference in responder rates between relugolix + 
E2/NETA group and the placebo group for the primary endpoint.  With an additional 130 women 
in the relugolix + delayed E2/NETA group, the total sample size will be approximately 390 
women. 
The assumed responder rate of 25% for the placebo group is within the range of responder rates 
observed from similar phase 3 trials in uterine fibroids (Stewart, 2017).  The sample size and 
power calculations are based on a chi-squared test. 
2.2.2. 
Sample Size Justifications for Percent Change in Bone Mineral Density at 
12 Weeks 
A pooled analysis of the percent change in BMD at 12 weeks using data from both phase 3 
studies is described separately in the statistical analysis plan for the Integrated Summary of 
Safety.  The results of this pooled analysis comparing the relugolix + E2/NETA group with the 
relugolix + delayed E2/NETA group will be presented in the Integrated Summary of Safety and 
will not be included in the CSRs for these studies. 
For the comparison of the relugolix + E2/NETA group with the relugolix + delayed E2/NETA 
group with respect to the percent change in BMD from Baseline to Week 12 at the lumbar spine 
(L1–L4), approximately 260 women in the relugolix + E2/NETA group (pooled between the 
LIBERTY 1 and LIBERTY 2 studies) and 260 women in the relugolix + delayed E2/NETA 
(pooled) will provide at least 90% power at a 2-sided 0.05 significance level to detect a 1.25% 
absolute treatment difference, assuming a standard deviation of 4% and up to 15% dropout rate 
for each treatment group.  Power calculations for this BMD comparison are based on a two-
sample t-test.  
Sample size and power calculations were performed using the software package nQuery 4.0 
(Statistical Solutions Ltd.).  


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No interim efficacy analyses were planned or performed for these two studies.  
An external, independent DSMB was established to review periodic safety analyses, including 
BMD assessments.  A separate SAP was created to document the specific safety data analyses 
that would be performed by an independent data coordinating center for the DSMB on an 
ongoing basis during the study. 
3.2. 
Final Analyses 
The final analysis of all efficacy and safety data from MVT-601-3001 and MVT-601-3002 will 
occur after approximately 390 patients have been randomized to each study and have had the 
opportunity to be followed for 24 weeks of study treatment and through the 30-day safety 
follow-up visit.  This document describes this final analysis. 
There will be periodic safety data review by the DSMB.  An independent data coordinating 
center has performed the periodic safety analyses and has provided results of these analyses to 
the DSMB, as defined in the DSMB charter and outlined in a separate DSMB SAP. 
3.3. 
Safety Follow-Up Analyses 
Patients who are not proceeding into the extension study and who have endometrial hyperplasia 
or endometrial cancer on the endometrial biopsy should be treated as per standard of care and 
additional follow up should be evaluated and managed, as needed, by a gynecologist.  In 
addition, they should undergo a repeat biopsy in 3 to 6 months after the Week 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.  
Patients who are not proceeding into the extension study and who have a BMD loss of > 2% at 
the lumbar spine (L1–L4) or total hip relative to the Baseline measurement at their Week 
24/Early Termination visit 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.  If the DXA scan 6 months post-
treatment continues to show BMD loss of > 1.5% at the lumbar spine and/or > 2.5% at the total 
hip compared to Baseline patients will have an additional scan at 12 months post-treatment.  All 
follow-up DXA scans will be submitted for central reading.  Patients whose menses had not 
resumed as of the safety follow-up visit for unexplained reasons will be contacted by telephone 
to determine if menses have resumed.  Patients with reductions in visual acuity will be referred 
for ophthalmology consultation.   
Data collected during the additional safety follow-up period will be summarized and reported in 
an addendum to the respective clinical study report. 


 
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4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING OF MISSING DATA 
4.1. 
Data Presentation Conventions 
All statistical analyses will be conducted using SAS® Version 9.2 or higher. 
A statistical test for the primary and secondary efficacy endpoints will be assessed at a two-sided 
α = 0.05 significance level, and all confidence intervals (CIs) will be reported as two-sided 
unless otherwise stated. 
Where appropriate, variables will be summarized descriptively by study visit.  For the 
categorical variables, the count and proportions of each possible value will be tabulated by 
treatment group.  For continuous variables, the number of patients with non-missing values, 
mean, median, standard deviation (SD), minimum, and maximum values will be tabulated. 
Unless otherwise specified, the following conventions will be applied to all analyses: 
• Mean and median values will be formatted to one more decimal place than the 
measured value.  Standard deviation values will be formatted to two more decimal 
places than the measured value; minimum and maximum values will be presented to 
the same number of decimal places as the measured value; if the measured value is 
large (eg, > 100), fewer decimal places may be displayed. 
• Percentages will be rounded to 1 decimal place; 
• p-values will be rounded to 4 decimal places.  p-values < 0.0001 will be presented as 
“< 0.0001” and p-values > 0.9999 will be presented as “> 0.9999”; 
• 1 month = 30.4375 days.  Month is calculated as (days/30.4375) rounded to 1 decimal 
place; 
• 1 year = 365.25 days.  Year is calculated as (days/365.25) rounded to 1 decimal place; 
• Age will be calculated using the date of randomization.  If only year of birth is 
collected, 1 July of the year of birth will be used to calculate age. 
• 1 pound = 0.454 kg; 
• 1 inch = 2.54 cm; 
• Missing efficacy or safety data will not be imputed unless otherwise specified; 
• For laboratory results above or below sensitivity limits displayed as “<” or “>” a 
quantification threshold, 0.0000000001 will be subtracted or added, respectively, to 
the threshold to derive a numeric result for analyses; 
• For MBL volume reported as below the limit of quantification (for example, MBL 
below Quantification Level <5.0 mL or <2.5 mL), 0.0000000001 will be subtracted 
from the reported quantification threshold for the visit to derive a numeric result for 
analyses; 
• For safety analyses, calculation of percentages will be calculated on the basis of the 
number of patients in the analysis population in each treatment group; 


 
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• For by-visit observed data analyses, calculation of percentages will be calculated on 
the basis of the number of patients with non-missing data as the denominator, unless 
otherwise specified; 
• For other continuous endpoints, the summary statistics will include mean, SD, 
median, and range (minimum and maximum); 
• For time-to-event endpoints, the summary statistics will include median time to 
event-free survival, 25th and 75th percentiles and number of patients at risk at 
specified time points; 
• For categorical endpoints, the summary statistics will include counts and percentages; 
• Confidence intervals, when presented, will generally be constructed at the 95% level.  
For binomial variables, exact methods will be employed, unless otherwise specified. 
4.2. 
Analysis Populations 
Three analysis populations are defined below.  Number and percent of patients meeting the 
definition of each analysis population will be summarized by treatment group. 
4.2.1. 
Modified Intent-to-Treat Population 
Efficacy analyses will be performed using the modified Intent-to-Treat (mITT) population, 
unless otherwise specified.  The mITT population is defined as all randomized patients who have 
received any amount of study drug (relugolix/placebo or E2/NETA/placebo).  Efficacy analyses 
will be performed by treatment group as randomized. 
4.2.2. 
Per-Protocol Population 
The Per-Protocol population will consist of those members of the mITT population who do not 
have any of the specified subset of important protocol deviations (see Section 5.3). 
The Per-Protocol population will not be analyzed if this population comprises > 95% or < 50% 
of the mITT population.  The Per-Protocol population will be used for sensitivity analysis of the 
primary efficacy endpoint.  The Per-Protocol population and the associated subset of important 
protocol deviations will be identified prior to unblinding the trial.  
4.2.3. 
Safety Population 
Safety analyses will be performed using the Safety population unless otherwise specified.  The 
Safety population is the same as the mITT population and is defined as all randomized patients 
who have received any amount of study drug.  Safety data will be analyzed by treatment group 
according to the actual treatment received (not the randomized treatment).  Any patient who 
received at least one dose of relugolix will be considered as a relugolix patient.   
4.3. 
Definitions, Computation, and Convention 
4.3.1. 
Definition of Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date when a patient receives the first 
dose of study drug (relugolix/placebo or E2/NETA/placebo).  The date of the last dose of study 


 
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drug is defined as the date a patient receives the last dose of study drug.  If the complete date of 
last dose of study drug is unknown, the last date the study drug was known to have been taken 
will be used.  
4.3.2. 
Study Day 
Study day will be calculated with respect to the date of the first dose of study drug (Study 
Day 1).  For assessments conducted on or after the date of the first dose of study drug, study day 
will be calculated as: 
(Assessment date – date of first dose of study drug) + 1 
For assessments conducted before the date (and time) of the first dose of study drug, study day 
will be calculated as: 
(Assessment date – date of first dose of study drug) 
For patients who do not receive any amount of study drug, study day will be calculated as above 
with respect to the date of randomization. 
4.3.3. 
Definition of Treatment Duration 
Treatment duration is defined as the duration of time from the date of the first dose of study drug 
to the date of the last dose of study drug as follows:  
(Date of last dose of study drug – Date of first dose of study drug) + 1 
For patients without complete date of last dose of study drug, the last date study drug was known 
to have been taken will be used to calculate treatment duration.  For patients who did not return 
for the Early Termination visits, the time after their last visit will not be included in calculations 
of treatment duration. 
4.3.4. 
Definition of Baseline Value and Post-Baseline Value 
Unless otherwise specified, Baseline values are defined as the last measurement before the first 
administration (date and time) of study drug.  A post-Baseline value is defined as a measurement 
taken after the first administration of study drug.  Change from Baseline is defined as (post-
Baseline value – Baseline value).  Both date and time of study drug administration and 
measurement will be considered when calculating Baseline value.  If the time is not available, 
then the date alone will be used.  For patients who receive no study medication, the date of 
randomization will be used in place of the date of first dose in determining Baseline and post-
Baseline values. 
4.3.5. 
Visit Windows 
Visit windows, which will be used to associate assessments with a scheduled visit, will be used 
only for summarizing data by visit.  The windows for scheduled assessments are shown in 
Table 2, Table 3 (electrocardiogram [ECG], BMD, Uterine Fibroid Symptom and Health-Related 
Quality of Life [UFS-QoL]), and Table 4 (transvaginal ultrasound, endometrial biopsy, and 
European Quality of Life Five-Domain Five-Level [EQ-5D-5L]), respectively.  For both efficacy 
and safety assessments, the study day will be used to determine the associated visit window.  


 
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The data collected in the electronic diary (eDiary) related to bleeding and use of feminine 
products will be assigned to visit windows as specified in Table 5 and will be used to calculate 
the feminine product return rate (FPRR) as specified in Section 7.3.3. 
If the results from more than one monthly or Week 12/Week 24 assessment are within a given 
visit window, the non-missing result from the assessment closest to the target date will be used.  
If two assessments are equally close to the target day, the earlier assessment will be used.  For 
summaries of shift from Baseline in safety parameters, all values will be considered for these 
analyses. 
Table 2: 
Visit Windows for Monthly Assessments 
Visit 
Start Day 
Target Day 
End Day 
Week 4a 
1 
29 
43 
Week 8 
44 
57 
71 
Week 12 
72 
85 
99 
Week 16 
100 
113 
127 
Week 20 
128 
141 
155 
Week 24 
156 
169 
196 
Safety Follow-Upb 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
a Start day of Week 4 for study day 1 includes only post-Baseline assessments that occurred after the first dose. 
b The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids. 
 
 


 
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Table 3: 
Visit Windows for Week 12/Week 24 Assessments (ECG, BMD, UFS-QoL) 
Visit 
Start Day 
Target Day 
End Day 
Week 12 
64 
85 
106 
Week 24 
148 
169 
196 
Safety Follow-upa 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
Abbreviations:  BMD, bone mineral density; ECG, electrocardiogram; UFS-QoL, Uterine Fibroid Symptom and 
Health-Related Quality of Life.   
a The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids  
Table 4: 
Visit Windows for Week 24 Assessments (Transvaginal Ultrasound, 
Endometrial Biopsy, EQ-5D-5L) 
Visit 
Start Day 
Target Day 
End Day 
Week 24 
128 
169 
196 
Safety Follow-upa 
Date of last dose + 
7 days 
Date of last dose + 
30 days 
Date of last dose + 
60 days 
Abbreviations:  EQ-5D-5L, European Quality of Life Five-Domain Five-Level. 
a The safety follow-up visit window will be restricted to assessments prior to the date of initiation of another 
investigational agent or hormonal therapy affecting the hypothalamic‑pituitary‑gonadal axis or surgical 
intervention for uterine fibroids. 
Table 5: 
Time Window for eDiary and Feminine Product Collection  
Visit 
Feminine Product Collection Visit Datea,b 
Time Windowa 
Week 4 
X1 
(Date of Study Day 1) - < X1 
Week 8 
X2 
(X1 +1) - ≤ X2 
Week 12 
X3 
(X2 +1) - ≤ X3 
Week 16 
X4 
(X3 +1) - ≤ X4 
Week 20 
X5 
(X4 +1) - ≤ X5 
Week 24 
X6 
(X5 +1) - ≤ X6 
Week 24/EOT 
XLastc 
(Previous Feminine Product Returned 
Visit +1)] – ≤ XLast   
a If feminine products are collected at more than 1 visit within a given visit window (Table 2), the last feminine 
product collection date will be used to define the time window.  If the patient missed the previous visit, a planned 
study visit date will be used to calculate the window. 
b In the absence of feminine product collection due to amenorrhea the visit date when amenorrhea was reported will 
be used. 
c   Date of last non-missing feminine product collection within the interval from (last dose date – 35) to (last dose date + 7 days) (see 
Section 7.3.3).  
 


 
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4.4. 
General Rules for Missing Data 
Handling of missing data for the primary efficacy analysis is described in Section 7.3.5. 
4.4.1. 
By-Visit Endpoints 
By-visit endpoints will be analyzed using observed data, unless otherwise specified.  For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included. 
4.4.2. 
Adverse Events and Concomitant Medications 
The following imputation rules for the safety analyses will be used to address the issues with 
partial dates.  The imputed dates will be used to determine the treatment-emergent period.  For 
adverse events with a partial date, available date parts (year, month, and day) of the partial date 
will be compared with the corresponding date components of the start date and end dates of the 
treatment-emergent period to determine if the event is treatment emergent.  When in doubt, the 
adverse event will be considered treatment emergent by default.   
The following rules will be applied to impute partial dates for adverse events: 
• If start date of an adverse event is partially missing, impute as follows: 
− If both Month and Day are missing and Year = Year of treatment start date, then 
set to treatment start date as long as adverse event end date is not prior to 
treatment start date; 
− If both Month and Day are missing and Year ≠ Year of treatment start date, then 
set to January 1; 
− If Day is missing and Month and Year = Month and Year of treatment start date, 
then set to treatment start date as long as adverse event end date is not prior to 
treatment start date; 
− If Day is missing and Month and Year ≠ Month and Year of treatment start date, 
then set to first of the month; 
− If start date is completely missing, set to treatment start date as long as adverse 
event end date is not prior to treatment start date. 
• If end date of an adverse event is partially missing, impute as follows: 
− If both Month and Day are missing, then set to December 31; 
− If only Day is missing, then set to last day of the month; 
− If end date is completely missing, do not impute. 
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant (or both).   
The following rules will be applied to impute partial dates for medications: 
• If start date of a medication is partially missing, impute as follows: 
− If both Month and Day are missing, then set to January 1; 


 
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− If only Day is missing, then set to the first of the month. 
• If end date of a medication is partially missing, impute as follows: 
− If both Month and Day are missing, then set to December 31; 
− If only Day is missing, then set to last day of the month. 
If start date or end date of a medication is completely missing, do not impute. 


 
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5. 
STUDY POPULATION 
5.1. 
Subjects Disposition 
The number of patients for each of the following categories will be summarized by treatment 
group: 
• All randomized patients; 
• Patients included in the Safety population;  
• Patients who completed the 12-Week randomized treatment period; 
• Patients who completed the 24-Week randomized treatment period; 
• Patients who discontinued early from the 24-Week randomized treatment period and 
reasons for discontinuation; 
• Patients who enrolled in the extension study; 
• Patients who entered the Post-Treatment Follow-Up Period and did not enroll in the 
extension study. 
Patient disposition will be summarized for all randomized patients.  Summaries will include the 
number and percentage of patients in the mITT and Safety populations.  The number and 
percentage of patients who prematurely discontinue study drug and the reasons for 
discontinuation will be summarized by treatment group.  The number and percentage of patients 
who continue into the extension study (MVT-601-3003) will also be summarized by treatment 
group. 
5.2. 
Screen Failure 
Reasons for screen failure will be summarized.  Number and percentage of patients who did not 
pass screening will be based on the patients who signed the informed consent form but were not 
randomized. 
5.3. 
Protocol Deviations 
Protocol deviations will be categorized as important or minor per the protocol deviation plan.  
Important protocol deviations will include, but will not be limited to, the following categories: 
• Randomized patient who did not satisfy key entry criteria; 
• Randomized patient who met withdrawal criteria during the study but was not 
withdrawn; 
• Randomized patient who received the wrong treatment; 
• Randomized patient who received a prohibited concomitant medication that met 
criteria for an important protocol deviation; 
• Unintentional unblinding of treatment assignment. 
Important protocol deviations will be summarized by deviation category for all patients in the 
mITT population.  A patient listing of all important protocol deviations will be provided. 


 
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In addition, patient eligibility, including inclusion criteria that are not met and exclusion criteria 
that are met at randomization enrollment, will be summarized for all patients in the mITT 
population. 
A selected subset of the major protocol deviations that are likely to affect analysis of efficacy 
will be identified to define the Per-Protocol population prior to the database lock.  This subset 
will include but will not be limited to the following important protocol deviations:  
• Did not satisfy key entry criteria (restricted to patients with missing Baseline MBL 
volume or ineligible Baseline MBL volume);  
• Drug compliance < 75%; 
• Patient received prohibited concomitant medications that met criteria for important 
protocol deviation: restricted to patients who received prohibited concomitant 
medications that may cause significant drug-drug interaction; 
• Unintentional unblinding of treatment assignment. 
5.4. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized by treatment group for the mITT 
population.  Categorical data will be summarized using frequencies and percentages, by 
treatment group and overall (see Table 6 below).  Summaries of continuous data will display the 
mean, SD, median, minimum, and maximum.  The numbers of missing values will also be 
summarized. 
 
 


 
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Table 6: 
Categories for Demographic and Baseline Characteristics  
Variable 
Category 
Age (years) 
< 40, ≥ 40  
Geographic region 
North America, Rest of World 
Race 
Black or African American, White, American Indian 
or Alaska Native, Asian, Native Hawaiian or Other 
Pacific Islander, Other  
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino or Not 
reported 
BMI (kg/m2) at Baseline 
< 18.5, 18.5 to <25, 25 to <30, 30 to < 35,  
35 to < 40, ≥ 40 
History of prior pregnancy  
Yes, No 
Disease duration of uterine fibroid (years) 
Min to <1, ≥ 1 to < 3, ≥3 to <5, ≥5 to <10, ≥ 10 
Type of uterine fibroids 
     Subserous fibroid 
Yes, No 
     Intramural fibroid 
Yes, No 
     Submucosal fibroid 
Yes, No 
     Other 
Yes, No 
Any surgery for uterine fibroids 
Yes, No 
Volume of myoma at Baseline (cm3) 
< 25, ≥ 25 
Volume of uterus at Baseline (cm3) 
< 300, ≥ 300 
Menstrual blood loss volume at Baseline (mL) 
< 225, ≥ 225 
Menstrual blood loss volume at Baseline (mL) 
< 160, ≥ 160 
Hemoglobin at Baseline (g/dL) 
Min to < 8, ≥ 8 to <10.5, ≥ 10.5 to <12, ≥ 12 
UFS-QoL 
Bleeding and Pelvic Discomfort Scale 
 
0 to < 25, 25 to <50, 50 to <75, 75 to 100 
Maximum NRS score for uterine fibroid-
associated pain at Baseline 
< 4, ≥ 4 
Patient Global Assessment 
 
     Function 
No limitation at all, mild limitation, moderate 
limitation, quite a bit of limitation, extreme 
limitation 
     Symptoms 
Not severe, mildly severe, moderately severe, very 
severe, extremely severe 
Abbreviations:  BMI = body mass index; NRS = Numerical Rating Scale; UFS-QoL = Uterine Fibroid Symptom 
and Health-Related Quality of Life. 
 


 
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5.5. 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
and will be summarized by system organ class (SOC) and preferred term (PT).  Additionally, 
summaries of uterine fibroid–specific medical and surgical treatment history will be provided.  A 
patient with multiple occurrences of medical history within a PT will be counted only once in 
that PT. 
5.6. 
Prior Medications and Concomitant Medications 
Prior medications and concomitant medications taken during the study treatment period will be 
summarized for all patients in the Safety population by treatment group.  Medications are 
considered concomitant if exposure occurs during the treatment period.   
The number and percentage of patients who took at least one dose of a prior medication for 
treatment of uterine fibroids will be summarized by treatment group and overall using the World 
Health Organization (WHO) Drug Dictionary and summarized according to the Anatomical 
Therapeutic Chemical (ATC) Classification System and generic medication name.  A patient 
who has been administered several medications with the same preferred medication name will be 
counted only once for that preferred medication name.  


 
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6. 
STUDY DRUG EXPOSURE AND COMPLIANCE 
Patients in the Safety population will be summarized for extent of exposure and compliance to 
study drug by actual treatment received.  Exposure to and compliance with relugolix (or 
relugolix placebo) and E2/NETA (or placebo) will be summarized separately and will be based 
on the drug accountability case report forms. 
Study drug exposure summaries will include the total dosage taken in milligrams, the total 
number of tablets (or capsules) taken, and the treatment duration. 
Study drug compliance will be summarized for the treatment period and will be calculated as 
follows: 
(total tablets taken / total tablets expected to be taken) x 100 
The total tablets taken will be calculated as:   
(total tablets dispensed - total tablets returned) 
The total tablets expected to be taken is calculated as the total number of tablets a patient is 
expected to take each day times the length of time (in days) that the patient was in the treatment 
period of the study.  Tablets that were dispensed and not returned will be assumed to have been 
taken.  For patients who did not return for their last scheduled visit, tablets that were dispensed 
and not returned will not be included in the calculation of study drug compliance.  For patients 
who did not return for any post-Baseline visits and did not return dispensed study drug, study 
drug compliance will not be calculated and will be categorized as “not able to calculate” in 
summaries of study drug compliance. 
Summary statistics of study drug compliance (eg, mean, median, etc.) will be presented, along 
with a categorical summary (eg, ≤ 80%, 80 to 100%, > 100%). 


 
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7. 
EFFICACY ANALYSES 
7.1. 
General Considerations 
Efficacy analyses will be conducted on the mITT population according to the randomized 
treatment assignment.  Stratified analyses will incorporate the randomization stratification 
factors.  If the group of patients at any factor level from a randomization stratification factor (eg, 
patients with Baseline MBL volume ≥ 225 mL) comprises < 10% of the entire mITT population, 
this stratification factor (eg, Baseline MBL volume) will not be used for stratified analyses.  In 
addition, if there are < 15 patients in 1 of the 4 strata (derived from the 2 stratification factors 
each with 2 levels), only stratification factor of Baseline MBL volume (< 225 versus ≥225 mL) 
will be used in the stratified analysis for more robust strata-adjusted estimation of treatment 
effect.  The stratification category used at the time of randomization (in the Interactive Web 
Recognition Service [IWRS] system) will be used for all analyses rather than data recorded on 
the electronic case report form (eCRF) unless otherwise specified.  A sensitivity analysis of the 
primary endpoint will be performed if the data in the IWRS and eCRF for stratification factors 
differ by > 5%.   
7.1.1. 
Analyses for Binary Data and Other Categorical Data 
Binary data will be summarized by frequency counts and percentages for each treatment group. 
7.1.2. 
Analyses for Categorical Data 
Qualitative variables will be summarized by frequency counts and percentages.  Unless 
otherwise specified, the calculation of proportions will include the missing category.  Therefore, 
counts of missing observations will be included in the denominator and presented as a separate 
category. 
7.1.3. 
Analyses for Continuous Data 
Continuous variables will be summarized using descriptive statistics (eg, n, mean, median, SD, 
minimum, maximum, and first and third quartiles).  For the analyses of change from Baseline, 
the mean at Baseline will be calculated for all patients with at least one post-Baseline value by 
treatment group.  Additionally, the mean will also be calculated for each visit, including only the 
patients who are in the analysis who have data for that visit by treatment group. 
7.1.4. 
Analyses for Time to Event Data 
Time-to-event endpoints will be summarized using the Kaplan-Meier method.  The median, 
quartiles, and probabilities of an event at particular time points will be estimated by the 
Kaplan-Meier method. 
Confidence interval for the Kaplan-Meier estimation is calculated using the exponential 
Greenwood formula via log-log transformation of the survival function. 
The variance of the treatment difference will be calculated using the following formula: 
𝑉𝑉ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡)൧= 𝑉𝑉෠ൣ𝑆𝑆𝑅𝑅
෢(𝑡𝑡)൧+ 𝑉𝑉෠[𝑆𝑆𝐿𝐿෡(𝑡𝑡)]; 


 
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where each of the component of the variance of the Kaplan-Meier estimate will be calculated 
using Greenwood’s formula: 
𝑉𝑉෠ൣ𝑆𝑆̂(𝑡𝑡)൧= 𝑆𝑆̂(𝑡𝑡)2 ෍
𝑑𝑑𝑖𝑖
𝑛𝑛𝑖𝑖(𝑛𝑛𝑖𝑖−𝑑𝑑𝑖𝑖)
𝑡𝑡𝑖𝑖≤𝑡𝑡
 
where 𝑛𝑛𝑖𝑖 denotes the number of patients at risk at time 𝑡𝑡𝑖𝑖, and 𝑑𝑑𝑖𝑖 denotes the number of events 
observed at time 𝑡𝑡𝑖𝑖. 
The 95% CI of the treatment difference will be calculated using a log-log transformation of the 
difference in survival function, as follows: 
[(𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡))𝑒𝑒𝑒𝑒𝑒𝑒(1.96 𝜏𝜏ො(𝑡𝑡)), (𝑆𝑆𝑅𝑅
෢(𝑡𝑡) −𝑆𝑆𝐿𝐿෡(𝑡𝑡))𝑒𝑒𝑒𝑒𝑒𝑒൫−1.96 𝜏𝜏ො(𝑡𝑡)൯] 
where 𝜏𝜏̂2(𝑡𝑡) =
𝑉𝑉෡[𝑆𝑆𝑅𝑅
෢(𝑡𝑡)−𝑆𝑆𝐿𝐿
෢(𝑡𝑡)]
{[𝑆𝑆𝑅𝑅
෢(𝑡𝑡)−𝑆𝑆𝐿𝐿
෢(𝑡𝑡)]log [𝑆𝑆𝑅𝑅
෢(𝑡𝑡)−𝑆𝑆𝐿𝐿
෢(𝑡𝑡)]}2. 
A stratified log-rank test will be used to compare each relugolix arm to placebo.  Randomization 
stratification factors will be used to stratify inferential testing. 
7.2. 
Multiplicity Adjustment 
The primary and the ranked secondary efficacy analyses will be performed at an overall alpha 
level of 0.05 (two-sided) comparing relugolix + E2/NETA (Group A) with placebo (Group C).  
A test will be deemed statistically significant if the two-sided p-value rounded to four decimal 
places is < 0.05.  A gate-keeping testing procedure will be applied to maintain the family-wise 
type I error rate for the testing of primary and ranked secondary endpoints (see Section 7.4.1 for 
details). 
Comparative statistics (p-values, 95% CIs for differences) will be provided for the treatment 
comparison of relugolix + E2/NETA with placebo for all other secondary efficacy endpoints.  A 
treatment comparison of relugolix + delayed E2/NETA (Group B) with placebo will be 
performed only for the primary efficacy endpoint.  There will be no statistical testing for 
treatment differences between the relugolix groups (Group A versus Group B) for any efficacy 
endpoints.  The relugolix + E2/NETA group and relugolix + delayed E2/NETA group will be 
compared for the following safety endpoints:  percent change from Baseline to Week 12 in BMD 
and incidence of vasomotor symptoms by 12 weeks (see Section 9.3.5 and Section 9.1.7, 
respectively).  The above comparative analyses are not part of the gate-keeping testing procedure 
for label claims.  p-values for primary and key secondary endpoints were adjusted for 
multiplicity.  All other p-values are provided at a nominal level of 0.05. 
7.3. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the proportion of women who achieve an MBL 
volume of < 80 mL AND at least a 50% reduction from Baseline in MBL volume over the last 
35 days of treatment as measured by the alkaline hematin method.  The primary endpoint will be 
referred to as responder rate and derived on the basis of the total MBL volume measured at the 
Week 24/EOT visit window taking into consideration the patient’s compliance with return of 
feminine products and completion of the eDiary (see Section 7.3.2 and Section 7.3.4 for details). 


 
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7.3.1. 
Primary Efficacy Analysis 
The following primary hypothesis for the primary efficacy endpoint will be tested: 
Null hypothesis H01:  πR ≤ πP     versus     Alternative hypothesis Ha1:   πR > πP  
where πR and πP are the responder rates at Week 24/EOT for relugolix + E2/NETA (Group A) 
and placebo (Group C), respectively.  
The treatment comparison between the relugolix + E2/NETA and the placebo will be analyzed 
using a Cochran-Mantel-Haenszel test statistic for proportions stratified by the Baseline mean 
MBL volume using the alkaline hematin method (< 225 mL versus ≥ 225 mL) and geographic 
region (North America versus Rest of World).  The difference in responder rates between the 
relugolix + E2/NETA and placebo and its two-sided 95% CI will be estimated using stratum-
adjusted Mantel-Haenszel proportions.  The unadjusted responder rates and the difference in 
responder rates between the relugolix + E2/NETA and placebo groups and the corresponding 
two-sided 95% CI also will be provided.  The study will be considered positive if the treatment 
effect for the primary endpoint is statistically significant with two-sided p-value < 0.05. 
For the primary analysis, primary endpoint will incorporate the missing data handling rules 
described in Section 7.3.5. 
7.3.2. 
Data Sources Supporting Derivation of Responder Status 
The data sources that will be used to support derivation of responder status, the primary 
endpoint, are depicted in Figure 2 below. They include: 
• Menstrual blood loss volume determined by the alkaline hematin method; 
• Daily patient report of bleeding (yes/no) and use of feminine product (yes/no) 
captured in the eDiary;  
• The status of feminine product (FP) collection return (yes/no) recorded on the eCRF 
page at each visit with specific reasons captured when no product collection was 
returned.  
The total MBL volume is reported from the analysis of FP returned for each collection interval.  
An inventory of days (with dates) for which FP was collected and returned is also available.  
This inventory is aligned with patients’ reports of bleeding and FP use in the eDiary.  The status 
of FP collection return, and specifically the reason for non-return of FP reported on the 
Feminine Product Collection eCFR page is used to support derivation of responder status (see 
Section 7.3.5 for details). 
 
 
 


 
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Figure 2: 
Data Sources Supporting Derivation of Primary Endpoint 
 
Abbreviations:  CRF = case report form. 
 
7.3.3. 
Definitions Related to Menstrual Blood Loss 
Menstrual Blood Loss Volume 
All returned feminine products (validated, validated but unauthorized, or unvalidated products) 
collected at each visit will be analyzed by the alkaline hematin method to obtain the MBL 
volume.  The MBL volume measured over the Week 24/EOT feminine product collection 
interval (up to 35 days prior to the last dose of treatment) will be used for analysis of the primary 
efficacy endpoint (see details below).  The vendor, KCAS, reports when unauthorized feminine 
products (products not dispensed for use in the trial) have been returned.  KCAS also reports 
whether the unauthorized products have previously been validated for their analysis.  The report 
details MBL volumes for authorized, unauthorized but validated, and unauthorized and 
unvalidated products. 
Validated Menstrual Blood Loss Volume 
All returned feminine products collected at each visit, with the exception of unvalidated 
products, will be assessed by the alkaline hematin method to obtain the validated MBL volume.  
The validated MBL volume is derived from assessments of all returned validated feminine 
products (including validated and validated but unauthorized products) and will be used for 
sensitivity analysis. 


 
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Baseline Menstrual Blood Loss Volume 
Baseline MBL volume is defined as the average MBL volume from the one or two consecutive 
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 as follows: 
For patients with MBL volume ≥ 160 mL during the screening period, the Baseline MBL volume 
is the last measurement collected before the first administration of study drug. 
If the MBL volume is < 160 mL, the Baseline MBL volume is defined as the average of the 
MBL volume 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 (see Figure 4-
2 of the study protocol for details). 
Week 24/EOT Feminine Product Collection Interval 
To ensure collection of all feminine products used during that menstrual cycle, an interval of up 
to 35 days for measurement of the primary endpoint was selected to accommodate women who 
continue to have cyclic bleeding on study treatment and whose natural cycle was at the upper end 
of the normal cycle duration range.  This method is consistent with that used during screening for 
collection of feminine products.  Specifically, the feminine product collection interval at Week 
24/EOT is driven by types of bleeding patterns experienced by the patients, as described below: 
• For patients who continue to have cyclic bleeding, the length of the interval depends 
on the duration of the patient’s natural cycle; this is consistent with the way the 
Baseline MBL volume was determined (eg, the interval ranging from approximately 
21 to 35 days); 
• Patients who report irregular, non-cyclic bleeding are instructed to collect and return 
all feminine product used between study visits, up to 35 days, as per the schedule of 
events; 
• For patients who report amenorrhea on the feminine production collection eCRF 
page, an interval of last 35 days of treatment will be reviewed to ensure that reported 
amenorrhea is not due to incomplete collection.  
 
For patients who are in the midst of an episode of cyclic bleeding at the time of the Week 
24/EOT visit, the visit window may be extended up to 7 days after the last dose of study drug to 
ensure patients return all used feminine products over that bleeding episode. 
Per protocol, all used feminine products are to be collected at each visit and returned for analysis 
using the alkaline hematin method.  For patients who continue to have menstrual bleeding, study 
visits are timed such that the feminine products used in the entire menstrual bleeding cycle are 
collected in one container provided at each visit.  
MBL Volume at Week 24/EOT 
MBL volume at Week 24/EOT is defined as the MBL volume obtained from the feminine 
product returned over the Week 24/EOT feminine product collection interval, as described 
above.  The MBL volume at Week 24/EOT will be used to derive the primary efficacy endpoint.  


 
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If a patient did not return feminine product over the last 35 days of treatment and reported 
amenorrhea on the feminine product return eCRF page, she will be considered as amenorrhoeic 
and her MBL volume will be assigned as 0 mL. 
Feminine Product Return Rate at Week 24/EOT  
To quantify degree of compliance with feminine product collection, the FPRR will be calculated 
based on the inventory of feminine product returned by day (dates) summarized on the Feminine 
Product Collection eCFR page (provided by the vendor, KCAS) and responses to the eDiary 
Question 4 regarding bleeding experience and Question 5 regarding the use of feminine product 
obtained for the corresponding eDiary window (see Table 5).  Specifically: 
• For those who returned feminine product at Week 24/EOT, the FPRR was calculated 
as the observed number of days with returned feminine products (based on the 
inventory of FP received by KCAS) divided by the expected number of days with 
bleeding and use of product as reported on the eDiary within the Week 24/EOT 
feminine product collection interval (as defined above). 
• For those who did not return any feminine products: 
o If the reason was amenorrhea reported on the eCRF or if spotting/negligible 
bleeding was reported on the eCRF and confirmed by eDiary over the 
Week 24/EOT visit window, their FPRR will be set to 100% because the lack of 
menstruation obviates the need for feminine product collection.  
o Otherwise if the reason is any other, their FPRR was set to 0.  
 
FPRR =
observed ( No. of days with returned FP [per KCAS])
expected  (No. of days reported bleeding and use of FP [per eDiary])  𝑥𝑥100 
Return of feminine products will be summarized in the CSR for Week 24/EOT visit. 
7.3.4. 
Definition of Responder at Week 24/EOT 
A responder at Week 24/EOT is defined as a patient who satisfies both the following: 
• Had MBL volume of < 80 mL at Week 24/EOT; 
• Had at least a 50% reduction from Baseline in MBL volume at Week 24/EOT. 
The reduction from Baseline in MBL volume at Week 24/EOT will be calculated as the absolute 
change at Week 24/EOT in MBL volume from the Baseline MBL volume divided by the 
Baseline MBL volume. 
Responder status at Week 24/EOT will be assessed based on the reported MBL volume at 
Week 24/EOT, in conjunction with treatment duration, compliance with feminine product 
collection, and compliance with eDiary entry over the same visit window (see Section 7.3.5 for 
details).  


 
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7.3.5. 
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules 
For the evaluation of primary endpoint, missing data handling rules will be implemented for 
deriving responder status at Week 24/EOT as described below.  The following elements will be 
checked:  duration of treatment exposure; compliance with feminine product collection against 
the eDiary, as measured by FPRR; compliance with eDiary entry, defined as the proportion of 
eDiary entry days over the length (days) of FP collection interval for Week 24/EOT visit; and 
reasons for no FP collection (as displayed in Table 7).  
Patients with < 4 weeks of treatment who withdraw from the study prematurely due to lack of 
efficacy or withdraw from the study prematurely to undergo surgical intervention for uterine 
fibroids will be considered as non-responders.  
All other patients will have their responder status determined as follows: 
• For patients with a FPRR of 100%, responder status will be determined based on the 
observed MBL volume;  
• For patients who had incomplete feminine product collection, with a FPRR of < 
100%, responder status will be derived based on either imputed or observed MBL 
volume; 
− Those with an MBL volume ≥ 80 mL or < 50% reduction from Baseline will be 
considered as non-responders; 
− Those with an MBL volume < 80 mL and ≥ 50% reduction from Baseline will be 
imputed for partial or complete missing MBL volume (see Section 7.3.6 for 
details).   
• For patients who did not return a feminine product collection, responder status will be 
determined depending on the reason reported on the Feminine Product Collection 
eCRF: 
- 
If the reason is reported as Amenorrhea, the last 35 days of treatment will be 
used to derive responder status: 
o If the Week 24/EOT interval was 35 days, then she will be considered 
as a responder;  
o If the Week 24/EOT interval was <35 days, the following supportive 
information will be used to derive responder status: 
 If a patient reported amenorrhea at the visit prior to 
Week 24/EOT, she will be defined as a responder; 
 If a patient did not report amenorrhea at the visit prior to 
Week 24/EOT, eDiary data from the prior visit interval will be 
reviewed to confirm whether the patient was amenorrheic for a 
total of 35 days. 


 
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• If the eDiary from the previous interval confirms 
amenorrhea, then the patient will be considered as a 
responder; 
• Otherwise, MBL volume will be imputed. 
- 
If the reason is Other and the specification describes spotting or negligible 
bleeding, responder status will be defined as follows: 
o The patient will be considered as a responder if it is supported by the 
eDiary data: the eDiary entry rate must exceed 70% and the patient 
must have reported no more than 5 total days of bleeding with product 
use and no more than 3 consecutive bleeding with product use over the 
collection interval.  
o If the eDiary entries did not confirm spotting or negligible bleeding, 
but the patient had at least 8 weeks of MBL volume data prior to the 
Week 24/EOT visit, her missing MBL volume will be imputed to 
determine responder status.  Eight weeks of MBL volume data 
represents a reasonable minimum length of observation to justify 
imputation of the remaining data in assessing the effects of hormonal 
therapy. 
o Otherwise if the patient had < 8 weeks of MBL volume data, she will 
be considered as a non-responder; 
- 
If the reason is any Other, the responder status will be derived as follows: 
o If the patient had at least 8 weeks of MBL volume data prior to the 
Week 24/EOT visit, her missing MBL volume will be imputed and her 
responder status will be based on the imputed MBL volume.  
o If the patient had < 8 weeks of MBL volume data, she will be 
considered as a non-responder. 
 
 
 


 
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Table 7: 
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules – for Primary Analysis 
Treatment 
Exposure 
FP 
Collection 
(FPRR)  
Observed MBL 
Volume 
Reason for  
No FP Collection 
Responder 
Status 
< 4 weeks 
N/A 
N/A 
N/A 
Imputed as non-
responder 
≥ 4 weeks 
100%  
FP 
Compliance 
N/A 
N/A 
Based on the observed 
MBL volume 
<100% 
FP 
Compliance 
 
MBL volume 
≥ 80 mL or <50% 
reduction from 
Baseline 
N/A 
Imputed as non-
responder based on the 
observed MBL volume 
MBL volume 
< 80 mL and 
≥ 50% reduction 
from Baseline 
N/A 
Based on the imputed 
MBL volume 
No FP 
Collection  
N/A 
 
 
Reported “Amenorrhea”  
Imputed as responder  
Reported “Spotting or 
negligible bleeding” and 
confirmed by eDiarya 
Imputed as responder  
Reported “Spotting or 
negligible bleeding” 
although not confirmed 
by eDiary or any other 
reason, had at least 8 
weeks of MBL volume 
data 
Based on the imputed 
MBL volume 
The entries in the eDiary 
did not verify “Spotting 
or negligible bleeding” or 
any other reason and if 
had < 8 weeks of MBL 
volume data  
Imputed as non-
responders 
Abbreviations:  eDiary, electronic diary; FP, feminine product; EOT, end of treatment; MBL, menstrual blood loss; 
N/A, not available. 
a Defined as those patients who meet the following criteria:  eDiary entry rate > 70% and no more than 3 
consecutive days and no more than 5 days of bleeding/spotting and use of feminine product reported on the eDiary 
over the Week 24/EOT visit window (see Table 5).  
 
 


 
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7.3.6. 
Mixed-Effects Model for Imputing Missing or Partially Missing MBL Volume at 
Week 24/EOT 
For the primary analysis, patients with missing MBL volumes at Week 24/EOT will be identified 
per missing data handling rules as described above.  For imputing missing data for the primary 
analysis, a mixed-effects model approach will be used, as the mixed-effects approach may better 
describe the effects of a hormonal treatment (such as suppression of the hypothalamic-pituitary-
ovarian axis by GnRH antagonists). 
Specifically, a mixed-effects model with repeated measures of MBL volumes at multiple time 
points (Weeks 4, 8, 12, 16, 20 and 24) will be fitted to predict percent change in MBL volume 
from Baseline (as a dependent variable) through the fixed-effects associated with covariates (ie, 
stratification factors of Baseline MBL volume and geographic region, visit, treatment, and visit 
by treatment interaction) and random effects (from the individual patients).  In this model, an 
unstructured variance-covariance matrix is assumed for each patient.   
See sample SAS codes below for illustration where PCHG_MBL is percent change in MBL 
volume from Baseline as a dependent variable, PID is patient identification number, BMBL is a 
randomization stratification factor (Baseline MBL < 225 vs ≥ 225), REGION is a randomization 
stratification factor (North America vs Rest of World), TRT is treatment group (relugolix + 
E2/NETA or Placebo), VISIT is visit time point (4, 8, 12, 16, 20, and 24 weeks) and TRT*VISIT 
is the visit by treatment interaction.  The specification of type=UN implements unstructured 
variance-covariance matrix for an individual patient with multiple measures of MBL volumes.  
 
proc mixed data=MBL_dataset method=REML covtest; 
class PID BMBL REGION TRT VISIT; 
model PCHG_MBL= BMBL REGION VISIT TRT VISIT*TRT/s outp=ufmi_mixed_p 
covb; 
repeated VISIT /type=UN subject=PID r; 
lsmeans TRT/diff; 
ods output SolutionF=mixparms CovB=mixcovb; 
 
Applying this model over the observed longitudinal MBL volume data, the fixed-effects will be 
estimated and relationship of percent change in MBL volume from Baseline with the covariates 
will be characterized by the fitted model.  From the fitted model, the percent change in MBL 
volume (whether missing or not) will be predicted for each patient at each visit and in a 
particular stratum.  The imputed MBL volume will be obtained by first multiplying the imputed 
percent change with the individual patient’s Baseline MBL volume to the difference, and then 
adding the Baseline BML volume to the difference.  
The main reason for using percent change in MBL volume over reported MBL volume as a 
dependent variable in the mixed-effects model is that the percent change is part of the derivation 
of the primary endpoint.  Secondly, the percent change is a normalized value adjusted for the 
Baseline value and less influenced by Baseline MBL volume, and therefore it is a better metric to 
describe the relationship of MBL volume reduction with hormonal treatment and to impute the 
missing volumes in a more robust fashion.  


 
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Since the purpose of using a mixed-effects model is imputing the missing MBL volumes 
identified at Week 24/EOT, the predicted MBL volumes at the corresponding Week 24/EOT 
visit will be used to determine responder status.  For patients without the need for imputation, 
their responder status will be derived according to the algorithms laid out in Table 7.  This 
imputation approach is consistent with the definition of responder at Week 24/EOT for the 
primary analysis.   
7.3.7. 
Sensitivity Analyses 
To assess the robustness of the primary analysis, the following sensitivity analyses of the 
primary endpoint will be conducted at Week 24/EOT. 
7.3.7.1. 
Sensitivity Analysis 1 
To assess the potential impact of unvalidated feminine product use, the primary endpoint will be 
analyzed as sensitivity analysis in a similar fashion to the primary analysis using the 
Week 24/EOT validated MBL volume (obtained from the validated or validated-but-
unauthorized feminine products only and excluding unvalidated products).  
7.3.7.2. 
Sensitivity Analysis 2 
To assess the potential impact of missing data due to inadequate collection of feminine products, 
the primary endpoint will be analyzed with a sensitivity analysis using the missing data handling 
rules as described in Table 8 below where the observed MBL volume will be used to assess the 
responder status at Week 24/EOT when feminine product collection was incomplete.  These 
rules differ from those used in the primary analysis in that no imputation will be implemented for 
patients with < 100% feminine product compliance and the reported MBL volume both < 80 mL 
and a ≥ 50% reduction from Baseline as highlighted in Table 8. 
 
 


 
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Table 8:  
Derivation of Responder Status at Week 24/EOT and Missing Data Handling 
Rules – for Sensitivity Analysis 
Treatment 
Exposure 
FP 
Collection 
(FPRR) 
Observed MBL 
Volume 
Reason for  
No FP Collection 
Responder Status 
< 4 weeks 
N/A 
N/A 
N/A 
Imputed as non-
responder 
≥ 4 weeks 
100% FP 
Compliance 
N/A 
N/A 
Based on the observed 
MBL volume 
< 100% FP 
Compliance 
MBL volume 
≥ 80mL or < 50% 
reduction from 
Baseline 
N/A 
Imputed as non-
responder based on the 
observed MBL volume 
MBL volume 
< 80mL and 
≥ 50% reduction 
from Baseline 
N/A 
Based on the observed 
MBL volume 
No FP 
Collection  
N/A 
 
 
Reported “Amenorrhea”  
Imputed as responder  
Reported “Spotting or 
negligible bleeding” and 
confirmed by eDiarya 
Imputed as responder  
Reported “Spotting or 
negligible bleeding” 
although not confirmed 
by eDiary or any other 
reason, had at least 8 
weeks of MBL volume 
data 
Based on the imputed 
MBL volume 
The entries in the eDiary 
did not verify “Spotting 
or negligible bleeding” or 
any other reason and if 
had < 8 weeks of MBL 
volume data  
Imputed as non-
responders 
Abbreviations:  eDiary, electronic diary; FP, feminine product; EOT, end of treatment; MBL, menstrual blood loss; 
N/A, not available. 
a Defined as those patients who meet the following criteria: eDiary entry rate >70% and no more than 3 consecutive days and no more than 5 days 
of bleeding/spotting and use of feminine product reported on the eDiary over the Week 24/EOT visit window (see Table 5).  
 
 
 


 
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7.3.7.3. 
Sensitivity Analysis 3 
To assess the potential impact of early discontinuation on the primary endpoint, the primary 
endpoint will be analyzed with a sensitivity analysis defining the patients’ responder status as 
follows: 
• Patients who discontinued study drug during the first 4 weeks for any reason or who 
discontinued study drug between Week 4 and Week 12 due to an adverse event, 
surgery or other intervention for heavy menstrual bleeding, reported lack of efficacy, 
or bleeding complaints will be considered as non-responders; 
• All other patients will have their responder status defined using data from the Week 
24/EOT assessment period using the last observation carried forward method. 
7.3.7.4. 
Sensitivity Analysis 4 
To assess the potential impact of the length and full exposure of the treatment, the primary 
endpoint will be analyzed for the Completers population as a sensitivity analysis.  The 
Completers population is defined as patients in the mITT population who completed 24 weeks of 
study treatment.  
7.3.7.5. 
Sensitivity Analysis 5 
The primary endpoint will be analyzed on the Per-Protocol population as a sensitivity analysis, 
using the methods specified for the primary analysis (see definition of Per-Protocol population in 
Section 4.2.2). 
7.3.7.6. 
Sensitivity Analysis 6 
As a sensitivity analysis to the primary analysis using the mixed-effects model for imputing 
missing MBL volumes at Week 24/EOT, multiple imputation approach will be implemented as 
described below. 
A multiple imputation method (Rubin, 1987; von Hippel, 2018) will be used to impute missing 
or partially missing MBL volume identified by the missing data handling rules (see Table 7 and 
Table 8) at Week 24/EOT as described in the following 5 steps.  In this method, an arbitrary 
missing pattern will be assumed using Markov Chain Monte Carlo imputation to generate a 
monotone missing pattern for the observed longitudinal MBL volume values (including 0 mL if 
the patient has amenorrhea).  Imputation will be performed separately by randomized treatment 
group (Sullivan, 2018), given the distinct bleeding patterns among the three treatment groups.  
Normalizing transformations will be applied to the statistics estimated from each imputed dataset 
before the Rubin’s combination rules can be applied (Ratitch, 2013).  This combined estimation 
and statistical test will account for the additional variability due to imputation to provide a robust 
assessment of the treatment effect. 
Step 1: Identifying patients with missing or incomplete MBL volume from the longitudinal 
MBL volume dataset as collected. 
Step 2: Generating a monotone missing pattern using the Markov Chain Monte Carlo technique 
by imputing missing MBL volume measurements that are between non-missing results. 


 
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Step 3: Imputing the remaining missing values m = 100 times using a regression model; 
therefore, generating 100 complete longitudinal MBL volume datasets. 
Note: if a patient missed Week 8 and prematurely discontinued study drug (eg, at 
Week 20) and MBL volume at Week 20 is missing or partially missing, MBL volume 
will be imputed for intermittent missing data at Week 8, Week 20 (EOT), and Week 24 
due to discontinuation. 
Step 4: Performing the same CMH test pre-specified for the primary endpoint analysis and 
estimating the responder rates for each arm using each of the 100 datasets based upon 
the MBL volume at Week 24/EOT. 
Note: in the example above, the imputed MBL volume at Week 20 (EOT) will be used 
in the analysis, although MBL volume is imputed at Week 24. 
Step 5: Combining the results from the 100 complete datasets to make inferences about the 
treatment effect on the responder rate. 
7.3.8. 
Subgroup Analyses 
Subgroup analyses of the primary efficacy endpoint comparing the relugolix + E2/NETA group 
versus the placebo group will be performed to assess whether treatment effects are consistent 
across clinically important subgroups.  The odds ratio and its 95% CI based on a logistic 
regression model will be displayed in a forest plot for each subgroup.  The logistic regression 
model will include treatment group, Baseline MBL volume value and geographic region as 
covariates.  Subgroups will include, but will not be limited to, the subgroups outlined in Table 9. 
 
 


 
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Table 9: 
Planned Subgroup Analyses  
Subgroup Name  
Subgroup Level 
Geographic region  
North America vs Rest of World 
Menstrual blood loss volume at Baseline (mL) < 225 vs ≥ 225 
< 120, 120 to < 160, 160 to < 225, ≥ 225 
Age category (years) 
 
< 40 vs ≥ 40 
< 35, 35 to < 40, 40 to < 45, ≥ 45  
Race 
Black or African American vs Not Black or 
African American; 
Black or African American, White, Other 
Volume of myoma at Baseline (cm3) 
< 25 vs ≥ 25 
Volume of uterus at Baseline (cm3) 
< 300 vs ≥ 300 
BMI (kg/m2) at Baseline 
< 30 vs ≥ 30 
 < 25, 25 to < 30, 30 to < 35, 35 to <40, ≥ 40 
Maximum NRS score for uterine fibroid–
associated pain at Baseline 
< 4 vs ≥ 4 
History of prior pregnancy 
Yes/No 
Abbreviations:  BMI = body mass index; NRS = Numerical Rating Scale. 
 
7.4. 
Secondary Efficacy Endpoints 
Secondary efficacy variables include seven key secondary endpoints with alpha-protection and 
other secondary endpoints.  All secondary efficacy endpoints and analyses are summarized in 
Appendix 1.  
The treatment effect of relugolix + E2/NETA (Group A) compared to placebo (Group C) will be 
tested for the alpha-protected secondary endpoints using a gate-keeping procedure (see 
Section 7.4.1).  
Comparative statistics (p-values, 95% CIs for differences) will be provided for treatment 
comparison of the relugolix + E2/NETA group with the placebo group for all other secondary 
efficacy endpoints.  Treatment difference between the relugolix + delayed E2/NETA group and 
the placebo group will be formally tested only for the primary efficacy endpoint.  There will be 
no statistical testing for treatment differences between the relugolix groups (relugolix + 
E2/NETA group against relugolix + delayed E2/NETA group) for any efficacy endpoint (see 
Section 7.4.2). 
7.4.1. 
Key Secondary Efficacy Endpoints with Alpha-Protection 
For testing whether relugolix + E2/NETA (Group A) is statistically significantly superior to 
placebo (Group C) for the primary efficacy endpoint as well as the seven key secondary 
endpoints listed below, a gate-keeping mixed sequence testing procedure will be applied to 
maintain the family-wise type I error rate.  Under this testing procedure, the primary endpoint 


 
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will be tested first at a 2-sided 0.05 significance level.  If the p-value for primary endpoint is 
< 0.05, the seven key endpoints listed below will be tested sequentially in the order depicted in 
Figure 3 (LIBERTY 1) and Figure 4 (LIBERTY 2).  
For the relugolix + E2/NETA group to be considered statistically superior to the placebo group 
on a secondary endpoint, the two-sided p-value must be < 0.05 for that secondary endpoint and 
for all higher-ranking secondary endpoints, as well as for the primary endpoint.  If the two-sided 
p-value is < 0.05 for the fourth endpoint (proportion of women with hemoglobin ≤ 10.5 g/dL at 
Baseline who achieve an increase of > 2 g/dL from Baseline at Week 24 for LIBERTY 1; 
proportion of women who achieve a maximum NRS score ≤ 1 for uterine fibroid-associated pain 
over the last 35 days of treatment in the subset of women with a maximum pain score ≥ 4 during 
the 35 days prior to randomization for LIBERTY2), the remaining three endpoints (the fifth, 
sixth, or seventh) will be tested using the Hochberg step-up procedure.   
Figure 3: 
Mixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints in LIBERTY 1 
 
Abbreviations:  BPD = Bleeding and Pelvic Discomfort; EP = endpoint; Hgb = hemoglobin; max = maximum; 
MBL = menstrual blood loss; M-vol = myoma volume; NRS = Numerical Rating Scale; PE = primary endpoint; 
Prop = proportion; UFS-QoL BPD = Uterine Fibroid Symptom and Health-Related Quality of Life Bleeding and 
Pelvic Discomfort; U-vol = uterine volume. 
 


 
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Figure 4: 
Mixed Sequence Testing Procedure for Primary and Key Secondary 
Endpoints in LIBERTY 2 
Abbreviations:  BPD = Bleeding and Pelvic Discomfort; EP = endpoint; Hgb = hemoglobin; max = maximum; 
MBL = menstrual blood loss; M-vol = myoma volume; NRS = Numerical Rating Scale; PE = primary endpoint; 
Prop = proportion; UFS-QoL BPD = Uterine Fibroid Symptom and Health-Related Quality of Life Bleeding and 
Pelvic Discomfort; U-vol = uterine volume. 
 
From the Hochberg procedure, the p-values will be calculated for the three endpoints (5, 6, and 
7) and ranked from the smallest to the largest.  The endpoint corresponding to the largest p-value 
gets tested first.  If the p-value is < 0.05, then no further testing will occur, and it will be 
concluded that all three endpoints are positive.  Otherwise, the endpoint corresponding to the 
second largest p-value will be tested.  If the p-value is < 0.025, then no further testing will occur, 
and it will be concluded that the endpoints corresponding to the middle and smallest p-values are 
positive.  Otherwise, the endpoint with the smallest p-value will be tested.  If the p-value is 
< 0.0167, no further testing will occur, and it will be concluded that only the endpoint with the 
smallest p-value is positive.  Otherwise, all three endpoints did not pass the statistical 
significance criterion at 0.05 level. 
The seven key secondary efficacy endpoints are as follows: 
1. Proportion of women who achieve amenorrhea over the last 35 days of treatment; 
2. Percent change from Baseline to Week 24 in MBL volume; 


 
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3. Change from Baseline to Week 24 in Bleeding and Pelvic Discomfort Scale score as 
measured by the UFS-QoL Symptom Severity Scale (Q1, Q2, Q5); 
4. Proportion of women with a hemoglobin ≤ 10.5 g/dL at Baseline who achieve an increase 
of > 2 g/dL from Baseline at Week 24  
5. Proportion of women who achieve a maximum NRS score ≤ 1 for uterine fibroid 
associated pain over the last 35 days of treatment in the subset of women with a 
maximum pain score ≥ 4 during the 35 days prior to randomization; 
6. Percent change from Baseline to Week 24 in uterine fibroid volume; 
7. Percent change from Baseline to Week 24 in uterine volume. 
 
For key secondary efficacy endpoints (1, 4, and 5) that are evaluating proportions, treatment 
comparisons will be performed using a stratified Cochran-Mantel-Haenszel test with the 
randomization stratification factors as strata.  Point estimates and 2-sided 95% CIs for treatment 
differences in proportions will be provided.  
For key secondary endpoint 4, an increase in hemoglobin of 2g/dL is considered clinically 
meaningful, because it corresponds to approximately the same increase as that expected after a 
transfusion of ~ 2 units of packed red blood cells (Man, 2016; Bachowski, 2017). 
For deriving the key secondary endpoint 5 (proportion of women who achieve a maximum NRS 
score ≤ 1 for uterine fibroid-associated pain over the last 35 days of treatment in the subset of 
women with a maximum pain score ≥ 4 during the 35 days prior to randomization), the patient 
subset and Week 24/EOT maximum value are determined as follows. 
Because patients were asked to begin eDiary entries after returning the first collection of 
feminine products, the number of eDiary entries made during screening varies with the duration 
of screening for each patient.  Some patients required only one collection to be randomized, 
whereas others required as many as four collections to confirm eligibility. 
Once the qualifying menstruation was completed and the patient qualified for randomization 
based upon resulting MBL volume(s), the recording of patient’s NRS scores for screening phase 
will be ended and the number of pain score days at Baseline can be as short as 7 days or as long 
as 70 days prior to randomization. If a patient meets the subset definition (maximum NRS score 
≥ 4 at Baseline) over a portion of the screening days (eg, 7-70 days), she will also meet the 
subset definition on the entire 35 days interval.   
Since the maximum NRS value is used to determine inclusion into the subset rather than an 
average NRS value, the variable number of days for inclusion of patients has no major impact on 
determining patient subset.  To ensure robust estimate of response, the minimum number of non-
missing daily pain scores required to calculate the maximum score at Week 24/EOT is at least 
28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary entry.   
The primary analysis of key secondary endpoint 5 will be analyzed for the subset of women who 
have a maximum pain score ≥ 4 during the 35 days prior to randomization and who have at least 
28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary at Week 
24/EOT.  In addition, a sensitivity analysis will be conducted on the subset of women who have 


 
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a maximum pain score ≥ 4 during the 35 days prior to randomization without restricting number 
of days of pain scores recorded in the e-Diary. 
The analysis for endpoint 5 (proportion of women who achieve a maximum NRS score ≤ 1 for 
uterine fibroid-associated pain over the last 35 days of treatment in the subset of women with a 
maximum pain score ≥ 4 during the 35 days prior to randomization) will also be performed using 
NRS scores reported on eDiary during menstrual and non-menstrual days. 
For key secondary efficacy endpoints (6 and 7) evaluating percent change from Baseline in 
uterine fibroid volume and uterine volume that are measured only at Week 24, an analysis of 
covariance (ANCOVA) model will be used to assess treatment effect with treatment, 
randomization stratification factors and Baseline value as covariates.  
For key secondary efficacy endpoints (2 and 3) evaluating the change (absolute or % change) 
from Baseline to Week 24, treatment comparisons will be performed using a mixed model 
repeated measures approach with treatment, visit, randomization stratification factors and 
treatment by visit interactions included as fixed effects and random effects (from the individual 
patients).  In this model, an unstructured variance-covariance matrix is assumed for each patient. 
7.4.2. 
Other Secondary Efficacy and Exploratory Endpoints 
The following describes the analysis methods for other secondary efficacy endpoints and 
exploratory endpoints.  There are three types of analyses corresponding to the three types of 
endpoints (time-to-event, continuous and binary) (see Appendix 1 for details).  
Time-to-Event Endpoint 
For time to achieving an MBL volume of < 80 mL AND at least a 50% reduction from Baseline 
MBL volume (as an event), time to event will be defined as weeks from date of first dose of 
study drug to response (event) based on the MBL volume as assessed by the alkaline hematin 
method.  The missing data handling rules described in Section 7.3.5 for deriving responder status 
at Week 24/EOT will be applied similarly at Weeks 8, 12, 16, and 20.  Patients without an event 
will be censored at the last assessment date prior to the last dose of the study drug.  
Kaplan-Meier methods will be used to describe the time to event distributions.  A log-rank test 
stratified by the randomization stratification factors using the proportional hazard model (p-value 
from score test) will be used to compare relugolix + E2/NETA to placebo.  Randomization 
stratification factors will be used to stratify inferential testing. 
Continuous Endpoints 
For endpoints evaluating the change (absolute or percent change) from Baseline to Week 24, 
treatment comparisons will be performed using a mixed model repeated measures approach with 
treatment, randomization stratification factors, visit, and treatment by visit interactions included 
as fixed effects.  The Baseline value will be included as a covariate, and an unstructured 
variance-covariance matrix will be assumed.  Calculation of the dependent variable (change from 
Baseline) for each patient at each visit will be calculated based on the visit windows specified in 
Section 4.3.5.  Based on this model, the least squares mean at Week 24 will be compared 
between treatment groups and summarized along with the corresponding 95% CIs for treatment 
difference.  In addition, summary statistics (mean change or mean % change) will be graphically 
presented as appropriate.   


 
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Binary Endpoints  
For endpoints evaluating proportions, treatment comparisons will be performed using a stratified 
Cochran-Mantel-Haenszel test as appropriate with the randomization stratification factors as 
strata.  Point estimates and 2-sided 95% CIs for treatment differences in proportions will be 
provided. 
Descriptive statistics (point estimates and corresponding 95% CIs) will be provided by treatment 
group and visit as appropriate for all secondary endpoints. 
Responder rate by visit (at Week 4, Week 8, Week 12, Week 16, and Week 20) will be derived 
in a similar fashion to the derivation of responder rate at Week 24/EOT.  The missing data 
handling rules described in Section 7.3.5 for deriving responder status at Week 24/EOT will be 
applied similarly at Weeks 4, 8, 12, 16, and 20. 
7.4.3. 
Derivation of Amenorrhea-Related Endpoints 
Determination of Amenorrhea 
Rules for determining amenorrhea in the treatment period is defined as those who meet 1 of the 
following requirements for 2 consecutive visits (approximately 56 consecutive days).  Patients 
will be deemed to have amenorrhea during a visit window according to the following rules: 
• No feminine product returned due to reported amenorrhea in 2 consecutive visits  
OR 
• No feminine product returned due to other reasons or feminine product collection with a 
negligible observed MBL volume coupled with other data indicating infrequent non-
cyclic bleeding/spotting as described in Table 10. 
Missing responses for menstrual bleeding questions in the eDiary will be treated as “No 
Bleeding” if eDiary compliance rate is > 70%.   
 
 


 
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Table 10: 
Rules for Determining Amenorrhea by Visit 
Feminine Product 
Collection (KCAS) a 
Supporting Data  
Menstruation Status 
eCRF 
eDiary  
No feminine product 
collection due to 
reported amenorrhea 
No menses start/stop dates 
reported 
N/A 
No feminine product 
collection due to 
other reasons 
Per instructions for non-
cyclic bleeding patterns, 
menses start date is 
reported but no menses 
stop date reported  
• Data indicating infrequent, non-cyclic 
bleeding/spotting defined as 
bleeding/spotting with feminine product 
use for no more than 3 consecutive days 
and no more than 5 days bleeding total 
per visit window 
• eDiary entry rate > 70% 
Feminine product 
collection with 
negligible observed 
MBL volume defined 
as <5 mL 
Full or partial menses start 
and stop dates 
• Data indicating infrequent, non-cyclic 
bleeding/spotting defined as 
bleeding/spotting with feminine product 
use for no more than 3 consecutive days 
and no more than 5 days bleeding total 
per visit window 
• eDiary entry rate > 70% 
Abbreviations:  eCRF, electronic case report form; eDiary, electronic diary; MBL, menstrual blood loss; N/A = not 
applicable. 
a  There is no requirement for feminine product return rate, as the determination of amenorrhea is based on the eDiary response. 
 
Amenorrhea During the Last 35 Days of Treatment 
Patients with amenorrhea over the last 35 days of treatment are defined as those who meet the 
definition of amenorrhea.  A patient’s amenorrhea status will also be summarized at Weeks 8, 
12, 16, and 20.  If a patient does not return for her Week 24/EOT visit, the eDiary responses for 
the last 35 days of treatment will be evaluated.  If the criteria for infrequent, non-cyclic bleeding 
or spotting as indicated in Table 10 is met and the criteria for amenorrhea is met at the prior visit, 
the patient will be categorized as amenorrheic at Week 24/EOT.  At all other timepoints, patients 
who do not return for a specific visit will be assigned as not amenorrheic at that visit. 
Time to Amenorrhea 
Time to amenorrhea is defined as the weeks from date of first dose of study drug to the start date 
of the amenorrhea window.  Time to sustained amenorrhea will also be estimated and plotted 
using the Kaplan-Meier method. 


 
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The start date of amenorrhea is defined as the last feminine product collection date prior to start 
of amenorrhea.  For example, if a patient’s feminine product was collected at her Week 4 visit 
and MBL volume for this cycle did not indicate amenorrhea, and the patient reported amenorrhea 
on Week 8 and 12 visits, then time to start amenorrhea will be defined as starting on the date of 
feminine product collection for Week 4.  Patients who are determined to have amenorrhea at 
Week 4 and Week 8 will use their Week 4 feminine product collection date as start date of 
amenorrhea.  Patients without an event will be censored at the last assessment date prior to the 
last dose of the study drug.   
Sustained Amenorrhea Rate by Visit 
A patient’s sustained amenorrhea status will be summarized at Weeks 8, 12, 16, 20, and 24, 
based on her time to achieving and maintaining amenorrhea until the date of last study drug dose 
as shown in Table 11.  For example, at Week 8, a patient is considered to have achieved 
sustained amenorrhea status if her amenorrhea started before Week 8 and was observed every 
visit thereafter until the last dose of the study treatment.  The proportion of patients with 
sustained amenorrhea will be summarized by visit.  If a patient met the criteria for sustained 
amenorrhea but discontinues from the study, this subject’s amenorrhea status will be carried 
forward to the Week 24 visit. 
Table 11: 
Sustained Amenorrhea Rate by Visit 
 
Amenorrhea Window 
Time 
Point 
Start 
End 
Week 8 
Determined amenorrhea at 
Week 4 
Amenorrhea observed at Week 8 and was 
observed at every visit thereafter until and 
including the last dose of study treatment 
Week 12 
Determined amenorrhea at 
Week 8 
Amenorrhea observed at Week 12 and was 
observed at every visit thereafter until and 
including the last dose of study treatment 
Week 16 
Determined amenorrhea at 
Week 12 
Amenorrhea observed at Week 16 and was 
observed at every visit thereafter until and 
including the last dose of study treatment 
Week 20 
Determined amenorrhea at 
Week 16 
Amenorrhea observed at Week 20 and was 
observed at every visit thereafter until and 
including the last dose of study treatment 
Week 24 
Determined amenorrhea at 
Week 20 
Amenorrhea observed at Week 24  
 


 
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7.4.4. 
Derivation of Patient-Reported Outcome  
7.4.4.1. 
Numerical Rating Scale Score for Pain Associated with Uterine Fibroids 
Patients completed daily eDiaries including assessment of uterine fibroid-associated pain by the 
Numerical Rating Scale (NRS).  Patients rated their worst pain in the last 24 hours caused by 
their uterine fibroids on a scale from 0 to 10, with 0 indicating no pain and 10 indicating pain as 
bad as you can imagine.  The maximum NRS score for pain at Week 24/EOT is calculated as the 
maximum NRS score during the last 35 days on study treatment.  If any NRS scores for pain 
during the last 35 days on study treatment are missing, the maximum score will be calculated as 
the maximum of all non-missing scores.  Baseline NRS score for uterine fibroid-associated pain 
is defined as the maximum NRS score from the 35 days of data collected prior to randomization.   
Proportion of women who achieve a maximum NRS score for pain associated with uterine 
fibroids over the last 35 days of treatment that is at least a 30% reduction from Baseline will be 
summarized in the subset of women with a maximum pain score ≥ 4 during the 35 days prior to 
randomization (subset).  In addition, for the subset, mean maximum NRS scores will be provided 
by treatment and visit.  Maximum NRS score for each patient at a visit is defined as the highest 
NRS score reported in the visit window specified in Table 2. 
7.4.4.2. 
UFS-QoL Score 
Calculation of UFS-QoL Symptom Severity Scale Score 
To calculate the Symptom Severity Scale score, a summed score is created for the items listed 
below and then the formula below the table is used to transform raw scores to a normalized score 
with a range of possible values from 0 to 100.  This provides Symptom Severity Scale scores, 
where higher scores are indicative of greater symptom severity and lower scores indicate lower 
symptom severity. 
 
Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Symptom Severity 
Sum 1 – 8 
8, 40 
32 
Formula for Transformation of Symptom Severity Raw Scores ONLY: 
Transformed Score = [(Actual raw score – lowest possible raw score)/(Possible raw score 
range)] * 100 
Calculation of UFS-QoL Bleeding and Pelvic Discomfort Scale Score  
The UFS-QoL Bleeding and Pelvic Discomfort (BPD) Scale has been derived from the UFS-
QoL Symptoms Scale; the derivation and validation of this new scale can be found in 
Appendix 3.  The new scale consists of the following three symptoms proximal to uterine 
fibroids: 
• Heavy bleeding during your menstrual period (Q1) 
• Passing blood clots during your menstrual period (Q2) 
• Feeling tightness or pressure in your pelvic area (Q5) 


 
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To calculate the score for the BPD Scale, a summed score of the items listed below is created 
and then the formula below the table is used to transform the raw score to a normalized score.  
This provides BPD Scale scores, where higher score values are indicative of greater symptom 
severity and lower scores will indicate minimal symptom severity (high scores = bad). 
 
Sub-Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Q1, Q2 and Q5 
Sum 1,2,5 
3, 15 
12 
Formula for Transformation of BPD Raw Scores ONLY: 
Transformed Score = [(Actual raw score – lowest possible raw score)/(Possible raw score 
range)] * 100 
On the basis of transformed score for BPD Scale, change from Baseline in the transformed score 
for BPD Scale at Week 24 will be defined as an alpha-protected key secondary endpoint 
comparing the relugolix + E2/NETA group with the placebo group.  The proportion of patients 
who are responders (defined as meeting a meaningful change threshold from Baseline in the 
BPD Scale) at Week 24 on the transformed score for the BPD Scale will be compared between 
the two treatment arms (the relugolix + E2/NETA group with the placebo group) using a 
stratified Cochran-Mantel-Haenszel test, as appropriate.  The proposed responder threshold is a 
20-point change.  Details in the determination of the meaningful change in the BPD Scale can be 
found in Appendix 4.   
As a descriptive assessment on robustness of the responder analysis, a plot of the cumulative 
distribution function (CDF) will be provided for each treatment group to display the change from 
Baseline to Week 24 in the transformed score for BPD Scale on the x-axis and cumulative 
percentage of patients experiencing up to that change on the y-axis.  
Calculation of Other UFS-QoL Scale Scores and UFS-QoL Total Score 
For the other UFS-QoL scales (concern, activities, revised activities, energy/mood, control, self-
conscious, and sexual function), a summed score of the items listed below is created for each 
individual scale.  To calculate the UFS-QoL total score, the values for each individual scale are 
summed.  Using the formula below the table, all raw scores are transformed to normalized 
scores.  Higher scores are indicative of better health-related quality of life (high = good).  
For endpoints evaluating a single question, the raw score is used in the analysis.  The activity and 
revised activity domain scores will be summarized by treatment group. 
 


 
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Scale 
Sum Item Values 
Lowest and Highest 
Possible Raw Scores 
Possible Raw Score 
Range 
Concern 
9+15+22+28+32 
5, 25 
20 
Activities 
10+11+13+19+20+27+29 
7, 35 
28 
Revised activities 
11+13+19+20+27 
5,25 
20 
Energy/mood 
12+17+23+24+25+31+35 
7, 35 
28 
Control 
14+16+26+30+34 
5, 25 
20 
Self-conscious 
18+21+33 
3, 15 
12 
Sexual function 
36+37 
2, 10 
8 
HRQL TOTAL 
Sum of 6 Subscale 
Scoresa 
29, 145 
116 
Abbreviations:  HRQL, health-related quality of life. 
a HRQL Total includes following scales: concern, activities, energy/mood, control, self-conscious, and sexual 
function. 
Formula for Transformation of Raw Scores of Other Scale Scores ONLY: 
Transformed Score = [(Highest possible score – Actual raw score)/(Possible raw score 
range)] * 100 
For revised activities, the proportion of patients who are responders (defined as meeting a 
meaningful change from Baseline in the revised activity score) at Week 24 will be analyzed 
similarly to that for the change in BPD Scale score between the two treatment arms (relugolix + 
E2/NETA and placebo).  The proposed responder threshold is a 20-point increase.  Details of the 
determination of the meaningful change in the Revised Activities Scale score can be found in 
Appendix 5.   
Missing Items 
For any scale analyses, if < 50% of the scale items are missing, the scale should be retained using 
the mean scale score of the items present.  If ≥ 50% of the items are missing, no scale score 
should be calculated; the subscale score will be considered missing.   
7.4.4.3. 
Patient Global Assessment 
The PGA for function and symptoms will be evaluated using a 5-point response scale (eg, 
absent, mild, moderate, severe, and very severe).  To calculate change from Baseline to Week 
24, the following numerical scores will be assigned to each response level: 
Response Scale (Function) 
Response Scale (Symptoms) 
Numerical Score 
No limitation at all 
Not severe 
1 
Mild limitation 
Mildly severe 
2 
Moderate limitation 
Moderately severe  
3 
Quite a bit of limitation 
Very severe 
4 
Extreme limitation 
Extremely severe 
5 
 


 
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For each item, the count and proportion of improvement by level or at least one level will be 
tabulated by treatment group and by visit.  The denominator for the proportion will be based on 
the number of patients who provided non-missing responses to the items. 
7.4.4.4. 
Menorrhagia Impact Questionnaire 
The Menorrhagia Impact Questionnaire items 3 and 4 will be evaluated using the 5-point 
response scales (Not at all, Slightly, Moderately, Quite a bit, and Extremely) to assess level of 
improvement from Baseline to Week 24. 
For each item, the count and proportion of improvement by level will be tabulated by treatment 
group and by visit.  The denominator for the proportion will be based on the number of patients 
who provided non-missing responses to the items. 
7.5. 
Exploratory Efficacy Endpoints 
The following exploratory endpoints will be assessed for both comparisons the relugolix + 
E2/NETA group with the placebo group and the relugolix + delayed E2/NETA group with the 
placebo group: 
• Change from Baseline to Week 24 in the EQ-5D-5L Scale score 
• Change from Baseline to Week 24 in EQ-5D-5L visual analogue score. 
7.5.1. 
Exploratory Efficacy Analyses 
Analysis methods previously described for primary and secondary efficacy endpoint analyses 
will be used for the analysis of these endpoints. 


 
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8. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Plasma relugolix, plasma NET, and serum E2 trough concentrations will be listed and 
summarized by study, treatment group (Group A, B, or C), and visit. 
Serum pharmacodynamic data (LH, FSH, E2, and progesterone) will be listed and summarized 
using descriptive statistics (including raw and change from Baseline) by study, treatment group 
(Group A, B, or C), and visit. 
For pharmacodynamic assessment, the number and percentage of patients with individual E2 
concentration values < 10 pg/mL, 10 to < 20 pg/mL, 20 to < 50 pg/mL, and ≥ 50 pg/mL and 
individual progesterone concentration values < 1 ng/mL, 1 to 5 ng/mL, and ≥ 5 ng/mL will be 
summarized by treatment group (Group A, B, or C) and visit. 
Scatter plots with LOESS smoothing lines for MVT-601-3001 and MVT-601-3002 separately 
will be used to examine the relationship between mean plasma relugolix trough concentration at 
the given time point (collected between 18 and 30 hours after the previous dose) and the 
following pharmacodynamic concentrations: 
• Week 12 serum LH, FSH, E2, and progesterone (separately for Groups A and B); 
• Week 24 serum LH, FSH, E2, and progesterone (separately for Groups A and B, and 
Groups A and B combined). 
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.  The analysis plan for population PK and exposure-response analyses will 
be specified in a separate document. 


 
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9. 
SAFETY ANALYSES 
Unless otherwise specified, safety analyses will be conducted using the safety population 
according to the treatment received by the patients.   
9.1. 
Adverse Events 
Adverse events will be collected from the time of the first dose of study drug through the safety 
follow up visit approximately 30 days after the last dose of study drug (the end of treatment 
period), or the date of initiation of another investigational agent or hormonal therapy or surgical 
intervention or entering extension study, whichever occurs first.  Serious adverse events reported 
to the investigator after the safety reporting period should be reported to the sponsor if the 
investigator assesses the event as related to study drug. 
The severity of all treatment-emergent adverse events will be evaluated by the investigator based 
on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
and will be coded to preferred term and system organ class using MedDRA 22.0 or higher. 
A treatment-emergent adverse event is defined as any adverse event that occurs after 
administration of the first dose of study drug. 
Adverse event summaries will be based on treatment-emergent adverse events, unless otherwise 
specified.  Adverse events occurring prior to administration of any study drug will be listed and 
flagged in by-patient listings. 
The following tabular summaries that include the number and percentage of patients will be 
provided: 
• Overview of adverse events; 
• All adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− By SOC, PT, and maximum severity; 
− Study drug-related per investigator by SOC and PT; 
− By time to onset, SOC and PT; 
• Grade 3 or above adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− Study drug-related per investigator by SOC and PT; 
• Grade 2 or above adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− By SOC, PT, and maximum severity; 


 
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− Study drug-related per investigator by SOC and PT; 
• Adverse events leading to study drug withdrawal; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events leading to dose interruption; 
− By SOC and PT; 
− By decreasing frequency of PT; 
• Adverse events resulting in fatal outcome; 
− By decreasing frequency of PT; 
• Serious adverse events; 
− By SOC and PT; 
− By decreasing frequency of PT; 
− By SOC, PT, and maximum severity; 
− By SOC, PT, and relationship to study drug; 
• Adverse events of clinical interest (ALT or AST ≥ 3 x ULN); 
− By SOC, PT, and maximum severity; 
− By decreasing frequency of PT. 
Additionally, adverse event categories defined in Table 12 will be summarized by decreasing 
frequency of PT. 
9.1.1. 
Relationship to Study Drug 
Adverse events will be classified as “related” to study treatment if the relationship was rated by 
the investigator as possibly related or probably related.  Adverse events related to any study drug 
(relugolix or placebo and E2/NETA or placebo) will be considered as related to study drug.  
9.1.2. 
Severity of Adverse Event 
Grade 2 or above adverse events will be summarized by SOC, PT, and/or maximum severity, 
relationship to study treatment.  
9.1.3. 
Serious Adverse Event 
Serious adverse events will be summarized by SOC, PT, and/or maximum severity, relationship 
to study treatment. 
The data handling conventions for and the definition of a serious adverse event are discussed in 
this section.  All deaths during the study, including the post treatment follow-up period, and 
deaths that resulted from a process that began during the study, should be included in the 


 
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analysis.  For more details, deaths occurring during the following time periods or under the 
following conditions should be considered:  
• Deaths occurring during participation in any study, or during any other period of drug 
exposure  
• Deaths occurring after a patient leaves a study, or otherwise discontinues study drug, 
whether or not the patient completes the study to the nominal endpoint, if the death:  
− Is the result of a process initiated during the study or other drug exposure, 
regardless of when it actually occurs; or  
− Occurs within a time period that might reflect drug toxicity for a patient leaving a 
study or otherwise discontinuing drug.  For drugs with prompt action and 
relatively short elimination half-lives, 4 weeks is a reasonable time period.  For 
drugs with particularly long elimination half-lives or drug classes with recognized 
potential to cause late occurring effects, deaths occurring at longer times after 
drug discontinuation should be evaluated. 
9.1.4. 
Adverse Event Leading to Withdrawal of Study Drug  
Adverse events leading to withdrawal of study drug are those adverse events collected from the 
adverse event CRF pages with “drug withdrawn” as the action taken with study drug.  
Adverse events with “drug withdrawn” as action taken due to any one of the components of 
study drug will be considered as leading to withdrawal of study drug.  
9.1.5. 
Adverse Events Leading to Dose Interruption 
Adverse events leading to dose interruption are those adverse events collected from the adverse 
event CRF pages with “drug interrupted” as their action taken with study drug.  
Adverse events with “drug interrupted” as action taken due to any one of the components of 
study drug will be considered as leading to dose interruption. 
9.1.6. 
Adverse Events Resulting to Fatal Outcome 
Adverse events resulting in a fatal outcome are those adverse events collected from the adverse 
event pages with “fatal” as their outcome.  
The fatal events, if any, will be provided in a by-subject listing. 
9.1.7. 
Adverse Event Categories 
In addition, adverse event categories defined in Table 12 will be summarized by decreasing 
frequency of PT under each safety population.  Incidence of vasomotor symptoms by 12 weeks 
will be compared between relugolix Group A and relugolix Group B.  Comparative statistics 
(such as p-values, 95% CIs, risk ratio) will be provided.  Vasomotor symptoms throughout the 
studies will be summarized by SOC, PT, and maximum severity. 


 
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Table 12: 
Constitution of Adverse Event Categories 
Category 
Search Criteria 
Bone health 
events  
Osteoporosis/Osteopenia SMQ (broad) 
Fracture (custom SMQ):  All preferred terms including the term “fracture,” excluding 
“Tooth fracture” and “Fracture of penis” 
Hepatic disorders 
Drug-related hepatic disorders – comprehensive SMQ (narrow) 
Metabolic 
disorders  
Dyslipidemia SMQ (broad) 
Hyperglycemia/new onset diabetes mellitus SMQ (narrow) 
 
 
Vasomotor 
symptoms 
The following 5 preferred terms will be included:  
Hyperhidrosis;  
Feeling hot;  
Hot flush;  
Night sweats;  
Flushing 
Mood disorders  
MedDRA Depression and Suicide/Self-Injury SMQ (broad)  
Abbreviations:  HLT, High-Level Term; MedDRA, Medical Dictionary for Regulatory Activities; SMQ, 
Standardised MedDRA Query.   
 
9.2. 
Laboratory Data 
Laboratory parameters, including chemistry and hematology panels, specified as per protocol, 
and collected from the central laboratory will be tabulated and presented in by-patient listings.  
Urinalysis and hepatitis virus serological test results will be provided in by-patient listing only. 
The National Cancer Institute CTCAE Grading Scale with numeric component will be used to 
categorize toxicity grade for laboratory parameters (CTCAE v5.0, dated 17 Nov 2017).  
Parameters that have criteria available for both low and high values (eg, hypercalcemia for a high 
value of calcium and hypocalcemia for a low value of calcium) will be summarized for both 
criteria (low and high).  Patients will only be counted once for each criterion.  The same patient 
can be counted for both criteria if she has laboratory values meeting each criterion.  Shift tables 
will be provided for each gradable parameter to summarize Baseline toxicity grade versus worst 
post-Baseline toxicity grade.  For laboratory parameters that are not gradable by the CTCAE, a 
shift table based upon the normal range (low, normal, and high) will be provided for each 
parameter to summarize the Baseline versus worst post-Baseline results. 
Boxplots of laboratory values over time will be plotted for key laboratory parameters.  These 
laboratory parameters include, but are not limited to, hematology (hemoglobin, platelets, 


 
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leukocytes, neutrophils), creatinine, glomerular filtration rate, and hepatic function panel (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and 
total bilirubin). 
The change from Baseline to each post-Baseline study visit will be presented by treatment group 
for each laboratory test in both tables and figures. 
The number and proportion of patients with liver test elevations will be presented by treatment 
group.  Liver test elevations are assessed by using post-Baseline results for ALT, AST, ALP, and 
total bilirubin based on the definitions presented in Table 13. 
Table 13: 
Categories of Liver Test Elevations 
Laboratory Test 
Category  
ALT or AST 
ALT or AST > ULN - < 3xULN 
ALT or AST ≥ 3x to < 5x ULN 
ALT or AST ≥ 5x to < 8x ULN 
ALT or AST ≥ 8x to < 10x ULN 
ALT or AST ≥ 10 to < 20x ULN 
ALT or AST ≥ 20x ULN 
Total bilirubin 
Total bilirubin > 2 × ULN 
ALT or AST and total bilirubin 
ALT or AST ≥ 3 × ULN + total bilirubin > 2 × ULN  
ALT or AST, total bilirubin, and ALP 
ALT or AST ≥ 3 x ULN + total bilirubin > 2 × ULN + ALP < 2 × ULN 
Abbreviations:  ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, 
upper limit of normal. 
The number and percentage of patients with concurrent (defined as measurements on the same 
day) ALT or AST ≥ 3 times ULN and total bilirubin > 2 times ULN will also be presented. 
9.3. 
Other Safety Analyses 
9.3.1. 
Electrocardiograms 
ECG interval results and changes from Baseline will be summarized descriptively for each 
scheduled visit in both tables and figures using data provided by and read by central reading. 
A categorical analysis of corrected QT interval using Fridericia’s calculation (QTcF) intervals 
will also be performed for each scheduled visit and for the maximum post-Baseline value.  The 
number and percentage of patients in each QTcF interval category (< 450 msec, 450 to 480 msec, 
481 to 500 msec, and > 500 msec) will be summarized.  Categories of changes from Baseline 
(≥ 30 msec and ≥ 60 msec) will be summarized as well. 
ECG intervals will be presented in by-patient listing.  Overall ECG assessments performed by 
local reading will also be listed. 
9.3.2. 
Visual Acuity 
Visual Acuity Score at Baseline and at each scheduled post-Baseline assessment time point will 
be presented in a by-patient listing. 


 
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9.3.3. 
Vital Signs 
Blood pressure (systolic and diastolic), heart rate, and BMI will be summarized at Baseline and 
each subsequent scheduled assessment by treatment group.  Change from Baseline will be 
calculated and presented for each parameter at all scheduled post-Baseline assessment time 
points in both tables and figures.  All vital sign data will also be provided in by-patient listings. 
Potentially clinically significant abnormalities in vital signs are defined in Table 14, and they 
will be summarized by using post-Baseline values that meet the defined criteria.  Potentially 
clinically significant abnormalities will also be flagged in by-patient listings. 
Table 14: 
Categories of Potentially Clinically Significant Abnormalities in Vital Signs 
Parameter 
Category 
Systolic blood pressure 
≥ 140 mmHg 
≥ 180 mmHg 
≤ 90 mmHg 
Increase of ≥ 20 mmHg from Baseline 
Decrease of ≥ 20 mmHg from Baseline 
Diastolic blood pressure  
≥ 90 mmHg 
≥ 105 mmHg 
≤ 50 mmHg 
Increase of ≥ 15 mmHg from Baseline 
Decrease of ≥ 15 mmHg from Baseline 
Heart rate 
≥ 120 bpm 
< 45 bpm 
Increase of ≥ 15 bpm from Baseline 
Decrease of ≥ 15 bpm from Baseline 
Abbreviations:  bpm, beats per minute; mmHg, millimeters of mercury. 
 
9.3.4. 
Endometrial Biopsy 
Primary diagnosis of endometrial biopsy assessment will be summarized at Baseline and at 
scheduled assessment by treatment group.  All endometrial biopsy data will also be provided in a 
by-patient listing. 
Primary diagnosis from pathologist evaluation will be categorized by medical monitor’s review 
in Table 15 and will be summarized using frequencies and percentages, summarized for each 
treatment group.  All endometrial biopsy data will also be provided in by-patient listings. 
 
 


 
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Table 15: 
Categories of Primary Diagnosis in Endometrial Biopsies 
Normal-Proliferative 
• 
Weakly proliferative 
• 
Proliferative 
• 
Disordered proliferative 
Normal-Secretory/Menstrual/Mixed 
• 
Secretory 
• 
Menstrual 
• 
Progestational/Decidulized/Mixed 
Normal-Atrophic or Minimally Stimulated 
• 
Atrophic 
• 
Indeterminate/Inactive 
Hyperplasia 
• 
Simple hyperplasia without atypia 
• 
Simple hyperplasia with atypia 
• 
Complex hyperplasia without atypia 
• 
Complex hyperplasia with atypia 
Carcinoma 
— 
Inadequate 
— 
Missing 
— 
Additional Diagnosis (Other reported finding) 
• 
Reactive/Inflammatory 
• 
Polyp 
• 
Metaplasia 
• 
Glandular and/or Stromal Breakdown 
 
9.3.5. 
Bone Mineral Density 
Corrected BMD data will be used for analysis as determined by the central radiology laboratory 
in the 3 prespecified anatomical locations:  lumbar spine (L1–L4), total hip, and femoral neck.  
BMD at Baseline, Week 12 and Week 24 visits will be summarized descriptively by treatment 
group and each anatomical location.  Percentage changes from Baseline along with 95% CIs of 
mean percentage changes will be also summarized by treatment group and anatomical location.  
Mean percentage change from Baseline with its corresponding 95% CI will be plotted by visit, 
treatment group, and anatomical location.  
To support the inclusion of E2/NETA in the treatment regimen, the safety endpoint of mean 
percent change from Baseline in BMD at the 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 


 
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comparison of  the relugolix + E2/NETA group (Group A) versus the relugolix + delayed 
E2/NETA group (Group B) (details in the Integrated Summary of Safety Statistical Analysis 
Plan).  
In addition, the difference of percentage change from Baseline between treatment groups 
(relugolix + E2/NETA group versus the relugolix + delayed E2/NETA group at 12 weeks, 
relugolix + E2/NETA versus placebo group at 12 and 24 weeks, and relugolix + delayed 
E2/NETA group versus placebo group at 12 weeks) will be summarized at each visit by 
anatomical location along with the corresponding 95% CIs.  
To account for participants whose BMD assessment may have been obtained outside of the 
protocol-specified window (Week 12 ± 3 weeks, Week 24 ± 3 and 4 weeks), a sensitivity 
analysis by visit will be conducted that includes all women who underwent DXA at both time 
points, regardless of whether the image was procured during the prespecified time window. 
A mixed-effects model with repeated measures will be used to describe treatment effect on BMD 
at 12 and 24 weeks.  The model will have treatment group, age at Baseline, visit, Baseline BMD 
value, stratification factors (geographic region and menstrual blood loss volume), race (African 
American versus Other), and BMI at Baseline as fixed effects using an unstructured variance-
covariance matrix.  Least square means on each anatomical location will be presented and 
plotted at each visit with associated 95% CIs.  Categorical representation of percentage change 
from Baseline to 12 and 24 weeks of treatment will be presented by the number and proportion 
of patients who had BMD declines of ≤ 2%, >2% to 3%, > 3% to 5%, > 5% to 8%, and > 8% by 
treatment group and anatomical location.  The 95% CIs will be provided for the respective 
proportions.   
Categorical changes from Baseline in overall BMD (defined as lumbar spine and total hip) also 
will be assessed at 12 and 24 weeks.  Femoral neck evaluates a smaller area of bone mass than 
the total hip and is prone to lower precision in the measurement (ISCD Official Positions, 2015; 
Leslie, 2007).  Since femoral neck BMD may be associated with discordant readings compared 
with the total hip or lumbar spine due to technical considerations, it will not add meaningful 
interpretation of overall BMD changes in response to treatment. 
Z-scores will be summarized by treatment group, visit, and anatomical location with descriptive 
statistics including 95% CIs, and the number and percentage of patients with a Z-score < -2.0 
will be presented by treatment group, visit, and anatomical location.   
BMD percentage changes from Baseline will also be summarized by intrinsic factors (eg, age, 
race, body mass index) and extrinsic factors (eg, geographic region). 
9.3.6. 
Bleeding Pattern 
Bleeding patterns will be summarized at Week 24/EOT by treatment group.  Three bleeding 
patterns will be considered:  amenorrhea (see Section 7.4.3), cyclic bleeding, and irregular 
bleeding.  Patients with the cyclic bleeding pattern are those who do not meet the definition of 
amenorrhea and do meet the following conditions:  
• 3 to ≤ 12 days of menstruation duration per eDiary at Week 24/EOT window (see 
Section 7.3.3)  


 
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• No more than 2 days of gap of no bleeding (per eDiary) within the menstruation 
duration. 
Patients with the irregular bleeding pattern are those who do not meet the definitions of cyclic 
bleeding or amenorrhea.  The number (and percent) of patients and mean number of bleeding 
days will be provided by treatment group for each bleeding pattern.  
For patients with cyclic or irregular bleeding pattern, the number (and percent) of patients with 
observed MBL volume falling into the following bleeding intensity groups will be provided: 
• Spotting/negligible bleeding:  MBL volume < 5 mL  
• Light:  MBL volume 10 - 50 mL  
• Moderate:  MBL volume >50 to ≤80 mL  
• Heavy:  MBL volume > 80 mL  
For each bleeding intensity category, the mean number of bleeding days will be summarized.   


 
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10. 
REFERENCES 
2015 International Society for Clinical Densitometry (ISCD) Official Positions – Adult 
(https://www.iscd.org/official-positions/2015-iscd-official-positions-adult/; accessed 
30 Apr 2019). 
Bachowski G, Borge D, Brunker P, Eder A, Fialkow L, Friday J, et al. A Compendium of 
Transfusion Practice Guidelines. American Red Cross; 2017 p. 81. Report No.: 3rd 
Edition.  
Leslie WD, Lix LM, Tsang JF, Caetano PA. Single-site vs Multisite Bone Density Measurement 
for Fracture Prediction.  Arch Intern Med 2007; 167 (15): 1641-7 
Man L, Tahhan HR. Body surface area: a predictor of response to red blood cell transfusion. 
JBM. 2016 Sep;Volume 7:199–204.  
Ratitch B, Lipkovich I, O’Kelly M. Combining analysis results from multiply imputed 
categorical data. PharmaSUG 2013. Paper SP03. 
Rubin D. The calculation of posterior distributions by data augmentation: comment: a 
noniterative sampling/importance resampling alternative to the data augmentation 
algorithm for creating a few imputations when fractions of missing information are 
modest: the SIR algorithm. J Am Stat Assoc. 1987 Jun; 82(398), 543-546.  
Stewart EA, Owens C, Duan WR, Gao J, Chwalisz K, Simon JA. Elagolix alone and with add-
back decreases heavy menstrual bleeding in women with uterine fibroids. Poster 
presented to American College of Obstetricians and Gynecologists Annual Clinical and 
Scientific Meeting 2017, San Diego, CA, May 6-9, 2017.  
Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of 
choice for handling missing data in randomized trials? Stat Methods Med Res. 2018 Sep; 
27(9):2610-2626. 
von Hippel PT. How many imputations do you need? A two-stage calculation using a quadratic 
rule. Sociol Methods Res. 2018 Jan. 
 


 
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APPENDICES 
 


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APPENDIX 1. SUMMARY OF SECONDARY ENDPOINT ANALYSES 
 
Secondary Endpoints 
Analysis 
Population 
Statistical 
Method/Test 
Declare 
Statistical 
Significance a 
Time Points of 
Summary 
Summary Statistics 
Key Secondary Efficacy Endpoints with Alpha Protection 
Proportion of women who achieve 
amenorrhea over the last 35 days of 
treatment 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Week 24 
Frequency and 
percentages 
% change from Baseline to Week 24 in MBL 
volume 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 24 
LS means for % change 
Proportion of women with a hemoglobin 
≤10.5 g/dL at Baseline who achieve an 
increase of > 2 g/dL from Baseline at 
Week 24 
Subset of 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Week 24 
Frequency and 
percentages 
Change from Baseline to Week 24 in the 
UFS-QoL Bleeding and Pelvic Discomfort 
Scale score, a sub-scale of the UFS-QoL 
Symptom Severity Scale  
mITT 
Mixed-effects 
model 
P < 0.05 
Week 24 
LS means for change 
Proportion of patients with a maximum NRS 
score ≤ 1 during the 35 days before the last 
dose of study drug in the subset of women 
with a maximum NRS score ≥4 for pain 
associated with uterine fibroids during the 35 
days prior to randomization  
Subset of 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Week 24/EOT 
Frequency and 
percentages 
% change from Baseline to Week 24 in 
uterine fibroid volume  
mITT 
ANCOVA 
model 
P < 0.05 
Week 24 
LS means for % change 
% change from Baseline to Week 24 in 
uterine volume 
mITT 
ANCOVA 
model 
P < 0.05 
Week 24 
LS means for % change 
Other Secondary Efficacy Endpoints 
Time to achieve MBL volume of < 80 mL 
AND at least a 50% reduction from Baseline 
MBL volume as measured by the alkaline 
hematin method 
mITT 
Log-rank 
test/KM method 
P < 0.05 
Monthly 
KM estimates at 
Week 12 and 24, KM 
plots, median time to 
response 
Time to achieve amenorrhea 
mITT 
Log-rank 
test/KM method 
P < 0.05 
Monthly 
KM plots, median time 
to response 


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Secondary Endpoints 
Analysis 
Population 
Statistical 
Method/Test 
Declare 
Statistical 
Significance a 
Time Points of 
Summary 
Summary Statistics 
Time to sustained amenorrhea 
mITT 
Log-rank 
test/KM method 
P < 0.05 
Monthly 
KM plots, median time 
to response 
Proportion of women in the relugolix Group 
A versus the placebo Group C who achieve 
an MBL volume of < 80 mL AND at least a 
50% reduction from Baseline MBL volume at 
Week 4, Week 12, Week 16, and Week 20 
mITT 
No comparison   
 
at Week 4, Week 12, 
Week 16, and Week 20 
Descriptive  
Sustained amenorrhea rate by visit 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Monthly 
Frequency and 
percentages 
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 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Monthly 
Frequency and 
percentages 
Change (absolute and %) from Baseline to 
Week 24 in hemoglobin for women with a 
hemoglobin ≤ 10.5g/dL at Baseline 
mITT 
Mixed-effects 
model 
P < 0.05 
Monthly 
LS means for % change 
Proportion of women who achieve a 
maximum 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 
Subset of 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05, 
Week 12, 24 
Frequency and 
percentages 
Mean maximum NRS scores over time 
Subset of 
mITT 
Descriptive  
 
Monthly  
Means  
Proportion of responders who had 
meaningful reduction of >20 points from 
Baseline to Week 24 in UFS-QOL Bleeding 
and Pelvic Discomfort Scale (Q1, Q2 and 
Q5) 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05, 
Week 12, 24 
Frequency and 
percentages 
Proportion of responders who had 
meaningful increase of > 20 points from 
Baseline to Week 24 in UFS-QOL revised 
activities 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05, 
Week 12, 24 
Frequency and 
percentages 


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Secondary Endpoints 
Analysis 
Population 
Statistical 
Method/Test 
Declare 
Statistical 
Significance a 
Time Points of 
Summary 
Summary Statistics 
Change from Baseline to Week 24 in impact 
of uterine fibroids based on the UFS-QOL 
revised activities domain 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in impact 
of uterine fibroids based on the UFS-QOL 
activities domain 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in the 
interference of uterine fibroids with physical 
activities based on UFS-QOL Q11 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in the 
interference of uterine fibroids with social 
activities based on UFS-QOL Q20 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in 
embarrassment caused by uterine fibroids 
based on UFS-QOL Q29 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in the 
UFS-QoL Symptom Severity Scale score 
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change from Baseline to Week 24 in the 
UFS-HRQL total score  
mITT 
Mixed-effects 
model 
P < 0.05 
Week 12, 24 
LS means for change 
Change in PGA for uterine fibroid related 
function from Baseline to Week 24 
mITT 
Mixed-effects 
model 
P <0.05 
Monthly 
LS means for absolute 
and change 
Change in PGA for uterine fibroid symptoms 
from Baseline to Week 24 
mITT 
Mixed-effects 
model 
P < 0.05 
Monthly 
LS means for absolute 
and change 
Proportion of patients achieving 
improvement in PGA for uterine fibroid 
symptoms from Baseline to Week 24 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Monthly 
Frequency and 
percentages 
Proportion of patients achieving 
improvement in PGA for uterine fibroid 
related function from Baseline to Week 24 
mITT 
Cochran-Mantel-
Haenszel test 
P < 0.05 
Monthly 
Frequency and 
percentages 
Safety Related Endpoints 
% Change from Baseline to Week 12 in 
BMD (pooled data) 
Safety 
population 
Mixed-effects 
model 
Relugolix Group 
A vs B 
P < 0.05, 
Week 12 
LS means 
Diff (95%CI) 


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Secondary Endpoints 
Analysis 
Population 
Statistical 
Method/Test 
Declare 
Statistical 
Significance a 
Time Points of 
Summary 
Summary Statistics 
% Change from Baseline in BMD 
Safety 
population 
Mixed-effects 
model 
Relugolix Group 
A vs Placebo at 
12/24 weeks; 
Relugolix Group 
B vs Placebo at 
12 weeks 
 
Week 12, 24  
LS means 
Diff (95%CI) 
Exploratory Secondary Efficacy Endpoints 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
physical activities 
mITT 
Descriptive 
 
Monthly 
Frequency and 
percentages 
Change from Baseline to Week 24 in the 
Menorrhagia Impact Questionnaire Score for 
social and leisure activities 
mITT 
Descriptive 
 
Monthly  
Frequency and 
percentages 
Abbreviations:  KM, Kaplan-Meier; LS, least squares; mITT, modified intent-to-treat; NRS, Numerical Rating Scale; Q, question; UFS-HRQL, Uterine Fibroid 
Scale – Health-related Quality of Life. 
a P-values are two-sided. 


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APPENDIX 2. 
DERIVATION AND PSYCHOMETRIC EVALUATION OF 
A UFS-QOL BLEEDING AND PELVIC DISCOMFORT 
SCALE 
The BPD Scale was derived from the Symptom Severity Scale of the Uterine Fibroid Symptom 
and Health-Related Quality of Life (UFS-QoL).  The BPD Scale consists of three items proximal 
to uterine fibroids that are experienced by most patients, (ie, heavy bleeding during the menstrual 
period [Question 1], passing blood clots during the menstrual period [Question 2], and feeling 
tightness or pressure in the pelvic area [Question 5]). 
The aim of this appendix is to describe the derivation and psychometric testing process of the 
BPD Scale.  Results of the analyses in this appendix are summarized in Appendix 3 and will be 
included in the Patient-Reported Outcomes dossier to be submitted at the time of filing for the 
uterine fibroids registration program. 
Exploratory factor analysis and subsequent confirmatory factor analysis were conducted to assess 
and confirm the factor structure of the Symptom Severity Scale of the UFS-QoL, using data from 
a phase 2 study of relugolix in uterine fibroids (TAK-385/CCT-001), as well as pooled, blinded 
data from one-third of patients in the phase 3 studies (MVT-601-3001 and MVT-601-3002).  
Respective analyses are described in Section 2.1.  Based on the results, the factor(s) reflecting 
symptoms proximal to uterine fibroids and experienced by most patients with uterine fibroids 
were selected for further psychometric testing. 
The psychometric properties of the new scale were assessed using the same pooled, blinded data 
from the two phase 3 studies of relugolix in uterine fibroids (MVT-601-3001 and 
MVT-601-3002).  These analyses are described in Section 2.2.  The blinded data consists of the 
first third of patients (approximately n = 260) enrolled into the two pivotal studies who have 
completed the patient global assessment (PGA) for symptoms and the UFS-QoL at Baseline and 
at Week 24.  Of note, for the analyses specified in Section 2.2, only data at Baseline and Week 
12 were used; the Week 24 data was used in the responder analyses described in Appendix 3. 
2.1. 
Development of the Bleeding and Pelvic Discomfort Scale Using 
Phase 2 and Phase 3 Data 
From a review of the eight items in the Symptom Severity Scale of the UFS-QoL, it was 
apparent that the scale consists of different constructs/dimensions.  Therefore, the factor structure 
of the Symptom Severity Scale was assessed, initially using data from the phase 2 study 
TAK-385/CCT-001 (n = 216). 
Of note, in the TAK-385/CCT-001 phase 2 study, the UFS-QoL with a one-month recall period 
was applied, whereas the UFS-QoL with a three-month recall period is used in the phase 3 
studies (MVT-601-3001 and MVT-601-3002).  Therefore, confirmatory factor analysis and final 
psychometric testing of the chosen factor was conducted using blinded phase 3 data (see 
Section 2.2). 


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Exploratory Factor Analysis 
The exploratory factor analysis was done on phase 2 data to identify the underlying constructs by 
the most parsimonious factor structure of the eight items in the Symptom Severity Scale.  
Identification of the number of factors was based on the following criteria: 
• Items with primary factor loading > 0.4; 
• Factors with large eigenvalues considered as common factors using Kaiser criterion 
(Kaiser, 1960). 
A scree plot was used as a supplemental tool to decide on the number of factors in the final 
model. 
Confirmatory Factor Analysis 
Once the number of factors was identified, a confirmatory factor analysis was conducted using 
blinded, pooled phase 3 data to confirm the factor structure.  Only patients who completed the 
Baseline and Week 24 PGA for symptoms and UFS-QoL assessments were included in this 
analysis.  Model fit was assessed based on the following:  
• The goodness of fit as measured by χ2 and Goodness of Fit Index; a Goodness of Fit 
Index > 0.9 is considered acceptable; 
• The Comparative Fit Index was used to determine the acceptability of the model fit of 
the discrepancy function adjusted sample size; a Comparative Fit Index > 0.9 
(Hu, 1995) was considered an acceptable fit; 
• The root mean square error of approximation was used to determine the acceptability 
of model fit of the square root of the discrepancy between the sample covariance 
matrix and the model covariance matrix; the root mean square error of approximation 
had to be < 0.06 (Browne, 1993) to be considered an acceptable fit; 
• P-value > 0.05. 
Once the final factor structure was identified, the factor reflecting items proximal to uterine 
fibroids and experienced by almost all patients with uterine fibroids were selected for further 
evaluation.  Of note, this was the BPD Scale. 
2.2. 
Psychometric Analyses Based on Phase 3 Data 
The same pooled, blinded data from the first third of patients enrolled in either of the two phase 
3 studies (MVT-601-3001 or MVT-601-3002) was used for the psychometric analyses of the 
BPD Scale.  The objective was to psychometrically evaluate the new scale in terms of item 
performance, reliability, validity, and ability to detect change.  Of note, for the analyses specified 
in this section, only data at Baseline and Week 12 were used.  The following analyses were 
performed: 
Item Level Analysis Assessing Ceiling and Floor Effects: 
• A descriptive summary of the eight items in the UFS-QoL Symptom Severity Scale at 
Baseline was provided to examine item distributions and ceiling/floor effects.  Low 
ceiling effects (< 20%) and higher floor effects (> 20%) were expected at Baseline 


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due to symptom severity of patients with uterine fibroids enrolled in the phase 3 
studies. 
Internal Consistency: 
Internal consistency reliability was assessed for the BPD Scale at Baseline and Week 12 by 
calculating Cronbach’s alpha.  Generally, a Cronbach’s alpha coefficient (α) ≥ 0.7 indicates an 
acceptable level of internal consistency. 
Item Performance: 
• Intercorrelation of items that contribute to the BPD Scale by means of item-total 
correlation was determined. 
• Item discrimination index was assessed for each item based on 1) the BPD Scale 
scores at single time points, and 2) the change from Baseline to Week 12 in the BPD 
Scale score to determine the degree to which individual items were able to 
discriminate between less and more severe patients (Cappelleri, 2014). 
Known-Groups Validity: 
• Known-groups validity was assessed based on groups defined by Baseline PGA for 
symptoms severity (five levels).  Descriptive statistics of the BPD Scale will be 
provided for each severity level. 
Ability to Detect Change: 
Evidence that the new scale can identify differences in scores over time in individuals or groups 
who have changed with respect to the measurement concept will be investigated by providing the 
following descriptive statistics: 
• Within person change from Baseline to Week 12 in each item on the BPD Scale 
• Standardized effect size statistic (SES) for change from Baseline to Week 12 in each 
item scale.  The ability to detect change will be judged based on Cohen’s 
recommendations:  small change (SES = 0.20), moderate change (SES = 0.50), and 
large change (SES = 0.80). 
2.3. 
References 
Browne MW, Cudeck R. Alternative ways of assessing model fit. In: Bollen KA, Long JS (eds), 
Testing structural equation models (Vol. 154, pp. 136-162). 1993.  Newbury Park, CA: 
Sage Focus Editions.  
Cappelleri JC, Bushmakin AG. Interpretation of patient-reported outcomes. Stat Methods Med 
Res. 2014;23(5), 460–483.  
Hu LT, Bentler PM. Evaluating model fit. In: Hoyle RH (ed), Structural equation modeling: 
concepts, issues, and applications (pp. 76-99). 1995. Thousand Oaks, CA, US: Sage 
Publications, Inc.  
Kaiser HF. The application of electronic computers to factor analysis. Educ Psychol Meas. 
1960;20:141-151. 


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APPENDIX 3. DERIVATION AND VALIDATION OF THE UFS-QOL 
BLEEDING AND PELVIC DISCOMFORT SCALE 
Results described in this appendix are based on the analyses described in Appendix 2. 
3.1. 
Development of the Bleeding and Pelvic Discomfort Scale Using 
Exploratory and Confirmatory Factor Analysis 
Exploratory factor analysis was conducted on data from the phase 2 study TAK-385/CCT-001 
study (n = 216) and the arising factor structure was assessed in a confirmatory factor analysis 
using data from the phase 3 studies MVT-601-3001 and MVT-601-3002. 
3.1.1. 
Exploratory Factor Analysis Using Phase 2 Data 
Exploratory factor analysis results revealed a two-factor solution based on the Kaiser criterion 
(eigenvalues > 1) and factor loading > 0.40 criteria specified in the analysis plan (see 
Appendix 2).  Factor 1 and Factor 2 had eigenvalues of 3.394 and 1.196, respectively (Table 
3.1-1).  Three items were found to load adequately onto Factor 1 with loadings greater than 0.40:  
Item 1 (Heavy Bleeding during Your Period), Item 2 (Passing Blood Clots during Your Period), 
and Item 5 (Feeling Tightness or Pressure in Pelvis; see Table 3.1-2).  Two items loaded onto 
Factor 2 with loadings larger than the prespecified level:  Item 6 (Frequent Urination in Daytime) 
and Item 7 (Frequent Nighttime Urination).  Item 8 (Feeling Fatigued) showed a loading value 
on Factor 1 just below the prespecified threshold (0.399) and showed evidence of cross-loading 
with the Factor 2 (0.288).  An additional factor with a moderate eigenvalue (0.62) was 
considered based the scree plot (Figure 3.1-1) and factor loadings of its associated items (Item 3: 
Fluctuation in Duration of Menstruation, 0.416; Item 4: Fluctuation in Length of Monthly Cycle, 
0.995; Table 3.1-2). 
Overall the results show support for a seven-item three-factor model.  Due to multi-factor 
loading, Item 8 (Feeling Fatigued) remains a single-item symptom and is not scored as part of 
any factor. 


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Figure 3.1-1: Scree Plot and Variance Explained for UFS-QoL Symptom Severity Scale 
Factors in TAK-385/CCT-001 
 
 
Table 3.1-1: Exploratory Factor Analysis for the UFS-QoL Symptom Severity Scale in 
TAK-385/CCT-001 
Item 
Eigenvalue 
Difference 
Proportion 
Cumulative 
1 
3.394 
2.198 
0.816 
0.816 
2 
1.196 
0.576 
0.288 
1.104 
3 
0.620 
0.458 
0.149 
1.253 
4 
0.162 
0.332 
0.039 
1.292 
5 
-0.170 
0.114 
-0.041 
1.251 
6 
-0.284 
0.057 
-0.068 
1.183 
7 
-0.341 
0.079 
-0.082 
1.101 
8 
-0.419 
— 
-0.101 
1.000 
 
 
 


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Table 3.1-2: Factor Loadings for the UFS-QoL Symptom Severity Scale in 
TAK-385/CCT-001 
Items 
 
Factor1 
Factor2 
Factor3 
Q2 
Passing blood clots during your period 
0.763 
0.105 
0.073 
Q1 
Heavy bleeding during your period 
0.759 
0.091 
0.123 
Q5 
Feeling tightness or pressure in pelvis 
0.467 
0.175 
0.167 
Q8 
Feeling fatigued 
0.399 
0.288 
0.078 
Q6 
Frequent urination in daytime 
0.114 
0.965 
0.069 
Q7 
Frequent nighttime urination 
0.212 
0.630 
0.013 
Q4 
Fluctuation in length of monthly cycle 
0.039 
0.092 
0.995 
Q3 
Fluctuation in duration of menstruation 
0.178 
0.003 
0.416 
Extraction method: maximum likelihood.  Rotation method: orthogonal. 
 
3.2. 
Development of the Bleeding and Pelvic Discomfort Scale Using 
Confirmatory Factor Analysis Based on Phase 3 Data 
The exploratory factor structure arising from the phase 2 data was assessed using data from the 
phase 3 studies MVT-601-3001 and MVT-601-3002. 
Analyses were based on pooled, blinded data from the first one third of patients enrolled in the 
two phase 3 studies of relugolix in uterine fibroids (MVT-601-3001 and MVT-601-3002), who 
completed the patient global assessment of symptoms (PGA) and the Uterine Fibroid Symptom 
and Health-Related Quality of Life (UFS-QoL) at Baseline and at Week 24. 
3.2.1. 
Confirmatory Factor Analysis using Phase 3 Data 
A confirmatory factor analysis was completed using blinded data from one third of phase 3 
patients.  The acceptance criteria of the confirmatory factor analysis were prespecified as a 
Goodness of Fit Index > 0.90 and a Comparative Fit Index > 0.90, a root mean square error of 
approximation < 0.06 and a non-significant p-value to show that the null-hypothesis that the data 
fits the three-factor model was not rejected (Table 3.2-1). 
Factor loadings for the seven-item three-factor model supported the three-factor solution 
proposed by the exploratory factor analysis in the above described analyses using phase 2 data.  
Results indicated that the three-factor model, excluding item 8, had a Goodness of Fit Index and 
a Comparative Fit Index of 1.00 and a root mean square error of approximation of 0.00  
(90% CI = 0.00-0.02).  The test of model fit returned a p-value of 0.9394.  The null hypothesis 
that the data fit the model was not rejected (see Table 3.2-1).  Under this model, Item 5 (Feeling 
Tightness or Pressure in Pelvis) also cross-loaded onto Factor 2, assessing urinary symptoms. 


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Table 3.2-1: Confirmatory Factor Analysis of the UFS-QoL Symptom Severity Scale 
without Item 8: Model Fit Statistics at Baseline (MVT-601-3001 and -3002) 
Abbreviations:  CFI, comparative fit index; CI, confidence interval; GFI, goodness of fit index; RMSEA, root mean 
square error approximation. 
a Model fit statistics allow for assessment of the model appropriateness. 
b Rotation Method: Orthogonal. 
 
In order to further assess the performance of the Fatigue item, which was excluded following the 
exploratory factor analysis due to cross-loading, the confirmatory factor analysis was 
reconducted with the inclusion of this item in Factor 1.  Results showed that the eight-item three-
factor model had a Goodness of Fit Index of 0.996, a Comparative Fit Index of 1.00 and a root 
mean square error of approximation of 0.00 (90% CI = 0.00-0.05).  The test of model fit returned 
a p-value of 0.8056.  However, the results for Item 8 showed a cross-loading of this item at 0.417 
on Factor 1 and 0.437 on Factor 2 (Table 3.2-2).  This continued cross-loading supports the 
exclusion of this item in the scoring of any factor (Table 3.2-2). 
Model Fit Statisticsa 
Model 
CFI 
RMSEA (90%CI) 
GFI 
P-value 
3-Factor Model (7-item) 
1.000 
0.000 (0.00-0.02) 
1.000 
0.9394 
Factor Loadingb 
 
Factor1 
Factor2 
Factor3 
Q1 
Heavy bleeding during your period 
0.7314 
0.2672 
0.2024 
Q2 
Passing blood clots during your period 
0.7620 
0.1503 
0.2099 
Q3 
Fluctuation in duration of menstruation 
0.3263 
0.1861 
0.6909 
Q4 
Fluctuation in length of monthly cycle 
0.1689 
0.1561 
1.0323 
Q5 
Feeling tightness or pressure in pelvis 
0.4644 
0.4657 
0.1965 
Q6 
Frequent urination in daytime 
0.2503 
0.7727 
0.1300 
Q7 
Frequent night time urination 
0.1553 
0.8605 
0.1538 


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Table 3.2-2: Confirmatory Factor Analysis of the UFS-QoL Symptom Severity Scale with 
Item 8 included: Model Fit Statistics at Baseline (MVT-601-3001 and 3002) 
Abbreviations:  CFI, comparative fit index; CI, confidence interval; GFI, goodness of fit index; Q, question; 
RMSEA, root mean square error of approximation. 
a  Model fit statistics allow for assessment of the model appropriateness. 
b  Rotation Method: Orthogonal. 
 
3.3. 
Classical Test Theory Psychometric Analyses of the Bleeding and 
Pelvic Discomfort Scale Based on Phase 3 Data 
Each of the above-described factor analyses showed that a seven-item three-factor solution was 
appropriate for the UFS-QoL Symptom Severity Scale.  Following this confirmation, blinded 
psychometric appraisal of the measure was implemented to further understand the performance 
of the items and subscales of the UFS-QoL Symptom Severity Scale.  For the item level analysis, 
all items were assessed.  For subscale level analysis, the analysis was focused, primarily, on the 
evaluation of the Factor 1 – the Bleeding and Pelvic Discomfort (BPD) Scale.  The BPD Scale 
was selected as the primary focus for further psychometric evaluation, as it presents clinical and 
patient-reported symptoms proximal to the disease and is associated with high symptom burden 
experienced by most patients. 
Analyses were based on pooled, blinded data from the first one third of patients enrolled in the 
two phase 3 studies of relugolix in UF (MVT-601-3001 and MVT-601-3002) who completed the 
PGA for symptoms and the UFS-QoL at Baseline and at Week 24.  Of note, for the analyses 
specified in this section, only data at Baseline and Week 12 were used. 
3.3.1. 
Item Level Analysis of the UFS-QoL Symptom Severity Scale 
UFS-QoL Symptom Severity Scale item responses were assessed for floor (highest possible 
severity) and ceiling effects (lowest possible severity).  Overall, the measure showed no ceiling 
effects (response option 1, Table 3.3-1, demonstrating that the items have scope to capture 
Model Fit Statisticsa 
Model 
CFI 
RMSEA (90%CI) 
GFI 
P-value 
3-Factor Model (8-item) 
1.000 
0.000 (0.00-0.05) 
0.996 
0.8056 
Factor Loadingb 
 
Factor1 
Factor2 
Factor3 
Q1 
Heavy bleeding during your period 
0.732 
0.265 
0.211 
Q2 
Passing blood clots during your period 
0.750 
0.150 
0.226 
Q3 
Fluctuation in duration of menstruation 
0.296 
0.175 
0.767 
Q4 
Fluctuation in length of monthly cycle 
0.180 
0.167 
0.932 
Q5 
Feeling tightness or pressure in pelvis 
0.473 
0.465 
0.206 
Q6 
Frequent urination in daytime 
0.251 
0.757 
0.137 
Q7 
Frequent night time urination 
0.150 
0.876 
0.156 
Q8 
Feeling fatigued 
0.417 
0.437 
0.136 


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patient improvement in disease burden.  A greater proportion of patients responded at floor level 
(response option 5; range =11.15 to 36.15%), which is expected at the start of a clinical trial.  All 
response options for all items were used, showing a good coverage of the range of disease 
burden.  When considering BPD Scale items, all items showed a range of responses that covered 
the response scale, with over 50% of patients reporting being a (very) great deal distressed by 
heavy bleeding during menstrual period (Item 1), passing blot clots during menstrual period 
(Item 2), and feeling of tightness or pressure in the pelvic area (Item 5). 
 


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Table 3.3-1: Summary of UFS-QoL Symptom Severity Scale Response at Baseline by Items in MVT-601-3001 and 3002 
Response 
Q1 
(N = 260) 
Q2 
(N = 260) 
Q3 
(N = 260) 
Q4 
(N = 260) 
Q5 
(N = 260) 
Q6 
(N = 260) 
Q7 
(N = 260) 
Q8 
(N = 260) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
n 
(%) 
1 
4 
(1.54%) 
4 
(1.54%) 
44 
(16.92%) 
63 
(24.23%) 
21 
(8.08%) 
48 
(18.46%) 
54 
(20.77%) 
13 
(5.00%) 
2 
15 
(5.77%) 
30 
(11.54%) 
48 
(18.46%) 
37 
(14.23%) 
24 
(9.23%) 
35 
(13.46%) 
53 
(20.38%) 
21 
(8.08%) 
3 
53 
(20.38%) 61 
(23.46%) 
66 
(25.38%) 
69 
(26.54%) 
57 
(21.92%) 
77 
(29.62%) 
64 
(24.62%) 
59 
(22.69%) 
4 
101 
(38.85%) 71 
(27.31%) 
64 
(24.62%) 
62 
(23.85%) 
96 
(36.92%) 
62 
(23.85%) 
55 
(21.15%) 
82 
(31.54%) 
5 
87 
(33.46%) 94 
(36.15%) 
38 
(14.62%) 
29 
(11.15%) 
62 
(23.85%) 
38 
(14.62%) 
34 
(13.08%) 
85 
(32.69%) 
Abbreviations:  N, number of patients; n, number of patients in subset; Q, question. 
 


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3.3.2. 
Scale Level Analysis of the BPD Scale  
3.3.2.1. 
Internal Consistency 
Internal consistency was assessed for the BPD Scale at Baseline and Week 12.  Reliability was 
acceptable at Baseline (> 0.70) and good at Week 12 (> 0.80; Table 3.3-2). 
Table 3.3-2: Cronbach’s Alpha Coefficient of BPD Scale by VISIT (MVT-601-3001 and 
3002) 
 
n 
Q1 
Q2 
Q3 
Alphaa 
Mean (SD) 
Mean (SD) 
Mean (SD) 
Baseline 
260 
3.97 (0.95) 
3.85 (1.09) 
3.59 (1.18) 
0.768 
Week 12 
258 
2.75 (1.47) 
2.69 (1.46) 
2.64 (1.36) 
0.882 
Abbreviations:  n, number of patients; Q, question; SD, standard deviation. 
a Cronbach Coefficient Alpha 
3.3.2.2. 
Item-to-Total Correlations 
Item-to-total correlations were assessed to ensure that each item was associated with the BPD 
Scale score.  Correlations demonstrate that each of the items have a strong relationship with the 
total score at Baseline and at Week 12 (r > 0.50) (Table 3.3-3).  Correlations improved at Week 
12, which represents a greater spread of the data across each item’s five-point response scale, 
further supporting the relationship of these items to the BPD total score. 
Table 3.3-3: Intercorrelation of Items in BPD Scale by Visit (MVT-601-3001 and 3002) 
Question 
Baseline 
N = 260 
Week 12 
N = 258 
Q1 
0.670 
0.802 
Q2 
0.620 
0.845 
Q5 
0.533 
0.674 
Note:  Intercorrelation calculated using Pearson’s correlations. 
3.3.2.3. 
Item Discrimination Indices 
An item discrimination index was employed to assess the ability of each item to discriminate 
between high and low severity patients.  At Baseline, the discrimination index represents each 
item’s ability to differentiate patients on the BPD Scale scores at a single time point, and at 
Week 12, the discrimination index represents the ability to differentiate patients based on their 
level of change from Baseline to Week 12 in the BPD Scale score. 
Results show that all items had a discrimination index above 0.60, demonstrating that BPD Scale 
items are able to discriminate between high- and low-severity patients both when assessing 
single time point scores and change over time (Table 3.3-4). 


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Table 3.3-4: Item Discrimination Index of BPD Scale (MVT-601-3001 and 3002) 
 
Q1 
Q2 
Q5 
Baseline (n = 260) 
0.815 
0.954 
0.923 
Week 12 (n = 258) 
0.915 
0.986 
0.836 
Abbreviations:  n, number of patients; Q, question. 
Note:  BPD scale upper/lower ranges: Upper = at least 65-point reduction, Lower = at most 10-point reduction. 
3.3.2.4. 
Known-Groups Validity 
A known-groups analysis assessed the descriptive BPD score and score ranges for patients 
stratified by level of severity reported on the PGA (symptoms).  Results from the known-groups 
validity assessment show that mean and median BPD Scale scores increase monotonically in line 
with PGA symptom severity (Table 3.3-5). 
3.3.2.5. 
Ability to Detect Change 
The BPD Scale’s ability to detect change was assessed though the difference in BPD Scale 
scores over time in patients who have changed with respect to the measurement concept as 
measured by the PGA (symptoms).  For each PGA stratified group, within person change from 
Baseline to Week 12 and standardized effect size statistics (SES) for change over the same 
period were assessed.  SES statistics judged were based on Cohen’s recommendations (small 
change, 0.20; moderate change, 0.50; large change, 0.80). 
Results showed that the mean change for improving PGA categories had a monotonically 
increasing pattern from patients who had a PGA change of 0 to patients who had a PGA 
improvement of -4 (Table 3.3-6).  Worsening groups (PGA change of +1 or +2) had very low 
levels of mean change, with wide standard deviations around the mean due to the low sample 
size in these categories. 
In line with expectations, the SES statistics for the improvement categories (PGA score change 
of -1 to -4) were large (> 0.80) compared to the moderate SES found in the patients who reported 
no change (PGA score change of 0; SES = 0.55). 
 


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Table 3.3-5: Summary Statistics of BPD Scale Score at Baseline by PGA (symptoms) Response (MVT-601-3001 and 3002) 
Baseline BPD Scale Scorea 
Baseline PGA 
N 
Mean 
SD 
Median 
Q1, Q3 
Min 
Max 
1 
7 
53.57 
28.81 
58.33 
25.00, 75.00 
16.67 
91.67 
2 
21 
59.92 
26.56 
58.33 
41.67, 75.00 
8.33 
100.00 
3 
96 
62.33 
21.18 
66.67 
41.67, 75.00 
8.33 
100.00 
4 
89 
75.09 
19.48 
75.00 
66.67, 91.67 
16.67 
100.00 
5 
47 
83.51 
16.53 
91.67 
75.00, 100.00 
41.67 
100.00 
Abbreviations:  BPD, bleeding and pelvic discomfort; max, maximum; min, minimum; N, number of patients; PGA, Patient Global Assessment; Q1, first 
quartile; Q3, third quartile; SD, standard deviation. 
a  Transformed Score. 
Table 3.3-6: Summary Statistics of Change from Baseline BPD Scale Score to Week 12 by PGA (symptoms) Change from 
Baseline (MVT-601-3001 and 3002) 
PGA Change Categorya 
N 
Mean 
SD 
95% CI 
Median 
Q1, Q3 
Min 
Max 
Effect Sizeb 
-4 
23 
-48.19 
(42.27) 
(-66.47, -29.91) 
-66.67 
-83.33, 0.00 
-100.00 
25.00 
-2.93 
-3 
50 
-49.33 
(33.16) 
(-58.76, -39.91) 
-54.17 
-75.00, -25.00 
-100.00 
33.33 
-2.41 
-2 
74 
-27.70 
(30.75) 
(-34.83, -20.58) 
-25.00 
-41.67, 0.00 
-91.67 
25.00 
-1.25 
-1 
48 
-23.09 
(28.57) 
(-31.39, -14.79) 
-16.67 
-33.33, -8.33 
-100.00 
33.33 
-1.01 
0 
39 
-10.68 
(20.32) 
(-17.27, -4.10) 
-8.33 
-25.00, 0.00 
-66.67 
33.33 
-0.55 
1 
14 
1.79 
(19.11) 
(-9.25, 12.82) 
-4.17 
-16.67, 8.33 
-16.67 
33.33 
0.07 
2 
6 
-1.39 
(29.54) 
(-32.39, 29.61) 
-12.50 
-25.00, 16.67 
-25.00 
50.00 
-0.05 
Abbreviations:  BPD, blood and pelvic discomfort; CI, confidence interval; max, maximum; min, minimum; N, number of patients; PGA, Patient Global 
Assessment; Q1, first quartile; Q3, third quartile; SD, standard deviation. 
Note:  Statistics calculated using transformed score of BPD scale. 
a The PGA is a five-point, single item patient-reported outcomes tool that measures patient’s symptoms.  The PGA change category with -4 = Marked 
Improvement; 0 = No Change, +4 = Markedly Worse. 
b Standardized effect sizes are calculated as the mean divided by the standard deviation. 


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3.4. 
Conclusions 
The exploratory factor analysis offered support for a three-factor solution, which included factors 
assessing Bleeding and Pelvic Discomfort, Urinary Symptoms, and Fluctuation in Menstruation.  
The Fluctuations in Menstruation factor had an eigenvalue < 1 but had items that loaded at 
greater than 0.40 and made theoretical sense as a construct. 
The exploratory factor analysis showed that Item 8, measuring fatigue, cross-loaded on two 
factors (Bleeding and Pelvic Discomfort and Urinary Symptoms).  Since fatigue is a 
multidimensional concept that can assess impacts and/or symptoms concurrently, it was not 
included in the final factor structure.  Confirmatory factor analysis on the seven-item three-factor 
solution provided support for the exploratory factor structure; however, Item 5 cross-loaded 
between the BPD and Urinary Symptoms factors in this analysis.  As Item 5 (Feeling Tightness 
or Pressure in Pelvis) is a proximal symptom of uterine fibroids, this item was retained as part of 
the BPD factor. 
To ensure that fatigue was not being inappropriately excluded from the three-factor structure, an 
additional confirmatory factor analysis was conducted with fatigue included within the BPD 
factor.  The inclusion of fatigue in this model continued to show the expected cross-loading of 
this item.  This analysis confirmed that the multidimensional concept of fatigue was not suitable 
for inclusion in the BPD factor. 
The BPD factor, which assesses symptomology most proximal to the disease, was further 
assessed through classical test theory psychometric evaluation.  The results showed that the items 
of the BPD Scale work cohesively to inform the total score of the measure, and adequately 
distinguish between severities.  At a score level, descriptive statistics were able to support the 
construct validity and responsiveness of the BPD Scale through showing a monotonic 
improvement in BPD Scale score in line with patient self-reported improvement on the PGA 
(symptoms).  Additionally, by showing that the items of the BPD Scale perform well together, 
the psychometric results help to further support the inclusion of the cross-loading Item 5 on the 
BPD Scale. 
 


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APPENDIX 4. APPROACH TO ESTIMATING THE RESPONDER 
THRESHOLD OF THE UFS-QOL BLEEDING AND 
PELVIC DISCOMFORT SCALE  
The Uterine Fibroid Symptom and Health-Related Quality of Life Bleeding and Pelvic 
Discomfort (UFS-QoL BPD) Scale includes the following items:  
During the previous 3 months, how distressed were you by:  
• Heavy bleeding during your menstrual period;  
• Passing blood clots during your menstrual period;  
• Feeling tightness or pressure in your pelvic area.  
Response options include:   
• Not at all;  
• A little bit;  
• Somewhat;  
• A great deal;  
• A very great deal.   
The summary score of the three items included in the UFS-QoL BPD Scale ranges from 0 to 100, 
where a higher score indicates a higher level of distress and a lower score indicates a lower level 
of distress.  
Change from Baseline to Week 24 in the BPD Scale score is an alpha-protected key secondary 
endpoint of the pivotal studies (MVT-601-3001 and MVT-601-3002) to evaluate the treatment 
benefit of relugolix + E2/NETA (Group A) compared with placebo (Group C).  Additionally, a 
responder analysis will be performed between the two groups with respect to proportion of 
patients who have achieved a meaningful reduction from Baseline to Week 24 in BPD Scale 
score. This appendix describes the approach used to derive the responder threshold, including 
both the quantitative and supportive qualitative methods and the respective results. 
The meaningful change threshold is the smallest reduction in the BPD Scale score that is 
considered meaningful by patients (Cohen, 1988; Crosby, 2003; Revicki, 2008; Cappelleri, 2014; 
Coon, 2018).  The magnitude of a meaningful change threshold depends on the magnitude of the 
correlation between the BPD Scale change score and the Patient Global Assessment (PGA) of 
symptom severity (anchor) change and the variability of change on the BPD Scale by 
improvement categories on the PGA of symptom severity (described in Section 4.2.2).  Several 
anchor-based methods will be used; however, the primary analysis will be a measure of central 
tendency for each improvement category (see Section 4.2.3).  Anchor-based methods will use 
data collected on: 
• The BPD Scale score at Baseline and Week 24; and 
• The PGA of symptom severity score at Baseline and Week 24. 
Results from the anchor-based analyses will be supported by qualitative data collected in a 
patient interview study (MVT-601-037), a sub-study of the phase 3 trials, in which patients from 


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selected sites in the United States (US) provided feedback on what they considered to be a 
meaningful change on the BPD Scale and the PGA of symptom severity (described in 
Section 4.2.4). 
4.2. 
Statistical Analyses Plan for Estimation of the Responder Threshold 
4.2.1. 
Anchor and Its Correlation with UFS-QoL Endpoint 
The PGA of symptom severity uses a five-point verbal rating scale and asks the patient:   
“How severe were your uterine fibroids symptoms, such as heavy bleeding over the last four 
weeks?” 
Response options include:   
• Not severe; 
• Mildly severe; 
• Moderately severe; 
• Very severe; 
• Extremely severe. 
The categorical change from Baseline to Week 24 in PGA of symptom severity score will be 
derived, leading to nine possible outcomes ranging from +4 (denoting worsening) to -4 (denoting 
improvement).  The change in PGA of symptom severity at Week 24 will be used as the anchor 
(see Table 4.2-1).   
4.2.2. 
Target Anchor Category 
The target anchor category is the anchor category that represents the minimum meaningful 
change and is used as the starting point to identify potential candidates for a meaningful change 
threshold.  For the two pivotal studies, the target anchor category will be a one-point category 
improvement on the PGA of symptom severity score (see Table 4.2-1), as this is typically 
considered as a minimal clinical important difference on a five-point Likert scale.   
Table 4.2-1: Change in PGA of Symptom Severity as Anchor 
Anchor 
Anchor Change Category 
Potential Target Anchor Change Category  
(To Be Used for Estimation of Meaningful 
Change Threshold) 
Change in PGA of 
symptom severity  
-4, -3, -2, -1 (improvement), 
0 (same), 
+1, +2, +3, +4 (worsening) 
-1-category change 
(improvement)   
Abbreviations:  PGA = patient global assessment. 
 


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4.2.3. 
Anchor-Based Methods 
To determine the meaningful change threshold for the reduction in USF-QoL BPD Scale score, 
the anchor-based analyses described below will be performed. 
The category (or point) change in PGA of symptom severity score will be used as the anchor to 
classify patients into response groups depending on their level of symptom severity change from 
Baseline to Week 24 (see Table 4.2-1).  Uncollapsed, categorical change on the PGA will range 
from +4 to -4.  Collapsed, categorical change will be considered based on the distribution of 
change categories on the PGA of symptom severity.  Usually the collapsing occurs on the tails 
with extreme worsening (+4) or improvement (-4). 
Among the anchor-based analyses described below, the within-group analysis will be primary 
and other analyses (including between-group analysis) are supportive.  
4.2.3.1. 
Correlation with Anchor 
Correlation between the categorical change on the PGA of symptom severity score and the 
change in the BPD Scale score will be evaluated at Week 24, using blinded pooled data from the 
first third of the enrolled patients from the two pivotal studies who have completed Week 24 
visits and have the corresponding PGA of symptom severity data available (denoted as the 
“threshold determination analysis set”).  Polyserial correlation coefficient will be used with a 
criteria value of > 0.30 indicating meaningful correlation (Crosby, 2003; Revicki, 2008; 
Cappelleri, 2014; Coon, 2018).   
4.2.3.2. 
Within-Group Meaningful Change 
Magnitude of change from Baseline to Week 24 in BPD Scale score will be calculated within 
each anchor category group.  Changes in BPD Scale scores are negative for symptom reductions 
and positive for symptom increases. 
Descriptive statistics (n, mean change, median change, 25th and 75th percentiles, standard 
deviation [SD], confidence interval [CI], and standardized effect size [SES]) will be reported for 
the changes in BPD Scale scores by anchor category.  The SES will be calculated for each level 
of anchor category group by dividing the mean change score of BPD Scale from Baseline by the 
Baseline SD of the anchor category group.  The impact of treatment will be judged based on 
Cohen’s recommendations (1988):  small change (SES = 0.20), moderate change (SES = 0.50), 
and large change (SES = 0.80).  Significance associated with within-patient change will be 
evaluated using paired t-tests on the change in BPD Scale score separately for each level of 
improvement on the anchor. 
4.2.3.3. 
Supportive Analysis of Between Group Meaningful Change Using Analysis of 
Variance 
Analysis of variance (ANOVA) will be used to determine whether a difference in mean change 
scores from Baseline to Week 24 on the UFS-QoL BPD Scale exists between the categorical 
change groups (or the collapsed groups, as appropriate).  Providing there is a significant change 
in UFS-QoL BPD Scale scores between the (collapsed) anchor groups, the between-group 
differences will be explored.  Any anchor group with at least 15 patients will be included in this 
analysis.  An anchor group with < 15 patients (usually occurring on the tails with extreme 


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worsening [+4] or improvement [-4]) will be collapsed with its adjacent group as appropriate.  
Comparison of the anchor groups of interest between the target anchor (-1 change category) and 
the “0 change” category will be performed using a t-test.  The statistically significant difference 
on the BPD Scale change scores corresponding to a 1-category change on the PGA of symptom 
severity can be used as supportive information for estimating the meaningful change threshold. 
4.2.3.4. 
Visualizing Cumulative Distribution Function and Probability Distribution 
Function Plots by Anchor Category Group 
Anchor-based meaningful change will also be evaluated using cumulative distribution function 
(CDF) plots utilizing the Kernel smoothing for all anchor category groups, based on cumulative 
change in UFS-QoL BPD Scale scores for all available changes from Baseline to Week 24.  
Specifically, the CDF plot for each anchor category displays the probability (presented on the y-
axis) of patients who have achieved a given absolute change of X or less in BPD Scale score 
from Baseline to Week 24 for each point change along the range of possible absolute changes 
(from -100 [maximum reduction] to 0 [no change] to 100 [maximum increase]) expressed on the 
x-axis. 
Similarly, the smooth probability density function (PDF) will also be plotted for each anchor 
category group over the range of absolute changes in BPD Scale scores.  These probabilities are 
plotted on the y-axis, with the BPD Scale change score on the x-axis. 
The CDF and PDF curves are delineated by anchor improvement category (from -4 to +4) 
displaying the center and separation between the curve for the target anchor group and the curve 
for the group reporting no change on PGA of symptom severity.  It is expected that the CDF 
curves will not cross between the change category groups (eg, monotonic increase from no 
change to slightly improved and moderately improved). 
4.2.4. 
Determining a Meaningful Change Threshold Using the Totality-of-Evidence 
Approach 
The meaningful change threshold will be determined using the totality of evidence from the 
results of above quantitative anchor-based analyses; results from the interview study 
(MVT-601-037) will be used as supportive evidence. 
The results of these analyses and proposed thresholds will be included into the Patient-Reported 
Outcome dossier to be submitted at the time of filing. 
4.3. 
Results from Anchor-Based Analyses  
4.3.1. 
Correlation of Change in BPD with PGA of Symptom Severity 
Meaningful change for the UFS-QoL BPD Scale was derived based on anchor-based methods, 
supported by cumulative distribution function (CDF) and probability density function (PDF) 
curves.  To assess the suitability of the selected anchor, PGA of symptom severity, a polyserial 
correlation was calculated between change on the PGA from Baseline to Week 24 and the 
change from Baseline to Week 24 on the BPD Scale.  The change in the PGA was moderately 
correlated (r = 0.57) with the change on the BPD Scale (Table 4.3-1).  Given that the PGA is less 
complex than the BPD scale, this result indicates that the PGA is a suitable anchor for the BPD 
Scale. 


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4.3.2. 
Improvement on BPD Scale by PGA Change Category 
Uncollapsed changes on the PGA were used to determine minimal meaningful improvement on 
the BPD Scale (Table 4.3-1).  Improvement on the BPD Scale increased monotonically for all 
the categories from “no change (0)” to “1-category improvement (-1)” to “2-category 
improvement (-2)” to “3 category improvement (-3)” with nonoverlapping 95% CIs for mean 
change of the groups.  Table 4.3-1 shows further that a 1-category improvement (-1) is 
associated with a 27.31-point mean improvement in the BPD Scale score at Week 24 compared 
with Baseline, with a 95% CI [-35.42, -19.19], a large SES = -1.21, and a median improvement 
of 25.00 points. 
Table 4.3-1: Summary of Change from Baseline to Week 24 in UFS-QoL BPD Scale by 
PGA for Symptom Severity Change Category (mITT Population) 
PGA Change 
Category 
N = 255 
Change in BPD 
Correlation 
between PGA 
Change and 
BPD Changea 
Mean (SD) 
Median 
95% CI 
p-
valueb 
SESc 
4-Category 
deterioration (+4) 
0 
 
 
 
 
 
0.57 
3-Category 
deterioration (+3) 
2 
-12.50 (5.89) 
-12.5 
-65.44, 40.44 
0.2048 
-2.12 
2-Category 
deterioration (+2) 
2 
0.00 (11.79) 
0 
-105.89, 105.88 
1.00 
  0.0 
1-Category 
deterioration (+1) 
21 
-10.32 (16.22) 
-8.33 
-17.70, -2.93 
0.0086 
-0.54 
0-Category 
deterioration (0) 
47 
-9.93 (23.09) 
-8.33 
-16.71, -3.15 
0.005 
-0.42 
1-Category 
improvement (-1) 
47 
-27.31 (27.62) 
-25.00 
-35.42, -19.19 
< 0.0001 
-1.21 
2-Category 
improvement (-2) 
68 
-42.16 (25.71) 
-41.67 
-48.38, -35.93 
< 0.0001 
-1.93 
3-Category 
improvement (-3) 
45 
-61.85 (26.62) 
-66.67 
-69.85, -53.85 
< 0.0001 
-3.25 
4-Category 
improvement (-4) 
23 
-54.35 (32.65) 
-66.67 
-68.47, -40.23 
< 0.0001 
-4.12 
Abbreviations:  BPD = bleeding and pelvic discomfort; CI = confidence interval; mITT = modified intent-to-treat; 
PGA = patient global assessment; SD = standard deviation; SES = standardized effect size. 
mITT is used to calculate change from Baseline score at Week 24 and includes patients from the mITT population 
who have available change from Baseline data at Week 24. 
a Polyserial correlation coefficient between change in BPD Scale and change in PGA of symptom severity. 
b The p-value for each individual change group is derived from a paired (within-sample) t-test assessing the 
difference over time. 
c SES is calculated as the mean divided by the SD of Baseline.  SES is judged as small = 0.2, moderate = 0.5, and 
large = 0.8 (Cohen 1988). 
 
Table 4.3-2 highlights that the difference between the “1-category improvement” and the “no 
change” groups (mean = -17.38 with a 95% CI of [-27.81, -6.94]) was statistically significant 
(p = 0.0013) and had a moderate SES = -0.736, which also supports the notion that patients 
interpreted these change categories as distinct. 
Patients were able to distinguish between the PGA improvement categories, as demonstrated by 
the nonoverlapping CIs (in Table 4.3-2) for their UFS-QoL BPD Scale scores and as illustrated 


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by the clear separation between the CDF curves presented in Figure 4.3-1.  Since statistically 
significant differences existed in patient responses on the BPD Scale between the “1-category 
improvement (-1)” option and the “no change” and “2-category improvement (-2)” options, a 1-
category improvement on the PGA was considered a meaningful target anchor category for 
assessing the responder threshold on the BPD Scale.  Although a 2-category improvement could 
have been considered for deriving the meaningful change threshold, such a threshold would not 
qualify as being the minimum threshold possible.  Given the statistical difference between the 1- 
and 2-category improvements and the fact that patients were able to distinguish between the two 
response options (to be taken up shortly), the evidence supports using a 1-category improvement 
on the PGA for estimating the minimum meaningful change threshold.  This decision is also 
supported by qualitative evidence generated from the Exit Interview study (see Section 4.2.4). 
Table 4.3-2: Summary of Change from Baseline to Week 24 in BPD Scale Between Target 
Anchor (-1) and No Change (0) in PGA of Symptom Severity (mITT 
Population) 
Anchor 
Categorical Change 
N 
Mean 
Change 
from BL 
SD 
95% CI 
p-valuea 
Baseline 
SD 
SES 
PGA 
1-category improvement (-1) 
47 
-27.31 
27.62 
-35.42, -19.19 
 
22.63 
 
 
No change (0) 
47 
-9.93  
23.09 
-16.71, -3.15 
 
23.61 
 
 
Difference  
 
-17.38 
25.46 
-27.81, -6.94 
0.0013 
 
-0.736b 
-0.790c 
Abbreviations:  ANOVA = analysis of variance; BL = Baseline; BPD = bleeding and pelvic discomfort; 
CI = confidence interval; mITT = modified intent-to-treat; PGA = patient global assessment; SD = standard 
deviation; SES = standardized effect size. 
a The p-value is based on t-test for difference in mean change in BPD score between the 2 anchor groups (-1 and 0) 
from the ANOVA in which the +2, +3, and +4 groups were collapsed with the +1 group due to 0 or few patients in 
the respective groups. 
b SES is calculated as the mean difference divided by the SD of Baseline for no change group.  They are judged as 
small = 0.2, moderate = 0.5, and large = 0.8 (Cohen 1988). 
c SES calculated as the mean difference divided by the standard deviation of Baseline for pooled from all categories 
(Glass 1976). 
4.3.3. 
Estimation of Responder Threshold 
Examination of the PDF curves, presented in Figure 4.3-1, indicates that the dispersion is 
roughly the same for the options between “> 3 category improvement” and “no change.”  The 
crossing of the “no change” and “1-category improvement” PDF curves at approximately -24 
points (ie, a 24-point improvement on the BPD between Baseline and Week 24) indicates the 
meaningful change threshold is greater (less negative) than this value, because to the left of the 
value the “1-category improvement” was more probable than the “no change” curve.  That is, to 
the left of this point (larger improvements) patients were more likely to be responders than to the 
right of this point.  However, since the goal is to establish the minimum meaningful change 
threshold, the value -24 points is likely too conservative. 
Using the mean or median values for measuring improvement in the BPD Scale would also yield 
estimates that are too conservative, because expected values do not necessarily constitute a 
minimum meaningful change threshold for patients.  That is, nearly half the patients stratified in 


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the PGA “1-category improvement” who reported changes smaller than (to the right of) the mean 
or median on the BPD Scale would be classified as nonresponders by using the mean or median 
as the threshold despite of their reporting “1-category improvement.”  A less conservative, 
though still plausible estimate for the minimal meaningful change threshold is the upper bound 
of the 95% CI for mean change in the “1-category improvement” group.  Its use will result in a 
smaller proportion of patients being classified as nonresponders in change on the BPD Scale than 
the expected value (ie, the mean).  According to the uncollapsed anchor-based analysis 
(Table 4.3-1), this value is approximately -19 (ie, a 19-point improvement on the BPD Scale 
between Baseline and Week 24).  Selection of this value is supported by the fact that the mean 
changes are statistically significantly different (Table 4.3-2) between “no change” and 
“1-category improvement” groups with clear separation of the respective 95% CIs for mean 
change.  Of note, a value as low as -17 could also be selected, since it is less than the lower-
bound 95% CI estimate of -16.71 for the “no change” group. 
Figure 4.3-1: PDF of the Change in UFS-QoL BPD Scale by PGA Anchor Change 
Category (Collapsed) 
 
Abbreviations:  BPD = bleeding and pelvic discomfort; PGA = patient global assessment; UCL = upper confidence 
limit. 
 
Examination of the CDF curves for the potential minimum meaningful threshold value of -19 
points on the BPD Scale allows one to estimate the cumulative percent of patients that would 


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experience the improvement.  As illustrated in Figure 4.3-2, approximately 35% of the “no 
change” group and 61% of the “1-category improvement” group experienced at least a 19-point 
improvement on the BPD Scale by Week 24.  The high percent of patients in the “no change” 
group who improved on the BPD Scale by Week 24 indicates that setting the minimum 
meaningful change threshold at 19 points may be too liberal.  The percent of misclassified 
responders can be improved by selecting a slightly larger value.  Setting the minimum 
meaningful change threshold at 20-point improvement on the BPD Scale would decrease slightly 
the percent of misclassified responders for the “no change” group to 33% while decreasing 
slightly the percent of patients classified as responders to 60% for the “1-category improvement” 
group.  As supportive information, the empirical CDFs were step-curves (reflecting the discrete 
nature of the BPD scores) are provided (Figure 4.3-3), indicating that smooth curves are 
reasonably close to the empirical CDFs.   
Figure 4.3-2: Cumulative Distribution Function of Change at Week 24 in UFS-QoL BPD 
Scale Score by PGA Anchor Change Category (Collapsed) 
 
Abbreviations:  BPD = bleeding and pelvic discomfort; PGA = patient global assessment. 


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Figure 4.3-3: Empirical Cumulative Distribution Function of Change at Week 24 in 
UFS-QoL BPD Scale Score by PGA Anchor Change Category (Collapsed) 
 
Abbreviations:  BPD = bleeding and pelvic discomfort; PGA = patient global assessment. 
 
4.4 
Exit Interview Study Synthesis  
4.4.1 
Objectives 
The objectives of the exit interviews were to: 1) provide qualitative evidence to understand 
meaningful change for patients following clinical intervention and 2) to elicit data on what 
patients consider to be a minimum meaningful improvement on different patient-reported 
outcomes (PROs), including: 
• The UFS-QoL BPD Scale, 
• The PGA symptoms severity. 
These objectives were achieved through conducting web/Internet-based video or telephone 
interviews with English-speaking patients in the US within 3 to 14 days after their Week 24 visit 
of either ongoing phase 3 clinical study (MVT-601-3001 [LIBERTY 1] or MVT-601-3002 
[LIBERTY 2]). 
Minimum meaningful improvements on other PROs were also explored as part of the exit 
interview study; results of the respective exercises will be included in the full report for this exit 
interview study.  


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4.4.2 
Methodology – Qualitative Interviews 
The exit interviews were conducted via a web/Internet-based video platform (Doxy.me 
[https://doxy.me/]) or via telephone by trained and experienced Endpoint Outcomes interviewers.  
In the event that a patient did not improve by at least 1 point from Baseline Day 1 to Week 24 
based on her PGA of symptom severity scores, meaningful change exercises were not conducted 
for any of the PROs.  An improvement on the PGA of symptom severity was required so that 
patients could provide contextually relevant feedback related to positive changes in uterine 
fibroid symptoms, as they would have experienced an improvement throughout the trial.  Table 
4.4-1 summarizes the measures/scales of interest, the type of data that was used in the respective 
meaningful change exercises, and the criteria that must have been met in order for the patient to 
participate in the respective meaningful change exercise. 
Table 4.4-1: Overview of Procedures for Meaningful Change Exercises 
Measure/Scale 
Type of Data Used 
Criteria That Must Have Been Met in 
Order to Conduct the Respective 
Meaningful Change Exercise 
UFS-QoL BPD 
Scale 
(calculated) 
MVT-601-3001 (LIBERTY 1) or MVT-601-3002 
(LIBERTY 2) Baseline Day 1 response 
Improvement on PGA of symptom severity 
from Baseline Day 1 to Week 24 
PGA of 
symptom 
severity 
MVT-601-3001 (LIBERTY 1) or MVT-601-3002 
(LIBERTY 2) responses (Baseline Day 1 and Week 24) 
Improvement on PGA of symptom severity 
from Baseline Day 1 to Week 24 
Abbreviations:  PGA = patient global assessment; UFS-QoL BPD = Uterine Fibroid Symptom and Health-Related 
Quality of Life bleeding and pelvic discomfort. 
 
For the UFS-QoL BPD Scale, only patients’ clinical study (ie, MVT-601-3001 [LIBERTY 1] or 
MVT-601-3002 [LIBERTY 2]) Baseline Day 1 data were used during interviews; the meaningful 
change discussions were hypothetical as Week 24 data were not made available to Endpoint 
Outcomes.1  For the UFS-QoL BPD Scale, patients were provided with both their Baseline item-
level scores and the summary score calculated based on the three items in the scale.  Patients 
were also given a copy of the three items that comprise the UFS-QoL BPD Scale for reference 
during the meaningful change exercise.  Patients were then presented with prespecified point 
change increments (ie, 10 points) and asked whether those changes reflected a meaningful 
improvement.  If a patient indicated that a 10-point increment change would be meaningful, she 
was asked if an increment 5 points fewer would still be meaningful.  Using a stepwise approach, 
interviewers then moved along the scale to identify the point at which minimum meaningful 
improvement was achieved for the respective patient.  
 
For the PGA of symptom severity, patients were presented with their clinical study scores at 
Baseline Day 1 and Week 24 and asked if the change was meaningful.  Next, patients were 
presented with a series of hypothetical point changes (ie, more change if the change was not 
                                                 
1 For secondary endpoint data, only Baseline responses were shared with Endpoint Outcomes. 


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meaningful or less change if the change was meaningful, as warranted) and asked if those would 
be meaningful.  This process continued until the minimum meaningful change on the PGA of 
symptom severity for that patient was identified.   
Audio recordings of the interviews were transcribed verbatim and anonymized by removing 
identifying information such as names and places.  Each transcript was considered a unit of 
analysis, and data from all transcripts were aggregated following coding.  An initial coding 
scheme was developed based on the semistructured interview guide and research objectives.  The 
coding scheme was applied and operationalized using Atlas.ti version 8.2.30 (Atlas.ti GmbH, 
Berlin), a software program designed specifically for qualitative data analysis.  Specifically, 
codes were applied to selected text within each transcript and then queried for frequency across 
transcripts.  Frequencies of patients’ interview responses (eg, minimum meaningful change 
responses) are reported.  Minimum meaningful point change medians and ranges were calculated 
in Excel.  As the sample size for the study was small and to reduce the influence of potential 
outliers, the median is the preferred measure of central tendency reported. 
4.4.3 
Results 
Thirty patients with heavy menstrual bleeding associated with uterine fibroids participated in exit 
interviews.  The average age of these patients was 44, with ages ranging from 
  
More than half of the patients (n = 
 self-reported as black or African American, and 
most patients (n = 
 were not Hispanic or Latino.  In addition, the majority of patients 
(n = 26, 86.7%) self-reported some college or higher education as their highest education level.  
Two patients selected “Other” as the highest level of education and self-reported that they had 
medical assistant credentials. 
The demographic characteristics of the patients from this exit interview study closely matched 
those of the LIBERTY 1 (MVT-601-3001) and LIBERTY 2 (MVT-601-3002) total sample and 
the LIBERTY 1 and 2 US sample (see Table 4.4-2).  The average age for both the LIBERTY 1 
and 2 total sample and US sample was approximately 42 years.  Approximately half of 
participants (n = 396, 51.4%) in the total sample self-reported as black or African American, and 
over half of the US sample (n = 372, 63.9%) self-reported as black or African American.  
Additionally, most participants in both the total sample (n = 588, 76.4%) and US sample 
(n = 450, 77.3%) self-reported as not Hispanic or Latino.  Highest level of education data was 
collected during patient interviews by Endpoint Outcomes; therefore, education level data for all 
LIBERTY 1 and 2 patients are not available. 
Table 4.4-2 includes demographic data for the interviewed study sample as well as the totality of 
LIBERTY 1 and 2 and the US-based LIBERTY 1 and 2 sample (based on a database snapshot as 
of 26 Apr 2019). 
 
 
PPD
PPD
PPD


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Table 4.4-2: Patient Demographic Information (from Baseline MVT-601-3001 
[LIBERTY 1] or MVT-601-3002 [LIBERTY 2]) and Education Information 
Collected during Patient Interviews 
Baseline Characteristics 
Exit Interview 
Study Sample 
(N = 30) 
LIBERTY 1 and 2 
Total Sample 
(N = 770) 
LIBERTY 1 and 2  
US Sample 
(N = 582) 
Age (years) 
   Mean (SD) 
43.9 (4.5) 
42.0 (5.4) 
42.1 (5.2) 
   Range 
   Race 
   Black or African American 
396 (51.4%) 
372 (63.9%) 
   White 
329 (44.4%) 
183 (31.4%) 
Ethnicity 
   Not Hispanic/Latino 
588 (76.4%) 
450 (77.3%) 
   Hispanic/Latino  
174 (22.6%) 
130 (22.3%) 
Highest level of education 
   High school (no degree) or less 
2 (6.7%) 
 
 
   High school graduate 
2 (6.7%) 
 
 
   Some college (no degree) 
11 (36.7%) 
 
 
   Associate’s degree 
4 (13.3%) 
 
 
   Bachelor’s degree 
5 (16.7%) 
 
 
   Master’s degree 
4 (13.3%) 
 
 
   Other 
2 (6.7%) 
 
 
Abbreviations:  SD = standard deviation. 
 
Table 4.4-3 below summarizes the total number of exit interview study patients who completed 
each meaningful change exercise based on the required criteria. 
 
 
PPD
PPD
PPD


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Table 4.4-3: Summary of the Total Number of Exit Interview Study Patients Who 
Completed Each Meaningful Change Activity 
Measure/Scale 
Number of Exit Interview 
Study Patients Participating in 
Each Exercise 
(Total N = 30)2 
Criteria that Must Have Been Met in Order to 
Conduct the Respective Meaningful Change 
Exercise 
UFS-QoL BPD Scale 
(calculated) 
25 
Improvement on PGA of symptom severity from 
Baseline Day 1 to Week 24 
PGA of symptom 
severity 
25 
Improvement on PGA of symptom severity from 
Baseline Day 1 to Week 24 
Abbreviations:  PGA = patient global assessment; UFS-QoL BPD = Uterine Fibroid Symptom and Health-Related 
Quality of Life bleeding and pelvic discomfort. 
 
UFS-QoL Bleeding and Pelvic Discomfort Scale 
Twenty-five patients improved from Baseline Day 1 to Week 24 on the PGA of symptom 
severity and participated in the UFS-QoL BPD Scale meaningful change exercise.  Data for 
24 patients were included in the analysis as one patient provided meaningful change exercise 
information that was not informative and therefore was excluded from the analysis.3  The median 
minimum point change considered to be a meaningful improvement was 10 points (n = 24; 
range = 5 to 80).  The majority of patients completing the UFS-QoL BPD meaningful change 
activity (n = 15, 62.5%) considered a minimum change of 5 points or 10 points as meaningful 
(Table 4.4-4).  
                                                 
2 A total of 30 patients completed exit interviews as part of this study; however, not all 30 patients completed each meaningful 
change exercise as additional criteria were required in order for a patient to complete the meaningful change exercises. The 
numbers in this table represent the total number of exit interview patients who met the criteria for participation for the specific 
meaningful change exercises listed. 
3 This patient did not understand how the three items comprising the UFS-QoL BPD led to the generation of her summary score 
and could not describe the minimum point change needed for meaningful improvement. 


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Table 4.4-4: UFS-QoL BPD Scale Meaningful Improvement Results 
Minimum Point Change Considered to be a 
Meaningful Improvement 
n (%) [N = 24] 
5-point change 
11 (45.8%) 
10-point change 
4 (16.7%) 
15-point change 
2 (8.3%) 
20-point change 
0 (0.0%) 
25-point change 
1 (4.2%) 
30-point change 
1 (4.2%) 
35-point change 
1 (4.2%) 
40-point change  
1 (4.2%) 
45-point change 
2 (8.3%) 
80-point change 
1 (4.2%) 
Overall point change 
   Median 
10 
   Range 
5 – 80 
 
Patient Global Assessment of Symptom Severity   
Twenty-five patients improved by at least 1 point from Baseline Day 1 to Week 24 on the PGA 
(for symptoms) and participated in the PGA of symptom severity meaningful change exercise.  
All patients participating in the PGA of symptom severity meaningful change exercise (n = 25, 
100.0%) reported that the actual improvement experienced during the clinical study was 
meaningful to them.  
The median minimum point change considered to be a meaningful improvement was 1 point 
(n = 24; range = 1 to 3); the most frequently reported minimum meaningful improvement 
reported by patients was a 1-point change (n = 17, 68.0%) (Table 4.4-5). 


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Table 4.4-5: PGA Symptom Severity Meaningful Improvement Results 
Minimum Point Change Considered to Be a Meaningful Improvement 
n (%) [N = 25] 
1-point change 
17 (68.0%) 
2-point change 
7 (28.0%) 
3-point change 
1 (4.0%) 
Overall point change 
Median 
1 
Range 
1 – 3 
4.4.4 
Discussion 
The exit interviews provided supportive qualitative evidence to assist in the interpretation of 
meaningful change in patients following clinical intervention.  Patients were required to improve 
by at least 1 point on the PGA of symptom severity over the course of the clinical study to ensure 
that patients interviewed had experienced improvement and could reflect upon meaningful 
improvements in uterine fibroid symptoms.  
The decision to use actual clinical trial data in the qualitative interviews was guided by an effort 
to increase the contextual relevance of each of the meaningful change activities.  Providing 
patients with their Baseline scores for the three PROs created a unique opportunity for patients to 
reflect on their experience since starting treatment, thereby making the exercises more relevant to 
them.  Further, participation in the meaningful change exercises was predicated on experiencing 
an improvement in uterine fibroid symptoms over the course of the study, which ensured that 
patients could speak to meaningful changes stemming from their personal experience.  This was 
confirmed, as all patients participating in the PGA of symptom severity meaningful change 
exercise (n = 25, 100.0%) reported that the change during the trial was meaningful to them.  
These qualitative findings provide patient insight which can be used to supplement psychometric 
analyses to determine target anchor categories (for the PGA of symptom severity) and responder 
definitions for the UFS-QoL BPD Scale.   
 
 
4.5. 
Determination of Responder Threshold via Triangulation of Findings 
Based on the analyses of individual patients’ changes in BPD Scale scores, anchored by changes 
in their response to the PGA of symptom severity, a 20-point change is recommended as the 
minimum meaningful change threshold for defining a responder.  This threshold estimation used 
the “1-category improvement” PGA group as the target anchor, which is a significantly separated 
from the “no change” group with respect to the mean change on the BPD Scale.  The choice of 
“1-category improvement” as the target anchor is supported by the majority (17/25, 68%) of the 
interviewed patients in the exit interview study reporting that a 1-category improvement on the 
PGA of symptom severity is meaningful to them.  The responder threshold of a 20-point change 


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on the BPD Scale score is larger than what the majority of patients in the exit interview study 
reported to be meaningful to them, ie, an improvement between 5- to 15-points.   
In summary, based on the triangulation of findings from the anchor-based analyses supported by 
patients’ feed-back during exit interviews, a 20-point change in the BPD Scale is proposed as the 
responder threshold for change in BPD Scale. 
4.6. 
References 
Cappelleri JC, Bushmakin AG. Interpretation of patient-reported outcomes. Statistical methods in medical research 
2014;23:460-483. 
Cohen J.  Statistical power analysis for the behavioral sciences (1988, 2nd ed.). Hillsdale, NJ: Lawrence Earlbaum 
Associates. 
Coon CD, Cook KF. Moving from significance to real-world meaning: methods for interpreting change in clinical 
outcome assessment scores. Quality of Life Research 2018;27:33-40. 
Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. 
Journal of clinical epidemiology 2003;56:395-407.Wyrwich KW, Norquist JM, Lenderking WR, Acaster S. 
Industry Advisory Committee of International Society for Quality of Life R. Methods for interpreting change 
over time in patient-reported outcome measures. Qual Life Res 2013;22:475-483. 
Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally 
important differences for patient-reported outcomes. Journal of clinical epidemiology 2008;61:102-109. 
 


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APPENDIX 5. ESTIMATION OF RESPONDER THRESHOLD FOR THE 
UFS-QOL REVISED ACTIVITIES SCALE 
5.1. 
Approach to Estimating the Responder Threshold of the Revised 
Activities Scale 
The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) Revised Activities 
Scale includes five of the seven most relevant items pertaining to physical and social activities 
(Coyne 2018).  These are:  
During the previous 3 months, how often have your symptoms related to uterine fibroids:  
• Interfered with your physical activities?  
• Made you decrease the amount of time you spent on exercise or other physical 
activities? 
• Made you feel that it was difficult to carry out your usual activities? 
• Interfered with your social activities? 
• Caused you to plan activities more carefully?  
Response options include:   
• None of the time; 
• A little of the time; 
• Some of the time; 
• Most of the time; 
• All of the time.   
The summary score of the five items ranges from 0 to 100, where a lower score indicates a 
higher ability to do activities (ie, lower score = good) and a higher score indicates a lower ability 
to do activities.  
Change from Baseline to Week 24 in the Revised Activities Scale score is a secondary endpoint 
of the pivotal studies (MVT-601-3001 and MVT-601-3002) to evaluate the treatment benefit of 
relugolix + E2/NETA (Group A) compared with placebo (Group C).  Additionally, a responder 
analysis will be performed between the two groups with respect to the proportion of patients who 
have achieved a meaningful reduction from Baseline to Week 24 in the Revised Activities Scale.  
The approach used to derive the responder threshold for improvement in the Revised Activities 
Scale is similar to that used for the Bleeding and Pelvic Discomfort (BPD) scale (see details in 
Appendix 4).  
This appendix briefly describes the quantitative and supportive qualitative methods and 
summarizes the respective analysis results. 
The meaningful change threshold is the smallest reduction in the Revised Activities Scale score 
that is considered meaningful by patients (Cohen, 1988; Crosby, 2003; Revicki, 2008; Wyrwich, 
2013; Cappelleri, 2014; Coon, 2018).  The magnitude of a meaningful change threshold depends 


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on the magnitude of the correlation between the change in the Revised Activities Scale score and 
change in anchor (ie, the Patient Global Assessment [PGA] for function anchor) as well as the 
variability of change on the Revised Activities Scale by improvement categories on the PGA of 
symptoms (described in Section 5.2.2).  Several anchor-based methods will be used; however, 
the primary analysis will be a measure of central tendency for each improvement category (see 
Section 5.2.3).  Anchor-based methods will use data collected on: 
• The UFS-QoL Revised Activities Scale score at Baseline and Week 24; and 
• The PGA of function score at Baseline and Week 24. 
Results from the anchor-based analyses will be supported by qualitative data collected in a 
patient interview study (MVT-601-037), a substudy of the phase 3 trials, in which patients from 
selected sites in the United States (US) provided feedback on what they considered to be a 
meaningful change on the Revised Activities Scale and the PGA of function (described in 
Section 5.4). 
5.2. 
Statistical Analysis Plan for Estimation of the Responder Threshold 
5.2.1. 
Anchor and Its Correlation with UFS-QoL Endpoint 
The PGA of function uses a five-point verbal rating scale and asks the patient:  
How much were your usual activities limited by uterine fibroid symptoms such as heavy 
bleeding over the last 4 weeks? 
Response options include:   
• No limitation at all  
• Mild limitation  
• Moderate limitation  
• Quite a bit of limitation  
• Extreme limitation  
The categorical change from Baseline to Week 24 in PGA of function score will be derived, 
leading to nine possible outcomes ranging from +4 (denoting worsening) to -4 (denoting 
improvement).  The change in PGA of function at Week 24 will be used as the anchor (see Table 
5.2-1).   
5.2.2. 
Target Anchor Category 
The target anchor category is the anchor category that represents the minimum meaningful 
change and is used as the starting point to identify potential candidates for a meaningful change 
threshold.  For the two pivotal studies, the target anchor category will be a one-point category 
improvement on the PGA of function (see Table 5.2-1), as this is typically considered as a 
minimal clinical important difference on a five-point Likert scale.   


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Table 5.2-1: Change in PGA as Anchor 
Anchor 
Anchor Change Category 
Potential Target Anchor Change Category  
(To Be Used for Estimation of Meaningful 
Change Threshold) 
Change in PGA of 
function 
-4, -3, -2, -1 (improvement), 
0 (same), 
+1, +2, +3, +4 (worsening) 
-1-category change 
(improvement)   
Abbreviations:  PGA = patient global assessment. 
 
5.2.3. 
Anchor-Based Methods 
To determine the meaningful change threshold for the reduction in UFS-QoL Revised Activities 
Scale score, the anchor-based analyses described below will be performed. 
The category (or point) change in PGA of function score will be used as the anchor to classify 
patients into response groups, depending on their level of change in the Revised Activities Scale 
from Baseline to Week 24 (see Table 5.2-1).  Uncollapsed, categorical change on the PGA will 
range from +4 to -4.  Collapsed, categorical change will be considered based on the distribution 
of change categories on the PGA of function.  Usually, the collapsing occurs on the tails with 
extreme worsening (+4) or improvement (-4). 
Among the anchor-based analyses described below, the within-group analysis will be primary 
and other analyses (including between-group analysis) are supportive.  
5.2.3.1. 
Correlation with Anchor 
Correlation between the categorical change on the PGA of function score and the change in the 
Revised Activities Scale score will be evaluated at Week 24, using blinded pooled data from the 
first third of the enrolled patients from the two pivotal studies who had completed Week 24 visits 
and had the corresponding PGA of function data available (denoted as the “threshold 
determination analysis set”).  Polyserial correlation coefficient will be used with a criteria value 
of > 0.30 indicating meaningful correlation (Cohen, 1988; Crosby, 2003; Revicki, 2008; 
Cappelleri, 2014; Coon, 2018).   
5.2.3.2. 
Within-Group Meaningful Change 
The magnitude of change from Baseline to Week 24 in Revised Activities Scale score will be 
calculated within each anchor category group.  Changes in Revised Activities Scale scores are 
negative for reduced ability to do activities (indicating a worse outcome) and positive for 
increased ability to do activities (indicating a better outcome).  
Descriptive statistics (n, mean change, median change, 25th and 75th percentiles, standard 
deviation [SD], confidence interval [CI], and standardized effect size [SES]) will be reported for 
the changes in Revised Activities Scale scores by anchor category.  The SES will be calculated 
for each level of anchor category group by dividing the mean change score of Revised Activities 
Scale from Baseline by the Baseline SD of the anchor category group.  The impact of treatment 
will be judged based on Cohen’s recommendations (1988):  small change (SES = 0.20), 


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moderate change (SES = 0.50), and large change (SES = 0.80).  Significance associated within-
patient change will be evaluated using paired t-tests on the change in Revised Activities Scale 
score separately for each level of improvement on the anchor. 
5.2.3.3. 
Supportive Analysis of Between Group Meaningful Change Using Analysis of 
Variance 
Analysis of variance (ANOVA) will be used to determine whether a difference in mean change 
scores from Baseline to Week 24 on the Revised Activities Scale exists between the categorical 
change groups (or the collapsed groups, as appropriate).  Providing there is a significant change 
in Revised Activities Scale scores between the (collapsed) anchor groups, the between-group 
differences will be explored.  Any anchor group with at least 15 patients will be included in this 
analysis.  An anchor group with < 15 patients (usually occurring on the tails with extreme 
worsening [+4] or improvement [-4]) will be collapsed with its adjacent group as appropriate.  
Comparison of the anchor groups of interest between the target anchor (“-1 change” category) 
and “0 change” category will be performed using a t-test.  A statistically significant difference on 
the Revised Activities Scale change scores corresponding to a 1-category change on the PGA of 
function can be used as supportive information for estimating the meaningful change threshold. 
5.2.3.4. 
Visualizing Cumulative Distribution Function and Probability Distribution 
Function Plots by Anchor Category Group 
Anchor-based meaningful change will also be evaluated using cumulative distribution function 
(CDF) plots utilizing the Kernel smoothing for all anchor category groups, based on cumulative 
change in the Revised Activities Scale scores for all available changes from Baseline to 
Week 24.  Specifically, the CDF plot for each anchor category displays the probability 
(presented on y-axis) of patients who have achieved a given absolute change of X or less in the 
Revised Activities Scale score from Baseline to Week 24 for each point change along the range 
of possible absolute changes (from -100 [maximum reduction] to 0 [no change] to 100 
[maximum increase]) expressed on the x-axis. 
Similarly, the smooth probability density function (PDF) will also be plotted for each anchor 
category group over the range of absolute changes in the Revised Activities Scale scores.  These 
probabilities are plotted on the y-axis with the Revised Activities Scale change score on the x-
axis. 
The CDF and PDF curves are delineated by anchor improvement category (from -4 to +4) 
displaying the center and separation between the curve for the target anchor group and the curve 
for the group reporting no change on PGA of function.  It is expected that the CDF curves will 
not cross between the change category groups (eg, monotonic increase from no change to 
slightly improved and moderately improved). 
5.2.4. 
Determining a Meaningful Change Threshold Using Totality-of-Evidence 
Approach 
The meaningful change threshold will be determined using the totality of evidence from the 
results of above quantitative anchor-based analyses; results from the interview study 
(MVT-601-037) will be used as supportive evidence. 


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The results of these analyses and proposed thresholds will be included into the Patient-Reported 
Outcome dossier to be submitted at time of filing. 
5.3. 
Results from Anchor-Based Analyses  
5.3.1. 
Correlation of Change in Revised Activities Scale Score with PGA of Function 
Meaningful change for the UFS-QoL Revised Activities Scale was derived based on 
anchor-based methods, supported by CDF and PDF curves.  To assess the suitability of the 
selected anchor, PGA of function, a polyserial correlation was calculated between change on the 
PGA from Baseline to Week 24 and the change from Baseline to Week 24 on the Revised 
Activities Scale.  The change in the PGA was moderately negatively correlated (r = -0.60) with 
the change on the Revised Activities Scale (Table 5.3-1).  Given that the PGA of function is less 
complex than the Revised Activities Scale, this result indicates that the PGA of function is a 
suitable anchor for the Revised Activities Scale. 
Table 5.3-1: Summary of Change from Baseline to Week 24 in UFS-QoL Revised 
Activities Scale by PGA of Function Change Category (mITT Population) 
PGA of Function 
Change Category 
N = 254 
Change in Revised Activities 
Correlation 
between 
PGA Change 
and Revised 
Activities 
Changea 
Mean 
(SD) 
Median 
95% CI 
p-valueb 
SESc 
4-category 
deterioration (+4) 
2 
5.00 
(7.07) 
5 
-58.53,68.53 
0.500 
0.28 
-0.60 
3-category 
deteriorations (+3) 
2 
0  
0 
- 
- 
0.00 
2-category 
deteriorations (+2) 
5 
7.00 
(22.80) 
0 
-21.31,35.31 
0.5302 
0.61 
1-category 
deteriorations (+1) 
22 
-1.59 
(23.82) 
-5 
-12.15,8.97 
0.7572 
-0.06 
0 Category 
deteriorations (0) 
71 
11.55 
(28.51) 
5 
4.80,18.30 
0.0011 
0.38 
1-category 
improvement (-1) 
53 
27.92 
(25.65) 
20 
20.85,35.00 
< 0.0001 
1.06 
2-category 
improvement (-2) 
51 
51.86 
(27.60) 
60 
44.10,59.63 
< 0.0001 
2.17 
3-category 
improvement (-3) 
35 
56.81 
(27.49) 
57.50 
47.50,66.11 
< 0.0001 
2.91 
4-category 
improvement (-4) 
13 
60.77 
(31.55) 
70 
41.71, 79.83 
< 0.0001 
4.40 
Abbreviations:  CI = confidence interval; mITT = modified intent-to-treat; PGA = patient global assessment; SD = 
standard deviation; SES = standardized effect size. 
mITT is used to calculate change from Baseline score at Week 24 and includes patients from the mITT population 
who have available change from Baseline data at Week 24. 
a 
Polyserial correlation coefficient between change in Revised Activities Scale and change in PGA of function. 
b 
The p-value for each individual change group is derived from a paired (within-sample) t-test assessing the difference over 
time. 
c 
SES calculated as the mean divided by the SD of Baseline.  SES is judged as small = 0.2, moderate = 0.5, and large = 0.8 
(Cohen 1988). 
 


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5.3.2. 
Improvement on Revised Activities Scale by PGA Change Category 
Uncollapsed changes on the PGA of function were used to determine minimal meaningful 
improvement on the Revised Activities Scale (Table 5.3-1).  Improvement on the Revised 
Activities Scale increased monotonically for all the categories from “no change (0)” to “1-
category improvement (-1)” to “2-category improvement (-2)” with non-overlapping 95% CIs 
for mean change of the three groups.  Table 5.3-2 shows that a one category improvement (-1) is 
associated with a 27.92-point mean improvement in the Revised Activities Scale score at Week 
24 compared to Baseline, with a 95% CI [20.85, 35.00], a large SES = 1.06, and a median 
improvement of 20 points. 
Table 5.3-2 highlights that the difference between the “1-category improvement” and the “no 
change” groups (mean =11.55 with a 95% CI of [4.80, 18.30]) was statistically significant 
(p = 0.0013) with a moderate SES = 0.54, which reasonably supports the notion that patients 
interpreted these change categories as distinct. 
Table 5.3-2: Summary of Change from Baseline to Week 24 in Revised Activities Scale 
Between Target Anchor (-1) and No change (0) in PGA of Function 
(mITT Population) 
Anchor 
Categorical Change 
N 
Mean 
Change 
from BL 
SD 
95% CI 
p-valuea 
Baseline 
SD 
SES 
PGA 
1-category improvement 
(-1) 
53 
27.92 
25.65 
20.85, 35.0 
 
 
 
 
No change (0) 
71 
11.55 
28.51 
4.80, 18.30 
 
 
 
 
Difference  
 
16.38 
27.33 
6.55, 26.20 
0.0013 
 
0.54b 
0.57c 
a The p-value is based on t-test for difference in mean change in BPD score between the 2 anchor groups (-1 and 0) 
from the ANOVA. 
b SES calculated as the mean difference divided by the standard deviation of Baseline for no change group. They are 
judged as small=0.2, moderate=0.5 and large=0.8 (Cohen, 1988). 
c SES calculated as the mean difference divided by the standard deviation of Baseline for pooled from all categories 
(Glass, 1976). 
 
That patients were able to distinguish between the PGA “1-category improvement” and the ‘no 
change” group is further supported by the nonoverlapping CIs (in Table 5.3-2) for the respective 
UFS-QoL Revised Activities Scale scores and as illustrated by the separation between the CDF 
curves presented in Figure 5.3-1.  Since statistically significant differences existed in patient 
responses on the Revised Activities Scale between the “1-category improvement (-1) ” option 
and the “no change” and the “2-category improvement (-2)” groups, a 1-category improvement 
on the PGA was considered a meaningful target anchor category for assessing the responder 
threshold on the Revised Activities Scale.  Although a two-category improvement could have 
been considered for deriving the meaningful change threshold, such a threshold would not 
qualify as being the minimum threshold possible.  The evidence (ie, the statistical difference 
between the1- and 2-category improvements and the fact that patients were able to distinguish 
between the two response options) supports using a 1-category improvement on the PGA of 


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function for estimating the minimum meaningful change threshold.  This decision is also 
supported by qualitative evidence generated from the Exit Interview study (see Section 5.4). 
Figure 5.3-1: PDF of the Change in UFS-QoL Revised Activities by PGA of Function 
Anchor Change Category (Collapsed) 
 
Abbreviations:  PGA = patient global assessment; LCL = lower confidence limit. 
 
5.3.3. 
Estimation of Responder Threshold 
Using the mean value for measuring improvement in the Revised Activities Scale would yield 
estimates that are conservative because expected values do not necessarily constitute a minimum 
meaningful change threshold for patients.  That is, nearly half the patients stratified in the PGA 
“1-category improvement” who reported changes smaller than the mean on the Revised 
Activities Scale would be classified as nonresponders by using the mean as the threshold despite 
of their reporting “1-category improvement”. A less conservative, though still plausible estimate 
for the minimal meaningful change threshold is the lower bound of the 95% CI for mean change 
in the “1-category improvement” group.  Its use will result in a smaller proportion of patients 
being classified as nonresponders on the Revised Activities Scale than the expected value (ie, the 
mean). Similarly, one can also consider the median value since it is less influenced by outliers 
than either the mean or CI estimates. 


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According to the uncollapsed anchor-based analysis (Table 5.3-1), the median value for a 
“1-category improvement” is 20-points, while the lower bound 95% CI for this group is about 
21-points (ie, a 21-point improvement on the revised activities between Baseline and Week 24).  
Given the large discrepancy between the mean and median values suggests that outliers were 
present in the data; hence, the median value is recommended as a potential minimum change 
threshold. 
Examination of the CDF curves for the potential minimum meaningful threshold value of 20 
points on the Revised Activities Scale allows one to estimate the cumulative percent of patients 
that would experience the improvement.  As illustrated in Figure 5.3-2, approximately 38% of 
the “no change” group and 61% of the “1-category improvement” group experienced at least a 
20-point improvement (eg, approximately 62% of the “no change” group and 39% of the 
“1-category improvement” group experienced less than a 20-point improvement to the left) on 
the Revised Activities Scale by Week 24.  
Figure 5.3-2: Cumulative Distribution Function of Change at Week 24in UFS-QoL 
Revised Activities Scale Score by PGA Anchor Change Category (Collapsed) 
 
Abbreviations:  PGA = patient global assessment. 
 
As supportive information, the empirical CDFs with step-curves (reflecting the discrete nature of 
the revised activities scores) are provided (Figure 5.3-3), indicating that smooth curves are 


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reasonably close to the empirical CDFs.  Examination of the PDF curves presented in 
Figure 5.3-1 indicates that the dispersion is roughly the same for the options between “> -3-
category improvement” and “no change.”  
Figure 5.3-3: Empirical Cumulative Distribution Function of Change at Week 24 in 
UFS-QoL Revised Activities Scale Score by PGA Anchor Change Category 
(Collapsed) 
 
Abbreviations:  PGA = patient global assessment. 
 
5.4. 
Exit Interview Study Synthesis 
5.4.1 
Objectives 
The objectives of the exit interviews were:  1) to provide qualitative evidence to understand 
meaningful change for patients following clinical intervention and 2) to elicit data on what 
patients consider to be a minimum meaningful improvement on different patient-reported 
outcomes (PROs), including: 
• The UFS-QoL Revised Activities Scale; 
• The PGA of function. 
These objectives were achieved through conducting web/Internet-based video or telephone 
interviews with English-speaking patients in the US within 3 to 14 days after their Week 24 visit 


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of either ongoing phase 3 clinical study (MVT-601-3001 [LIBERTY 1] or MVT-601-3002 
[LIBERTY 2]). 
Minimum meaningful improvements on other PROs were also explored as part of the exit 
interview study; results of the respective exercises will be included in the full report for this exit 
interview study.  
5.4.2 
Methodology – Qualitative Interviews 
The exit interviews were conducted via a web/Internet-based video platform (Doxy.me 
[https://doxy.me/]) or via telephone by trained and experienced Endpoint Outcomes interviewers.  
If a patient did not improve by at least 1 point from Baseline Day 1 to Week 24 based on her 
PGA of function, meaningful change exercises were not conducted for the PGA of function and 
the UFS-QoL Revised Activities Scale.  An improvement on the PGA of function was required 
so that patients could provide contextually relevant feedback related to positive changes as they 
would have experienced an improvement throughout the trial.  Table 5.4-1 summarizes the 
measures/scales of interest, the type of data that was used in the respective meaningful change 
exercises, and the criteria that must have been met in order for the patient to participate in the 
respective meaningful change exercise. 
Table 5.4-1: Overview of Procedures for Meaningful Change Exercises 
Measure/Scale 
Type of Data Used 
Criteria That Must Have Been 
Met in Order to Conduct the 
Respective Meaningful Change 
Exercise 
UFS-QoL Revised 
Activities Scale 
(calculated) 
MVT-601-3001 (LIBERTY 1) or 
MVT-601-3002 (LIBERTY 2) Baseline 
Day 1 response 
Improvement on PGA of function 
from Baseline Day 1 to Week 24 
PGA (for function) 
MVT-601-3001 (LIBERTY 1) or 
MVT-601-3002 (LIBERTY 2) responses 
(Baseline Day 1 and Week 24) 
Improvement on PGA of function 
from Baseline Day 1 to Week 24 
Abbreviations:  PGA = patient global assessment; UFS-QoL = Uterine Fibroid Symptom and Health-Related 
Quality of Life. 
 
For the UFS-QOL Revised Activities Scale, only patients’ clinical study (ie, MVT-601-3001 
[LIBERTY 1] or MVT-601-3002 [LIBERTY 2]) Baseline Day 1 data were used during 
interviews; the meaningful change discussions were hypothetical, as Week 24 data were not 
made available to Endpoint Outcomes.4  For the UFS-QoL Revised Activities Scale, patients 
were provided with both their Baseline item-level scores and the summary score calculated based 
on the five items in the scale.  Patients were also given a copy of the five items that comprise the 
UFS-QoL Revised Activities Scale for reference during the meaningful change exercise.  
Patients were then presented with pre-specified point change increments (ie, 10 points) and asked 
whether those changes reflected a meaningful improvement.  If a patient indicated that a 10-point 
                                                 
4 For secondary endpoint data, only Baseline responses were shared with Endpoint Outcomes. 


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increment change would be meaningful, she was asked if an increment 5 points fewer would still 
be meaningful.  Using a stepwise approach, interviewers then moved along the scale to identify 
the point at which minimum meaningful improvement was achieved for the respective patient.  
For the PGA of function, patients were presented with their clinical study scores at Baseline 
Day 1 and Week 24 and were asked if the change was meaningful.  Next, patients were presented 
with a series of hypothetical point changes (ie, more change if the change was not meaningful or 
less change if the change was meaningful, as warranted) and asked if those would be meaningful.  
This process continued until the minimum meaningful change on the PGA of function for that 
patient was identified.   
Audio-recordings of the interviews were transcribed verbatim and anonymized by removing 
identifying information such as names and places.  Each transcript was considered a unit of 
analysis, and data from all transcripts were aggregated following coding.  An initial coding 
scheme was developed based on the semi-structured interview guide and research objectives.  
The coding scheme was applied and operationalized using Atlas.ti version 8.2.30 (Atlas.ti 
GmbH, Berlin), a software program designed specifically for qualitative data analysis.  
Specifically, codes were applied to selected text within each transcript and then queried for 
frequency across transcripts.  Frequencies of patients’ interview responses (eg, minimum 
meaningful change responses) are reported.  Minimum meaningful point change medians and 
ranges were calculated in Excel.  As the sample size for the study was small and to reduce the 
influence of potential outliers, the median is the preferred measure of central tendency reported. 
5.4.3 
Results 
5.4.3.1 
PGA of Function5 
Twenty-two patients improved from Baseline Day 1 to Week 24 on the PGA of function and 
participated in the PGA of function meaningful change exercise.  The demographic 
characteristics of the 22 patients who completed the PGA of function closely match that of the 
entire substudy sample as the sample was mostly African-American (n = 
 not 
Hispanic or Latina (n = 
 had completed at least some college or higher (n = 19, 
86.4%), and had an average age of approximately 44 years.  The median minimum point change 
considered to be a meaningful improvement was 1 point (n = 22, range = 1-2); the most 
frequently reported minimum meaningful improvement reported by patients was a 1-point 
change (n = 16, 72.7%) (Figure 5.4-1).  
                                                 
5 The PGA of function asks:  How much were your usual activities limited by uterine fibroids symptoms such as 
heavy bleeding over the last 4 weeks? Response options include:  No limitation at all, mild limitation, moderate 
limitation, quite a bit of limitation, and extreme limitation. 
PPD
PPD


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Figure 5.4-1: Meaningful Change Estimation:  Results of the PGA (for Function) 
 
 
5.4.3.2 
UFS-QoL Revised Activities Subscale6  
Twenty-two patients improved from Baseline Day 1 to Week 24 on the PGA of function and 
participated in the UFS-QoL revised activities subscale meaningful change exercise.  Data for 21 
patients were included in the analysis as one patient provided meaningful change exercise 
information that was not informative and therefore was excluded from the analysis.7  The 
demographic characteristics of the 21 patients who completed the UFS-QoL Revised Activities 
Scale closely match that of the entire substudy sample as the sample was mostly African-
American (n = 
 not Hispanic or Latina (n = 
 had completed at least some 
college or higher (n = 19, 90.5%), and had an average age of approximately 44 years.  
                                                 
6 The UFS-QoL revised activities subscale includes five items, which ask:  During the previous 3 months, how often 
have your symptoms related to uterine fibroids … 11) interfered with your physical activities; 13) made you 
decrease the amount of time you spent on exercise or other physical activities; 19) made you feel it was difficult to 
carry out your usual activities; 20) interfered with your social activities; and 27) made you plan activities more 
carefully.  Response options include 1) None of the time, 2) A little of the time, 3) Some of the time, 4) Most of the 
time, and 5) All of the time.  The score range for the subscale is 0-100.  A higher score on the revised activities 
subscale indicates a lower interference in activities while a lower score on the subscale indicates a higher 
interference in activities. 
7 This patient was unwilling to describe the minimum point change needed for meaningful improvement for the 
UFS-QoL revised activity subscale. 
16
6
0
2
4
6
8
10
12
14
16
18
1-point change
2-point change
Number of sub-study patients (N=22)
Minimum point change reported as meaningful
PPD
PPD


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The median minimum point change considered to be a meaningful improvement was 5 points 
(n = 21, range = 5-80); the most frequently reported minimum meaningful improvement reported 
by patients was a 5-point change (n = 11, 52.4%) (Figure 5.4-2).  
Figure 5.4-2: Meaningful Change Estimation:  Results of the UFS-QoL Revised Activities 
Subscale 
11
2
1
1
3
1
1
1
0
2
4
6
8
10
12
5-point change
10-point
change
20-point
change
30-point
change
35-point
change
40-point
change
55-point
change
80-point
change
Number of sub-study patients (N=21)
Minimum point change reported as meaningful


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5.5. 
Determination of Responder Threshold via Triangulation of Findings 
Based on the analyses of individual patient’s change in Revised Activities Scale scores anchored 
by change in their response to the PGA of function, a 20-point change is recommended as the 
minimum meaningful change threshold for defining a responder.  This threshold estimation used 
the “1-category improvement” PGA group as the target anchor, which is significantly separated 
from the “no change” group with respect to the mean change on the Revised Activities Scale.  
The choice of “1-category improvement” as the target anchor is supported by the majority 
(16/22, 73%) of the interviewed patients in the exit interview study reporting that a 1-category 
improvement on the PGA of function is meaningful to them.  The responder threshold of a 
20-point change on the Revised Activities Scale score is larger than what the majority of patients 
in the exit interview study reported to be meaningful to them (ie, improvements of 5 points 
[11/21] and 10 points [2/21]).   
In summary, based on the triangulation of findings from the anchor-based analyses supported by 
patients’ feedback during exit interviews, a 20-point change in the Revised Activities Scale is 
proposed as the responder threshold for change in Revised Activities Scale. 
5.6. 
References 
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Cohen J.  Statistical power analysis for the behavioral sciences (1988, 2nd ed.). Hillsdale, NJ: Lawrence Earlbaum 
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Coon CD, Cook KF. Moving from significance to real-world meaning: methods for interpreting change in clinical 
outcome assessment scores. Qual Life Res 2018;27:33-40. 
Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. J 
Clin Epidemiol 2003;56:395-407. 
Coyne KS, Harrington A, et al. Psychometric validating of the 1-month recall Uterine Fibroid Symptom and Health-
Related Quality of Life Questionnaire (UFS-QOL). ISPOR 23rd Annual International Meeting, 2018 
Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally 
important differences for patient-reported outcomes. J Clin Epidemiol 2008;61:102-109. 
Wyrwich KW, Norquist JM, Lenderking WR, Acaster S. Industry Advisory Committee of International Society for 
Quality of Life R. Methods for interpreting change over time in patient-reported outcome measures. Qual Life 
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