Trial Outcomes & Findings for LIBERTY 2: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids (NCT NCT03103087)

NCT ID: NCT03103087

Last Updated: 2022-04-20

Results Overview

A responder was a participant who had MBL volume of \< 80 mL and at least a 50% reduction from baseline MBL volume over the last 35 days of treatment (up to Week 24). All returned feminine products collected at each clinical visit were analyzed by the alkaline hematin method to obtain the MBL volume. MBL volume was measured over the Week 24/early termination feminine product collection interval (up to 35 days prior to the last dose of treatment). The percentage of participants who were responders are presented. As per the objective of the study, the pre-specified primary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 382 participants
• Primary outcome timeframe: From Baseline up to the last 35 days of treatment (up to Week 24)
• Results posted on: 2022-04-20

Participant Flow

The study was conducted at 99 study centers throughout the world, including centers in the United States, Belgium, Brazil, Chile, Czech Republic, Hungary, Poland, and South Africa.

A total of 382 premenopausal women aged 18 to 50 years old (inclusive) with heavy menstrual bleeding (≥ 160 milliliters [mL] during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method) associated with uterine fibroids were randomized. One participant was randomized in error before eligibility confirmed.

Participant milestones

Measure	Relugolix Plus Estradiol (E2])/Norethindrone Acetate (NETA) (Group A) Relugolix 40 milligrams (mg) co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix Plus Delayed E2/NETA (Group B) Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Study STARTED	126	127	129
Overall Study COMPLETED	102	98	102
Overall Study NOT COMPLETED	24	29	27

Reasons for withdrawal

Measure	Relugolix Plus Estradiol (E2])/Norethindrone Acetate (NETA) (Group A) Relugolix 40 milligrams (mg) co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix Plus Delayed E2/NETA (Group B) Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Study Did not receive any study drug	1	0	0
Overall Study Protocol Violation	1	2	1
Overall Study Lack of Efficacy	2	1	1
Overall Study Pregnancy	0	0	1
Overall Study Adverse Event	2	15	6
Overall Study Withdrawal by Subject	13	6	6
Overall Study Lost to Follow-up	4	2	7
Overall Study Other reason not reported	1	3	5

Baseline Characteristics

LIBERTY 2: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Baseline characteristics by cohort

Measure	Relugolix Plus E2/NETA (Group A) n=126 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix Plus Delayed E2/NETA (Group B) n=127 Participants Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks	Total n=382 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	126 Participants n=5 Participants	127 Participants n=7 Participants	129 Participants n=5 Participants	382 Participants n=4 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Continuous	42.4 years STANDARD_DEVIATION 5.37 • n=5 Participants	42.1 years STANDARD_DEVIATION 5.25 • n=7 Participants	41.8 years STANDARD_DEVIATION 5.26 • n=5 Participants	42.1 years STANDARD_DEVIATION 5.29 • n=4 Participants
Sex: Female, Male Female	126 Participants n=5 Participants	127 Participants n=7 Participants	129 Participants n=5 Participants	382 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=5 Participants	34 Participants n=7 Participants	32 Participants n=5 Participants	84 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	106 Participants n=5 Participants	91 Participants n=7 Participants	96 Participants n=5 Participants	293 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	63 Participants n=5 Participants	66 Participants n=7 Participants	74 Participants n=5 Participants	203 Participants n=4 Participants
Race (NIH/OMB) White	58 Participants n=5 Participants	50 Participants n=7 Participants	49 Participants n=5 Participants	157 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	13 Participants n=4 Participants
Region of Enrollment Hungary	7 participants n=5 Participants	7 participants n=7 Participants	8 participants n=5 Participants	22 participants n=4 Participants
Region of Enrollment Belgium	0 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	4 participants n=4 Participants
Region of Enrollment United States	94 participants n=5 Participants	94 participants n=7 Participants	96 participants n=5 Participants	284 participants n=4 Participants
Region of Enrollment Czechia	4 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	9 participants n=4 Participants
Region of Enrollment Poland	7 participants n=5 Participants	6 participants n=7 Participants	4 participants n=5 Participants	17 participants n=4 Participants
Region of Enrollment Brazil	1 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	5 participants n=4 Participants
Region of Enrollment South Africa	7 participants n=5 Participants	3 participants n=7 Participants	7 participants n=5 Participants	17 participants n=4 Participants
Region of Enrollment Chile	6 participants n=5 Participants	9 participants n=7 Participants	9 participants n=5 Participants	24 participants n=4 Participants
Mean MBL Volume	247.62 mL STANDARD_DEVIATION 185.553 • n=5 Participants	227.41 mL STANDARD_DEVIATION 34.350 • n=7 Participants	211.75 mL STANDARD_DEVIATION 129.903 • n=5 Participants	228.45 mL STANDARD_DEVIATION 152.205 • n=4 Participants

PRIMARY outcome

Timeframe: From Baseline up to the last 35 days of treatment (up to Week 24)

Population: All randomized participants who received any amount of study drug.

A responder was a participant who had MBL volume of < 80 mL and at least a 50% reduction from baseline MBL volume over the last 35 days of treatment (up to Week 24). All returned feminine products collected at each clinical visit were analyzed by the alkaline hematin method to obtain the MBL volume. MBL volume was measured over the Week 24/early termination feminine product collection interval (up to 35 days prior to the last dose of treatment). The percentage of participants who were responders are presented.

As per the objective of the study, the pre-specified primary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants Who Achieved A Menstrual Blood Loss (MBL) Volume Of < 80 mL And A ≥ 50% Reduction From Baseline MBL Volume With Relugolix Plus E2/NETA	71.2 Percentage of participants Interval 62.42 to 78.95	14.73 Percentage of participants Interval 9.11 to 22.04

SECONDARY outcome

Timeframe: From Baseline up to last 35 days of treatment (up to Week 24)

Population: All randomized participants who received any amount of study drug.

Amenorrhea was defined as meeting 1 of the following criteria for 2 consecutive visits:

• No feminine product returned due to reported amenorrhea;
• No feminine product returned due to reports of spotting/negligible bleeding coupled with electronic diary (e-Diary) data indicating infrequent non-cyclic bleeding/spotting;
• Feminine product collection with a negligible observed MBL volume coupled with e-Diary data indicating infrequent non-cyclic bleeding/spotting.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment	50.40 Percentage of participants Interval 41.32 to 59.46	3.10 Percentage of participants Interval 0.85 to 7.75

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All randomized participants who received any amount of study drug.

MBL volume was measured using the alkaline hematin method. Least square (LS) means for test of difference is Relugolix plus E2/NETA minus Placebo based on mixed-effect model with treatment, visit, region, Baseline MBL, and treatment by visit interaction included as fixed effects.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 24 In MBL Volume	-84.3 percent change Interval -95.0 to -73.6	-15.1 percent change Interval -25.8 to -4.3

SECONDARY outcome

Timeframe: From Baseline up to Week 24

Population: All randomized participants who received any amount of study drug and had analyzable study data at the specified timepoint.

Blood samples were collected from participants for hemoglobin measurements. Percentages are based on number of participants with hemoglobin ≤ 10.5 gram (g)/deciliter (dL) at Baseline and reported at Week 24.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA with placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=31 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=37 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants With A Hemoglobin Level ≤ 10.5 g/dL At Baseline Who Achieved An Increase Of > 2 g/dL From Baseline At Week 24	61.29 Percentage of participants Interval 42.19 to 78.15	5.41 Percentage of participants Interval 0.66 to 18.19

SECONDARY outcome

Timeframe: From Baseline up to Week 24

Population: All randomized participants who received any amount of study drug.

Uterine fibroid-associated pain was assessed by a pain numerical rating scale (NRS). The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain).

Participants were asked to document, in an e-Diary, the worst pain associated with their uterine fibroids that they experienced during the last 24 hours, every day until the end of study drug administration. Pain evaluable participants, defined as those who had maximum NRS score ≥ 4 at baseline and had at least 28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary, were analyzed.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=68 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=82 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment	47.06 percentage of participants Interval 34.83 to 59.55	17.07 percentage of participants Interval 9.66 to 26.98

SECONDARY outcome

Timeframe: Baseline Week 24

Population: All randomized participants who received any amount of study drug and had analyzable study data at the specified timepoint.

The volume of the primary uterine fibroid was measured by transvaginal or transabdominal ultrasound.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=95 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=98 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume	-17.4 percent change Interval -29.1 to -5.7	-7.4 percent change Interval -19.1 to 4.2

SECONDARY outcome

Timeframe: From Baseline up to Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

The volume of the uterus was measured by transvaginal or transabdominal ultrasound.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=95 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=100 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 24 In Uterine Volume	-13.8 percent change Interval -20.4 to -7.1	-1.5 percent change Interval -8.2 to 5.1

SECONDARY outcome

Timeframe: Baseline Week 24

Population: All randomized participants who received any amount of study drug.

The Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QoL) Bleeding and Pelvic Discomfort (BPD) Scale has been derived from the UFS-QoL Symptoms Scale. The scale consists of the following 3 symptoms proximal to uterine fibroids: Heavy bleeding during your menstrual period (Question [Q] 1), passing blood clots during your menstrual period (Q2), and feeling tightness or pressure in your pelvic area (Q5), raw scores were transformed to a normalized score: Transformed Score = [(Actual raw score - lowest possible raw score)/(Possible raw score range)]*100 Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates symptom severity.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)	-51.7 units on a scale Interval -57.4 to -46.0	-18.3 units on a scale Interval -24.1 to -12.6

SECONDARY outcome

Timeframe: From Baseline up to Week 12

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA) at the lumbar spine (L1, L2, L3, and L4) at Baseline and at Week 12. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline MBL volume, age at Baseline, body mass index at Baseline, BMD at Baseline, race, and treatment by visit interaction included as fixed effects.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=103 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 to L4) As Assessed By DXA	-0.819 percent change Standard Error 0.2686	-1.919 percent change Standard Error 0.2767

SECONDARY outcome

Timeframe: Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

BMD was assessed by DXA at the lumbar spine (L1, L2, L3, and L4), total hip, and femoral neck (same leg across participants) at Baseline and at Week 24. The scans were read by the central radiology laboratory in accordance with the imaging charter. The same DXA machine was used at the local imaging center at each site and operated in the same scan mode for all images procured for an individual participant. All images were submitted for central reading. The central radiology laboratory collected and evaluated all DXA scans for acceptability and measured BMD. The LS means were based on a mixed-effect model with visit, region, Baseline MBL volume, age at Baseline, body mass index at Baseline, BMD at Baseline, race, and treatment by visit interaction included as fixed effects. For Relugolix plus E2/NETA Lumbar Spine (L1 to L4), number (n)=95.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only rel

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=98 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck As Assessed By DXA Lumbar Spine (L1-L4)	-0.126 percent change Standard Error 0.2971	0.315 percent change Standard Error 0.2909
Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck As Assessed By DXA Total Hip	-0.173 percent change Standard Error 0.2221	-0.044 percent change Standard Error 0.2200
Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck As Assessed By DXA Femoral Neck	-0.684 percent change Standard Error 0.3730	0.019 percent change Standard Error 0.3697

SECONDARY outcome

Timeframe: Baseline through Week 12

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

An adverse event was defined as an unfavorable or 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. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term. Reported confidence interval (CI) based on exact binomial 95% CI (Clopper-Pearson). As per the objective of the study, the secondary analysis compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12 and are presented below.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=126 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=126 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12	5.56 percentage of participants Interval 2.26 to 11.11	35.71 percentage of participants Interval 27.38 to 44.74

SECONDARY outcome

Timeframe: Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

An adverse event was defined as an unfavorable or 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. The preferred terms of hyperhidrosis, feeling hot, hot flush, night sweats, and flushing were combined to describe vasomotor symptoms. Participants with multiple events for a given preferred term were counted only once for each preferred term.

Reported percentages based on the total number of participants in each treatment group.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=126 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24	6.3 percentage of participants	3.9 percentage of participants

SECONDARY outcome

Timeframe: Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Blood samples for determination of relugolix and NET plasma concentrations were collected predose at Week 24. Relugolix and NET plasma concentrations were determined using validated bioanalytical methodology.

Concentrations below the quantification limit (BQL) were set to 0 for analysis of summary statistics. As per the objective of the study, only relugolix plus E2/NETA concentration is presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=93 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24 Relugolix	1.96 ng/mL Standard Deviation 2.025	—
Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24 NET	0.28 ng/mL Standard Deviation 0.285	—

SECONDARY outcome

Timeframe: Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Blood samples for determination of relugolix and NET plasma concentrations were collected predose at Week 24. Relugolix and NET plasma concentrations were determined using validated bioanalytical methodology.

Concentrations below the quantification limit (BQL) were set to 0 for analysis of summary statistics. As per the objective of the study, only relugolix plus E2/NETA concentration is presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=88 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24	45.34 pg/mL Standard Deviation 46.330	—

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Blood samples for determination of E2 serum concentrations were collected predose at Week 24. Relugolix and NET plasma concentrations were determined using validated bioanalytical methodology.

Concentrations below the quantification limit (BQL) were set to 0 for analysis of summary statistics. As per the objective of the study, only relugolix plus E2/NETA concentration is presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=93 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In Predose Concentrations Of E2 In The Relugolix Plus E2/NETA Group	-22.30 pg/mL Standard Deviation 66.552	—

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug.

Defined as the time to achieve an MBL volume of < 80 mL and a ≥ 50% reduction from Baseline MBL volume as measured by the alkaline hematin method.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=104 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=34 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Time To MBL Response	8.4 weeks Interval 8.1 to 9.0	27.1 weeks Interval 25.0 to 27.4

SECONDARY outcome

Timeframe: Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug.

Sustained amenorrhea is defined as participants time to achieve and maintain amenorrhea until the date of last study drug.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Sustained Amenorrhea Rate (No Or Negligible Bleeding)	63 Participants	4 Participants

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug.

Sustained amenorrhea status as determined based on time to achieve and maintain amenorrhea status.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=63 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=4 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)	16.3 weeks Interval 8.1 to Not evaluable.	NA weeks Sustained amenorrhea was not reached.

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Time to amenorrhea was defined as the weeks from date of first dose of study drug to the start of amenorrhea.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=71 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=11 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Time To Achieving Amenorrhea (No Or Negligible Bleeding)	8.9 weeks Interval 5.3 to 16.3	NA weeks Amenorrhea was not reached.

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment, received at least 1 dose of study drug, and had hemoglobin ≤ 10.5 g/dL at Baseline and an assessment at Week 24.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=31 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=37 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24	19 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All randomized participants who received any amount of study drug and had analyzable data at the specified timeframe.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=31 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=37 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline	24.3 percent change Standard Error 3.02	4.3 percent change Standard Error 2.68

SECONDARY outcome

Timeframe: Week 24

Population: All randomized participants who received any amount of study drug and had analyzable data at the specified timeframe.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=69 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=75 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal	35 Participants	18 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of time, most of the time and all of the time.) Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity. A negative change from baseline indicates improvement.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score	-36.1 score on a scale Standard Error 2.59	-13.7 score on a scale Standard Error 2.61

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Higher scores are indicative of better health-related quality of life (high score = good).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score	43.6 score on a scale Standard Error 2.77	17.1 score on a scale Standard Error 2.80

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (none of time, a little of time, some of the time, most of the time and all of the time). Higher scores are indicative of better health-related quality of life (high score = good). LS means and p-value for test of difference was relugolix plus E2/NETA minus placebo based on mixed-effect model with treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score	44.4 units on a scale Standard Error 2.90	16.5 units on a scale Standard Error 2.94

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

The UFS-QoL total score was the sum of 6 subscales (concern, activities, energy/mood, control, self-conscious, and sexual function). The raw scores were transformed to normalized scores. Transformed score ranges from 0 to 100. Higher scores are indicative of better health-related quality of life (high = good).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline In UFS-QoL Score by Health-Related Quality of Life Total Score	37.8 units on a scale Standard Error 2.49	13.8 units on a scale Standard Error 2.51

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score	78 Participants	42 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.

The Bleeding and Pelvic Discomfort Scale consists of 3 items proximal to uterine fibroids that are experienced by most participants (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]).Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity. A negative change from baseline indicates improvement.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline in UFS-QoL Bleeding and Pelvic Discomfort Scale Score	-51.7 score on a scale Standard Error 2.91	-18.3 score on a scale Standard Error 2.95

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug.

Responder was defined as meeting a meaningful change threshold, set as a 20-point change from Baseline, in the Bleeding And Pelvic Discomfort Scale at Week 24 on the transformed score.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=125 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=129 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Responders With At Least 20 Points Decrease in UFS-QoL Bleeding And Pelvic Discomfort Scale Score	79 Participants	37 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity. A negative change from baseline indicates improvement.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11	-2.0 score on a scale Standard Error 0.14	-0.7 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity. A negative change from baseline indicates improvement.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20	-1.8 score on a scale Standard Error 0.13	-0.6 score on a scale Standard Error 0.13

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Transformed score ranges from 0 to 100 based on Likert scale (None of time, a little of time, some of the time, most of the time and all of the time). Lower score indicates minimal symptom severity and higher score indicates maximum symptom severity. A negative change from baseline indicates improvement.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=96 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29	-1.4 score on a scale Standard Error 0.14	-0.7 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

PGAs assessed participants' limitation in activities and the severity of symptoms due to uterine fibroids over the previous 4 weeks, as perceived by the participant. The PGA for symptoms is a 1-item questionnaire designed to assess participant's impression of the severity of their symptoms related to uterine fibroids. The PGA for function and symptoms was evaluated using a 5-point response scale (no limitation at all [1], mild limitation [2], moderate limitation [3], quite a bit of limitation [4], and extreme limitation [5]).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=80 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=84 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire	-2.0 score on a scale Standard Error 0.14	-0.8 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

PGAs assessed participants' limitation in activities and the severity of symptoms due to uterine fibroids over the previous 4 weeks, as perceived by the participant. The PGA for symptoms is a 1-item questionnaire designed to assess participant's impression of the severity of their symptoms related to uterine fibroids. The PGA for function and symptoms was evaluated using a 5-point response scale (no limitation at all [1], mild limitation [2], moderate limitation [3], quite a bit of limitation [4], and extreme limitation [5]).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=80 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=84 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire	-1.7 score on a scale Standard Error 0.15	-0.8 score on a scale Standard Error 0.15

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The PGAs assessed participants' limitation in activities and the severity of symptoms due to uterine fibroids over the previous 4 weeks, as perceived by the participant. The PGA for function and symptoms was evaluated using a 5-point response scale (no limitation at all [1], mild limitation [2], moderate limitation [3], quite a bit of limitation [4], and extreme limitation [5]). Category improvements for symptoms are presented. A 1-category improvement would be severe at baseline to moderate.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=80 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=84 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 1 Category improvement (-1)	7 Participants	21 Participants
Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 3 Category improvement (-3)	22 Participants	8 Participants
Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 2 Category improvement (-2)	29 Participants	18 Participants
Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 4 Category improvement (-4)	10 Participants	2 Participants

SECONDARY outcome

Timeframe: From Baseline through Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The PGAs assessed participants' limitation in activities and the severity of symptoms due to uterine fibroids over the previous 4 weeks, as perceived by the participant. The PGA for function and symptoms was evaluated using a 5-point response scale (no limitation at all [1], mild limitation [2], moderate limitation [3], quite a bit of limitation [4], and extreme limitation [5]). Category improvements for symptoms are presented. A 1-category improvement would be severe at Baseline to moderate.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=80 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=84 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 1 Category improvement (-1)	13 Participants	19 Participants
Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 2 Category improvement (-2)	30 Participants	13 Participants
Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 3 Category improvement (-3)	18 Participants	10 Participants
Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 4 Category improvement (-4)	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The Menorrhagia Impact was evaluated using a 5-point response scale to assess level of improvement from Baseline to Week 24. Response scale: Not at all, 2. Slightly, 3.Moderately, 4. Quite a bit and 5. Extremely.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=94 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities	-1.8 score on a scale Standard Error 0.14	-0.9 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The Menorrhagia Impact was evaluated using a 5-point response scale to assess level of improvement from Baseline to Week 24. Response scale: Not at all, 2. Slightly, 3.Moderately, 4. Quite a bit and 5. Extremely.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=94 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities	-1.8 score on a scale Standard Error 0.14	-1.0 score on a scale Standard Error 0.14

SECONDARY outcome

Timeframe: From Baseline up to the last 35 days of treatment (up to 24 weeks)

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug who had a maximum NRS score ≥ 4 at baseline.

Uterine fibroid-associated pain was assessed by a pain NRS. The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=93 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=95 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Participants Who Achieved A Maximum NRS Score ≤ 1 For Uterine Fibroid-associated Pain Over The Last 35 Days Of Treatment Who Had Maximum Pain Scores ≥ 4 During The 35 Days Prior To Randomization	34 Participants	17 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug who had a maximum NRS score ≥ 4 at baseline and had at least 28 days (80% of the last 35 days of treatment) of pain scores recorded in the e-Diary.

Uterine fibroid-associated pain was assessed by a pain NRS. The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain).

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=68 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=82 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Number Of Participants With A ≥ 30% Reduction in NRS Score From Baseline to Last 35 Days of Treatment Who Had Maximum Pain Scores ≥ 4 At Baseline	48 Participants	34 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=92 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=93 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline In Luteinizing Serum Concentration At Week 24	-3.10 IU/L Standard Deviation 4.807	3.04 IU/L Standard Deviation 13.162

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=92 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=93 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline In Follicle Stimulating Serum Concentration At Week 24	-5.47 IU/L Standard Deviation 9.049	-0.67 IU/L Standard Deviation 7.422

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=93 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=90 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline In E2 Serum Concentration At Week 24	-22.30 pg/mL Standard Deviation 66.552	39.85 pg/mL Standard Deviation 99.578

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.

Outcome measures

Measure	Relugolix Plus E2/NETA (Group A) n=92 Participants Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo (Group C) n=93 Participants Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Change From Baseline In Progesterone Serum Concentration At Week 24	0.12 ng/mL Standard Deviation 3.963	3.48 ng/mL Standard Deviation 5.415

Adverse Events

Relugolix Plus E2/NETA (Group A)

Serious events: 1 serious events

Other events: 31 other events

Deaths: 0 deaths

Relugolix Plus Delayed E2/NETA (Group B)

Serious events: 2 serious events

Other events: 67 other events

Deaths: 0 deaths

Placebo (Group C)

Serious events: 4 serious events

Other events: 42 other events

Deaths: 0 deaths

Serious adverse events

Measure	Relugolix Plus E2/NETA (Group A) n=126 participants at risk Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix Plus Delayed E2/NETA (Group B) n=126 participants at risk Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	Placebo (Group C) n=129 participants at risk Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Injury, poisoning and procedural complications Radius fracture	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.78% 1/129 • Number of events 1 • From Day 1 to End of Study (24 Weeks)
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.78% 1/129 • Number of events 1 • From Day 1 to End of Study (24 Weeks)
Blood and lymphatic system disorders Anaemia	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.78% 1/129 • Number of events 1 • From Day 1 to End of Study (24 Weeks)
Nervous system disorders Syncope	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.78% 1/129 • Number of events 1 • From Day 1 to End of Study (24 Weeks)
Hepatobiliary disorders Cholecystitis	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/129 • From Day 1 to End of Study (24 Weeks)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	0.00% 0/129 • From Day 1 to End of Study (24 Weeks)
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	0.00% 0/129 • From Day 1 to End of Study (24 Weeks)
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	0.00% 0/129 • From Day 1 to End of Study (24 Weeks)
Infections and infestations Necrotising fasciitis	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.00% 0/126 • From Day 1 to End of Study (24 Weeks)	0.78% 1/129 • Number of events 1 • From Day 1 to End of Study (24 Weeks)

Other adverse events

Measure	Relugolix Plus E2/NETA (Group A) n=126 participants at risk Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix Plus Delayed E2/NETA (Group B) n=126 participants at risk Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	Placebo (Group C) n=129 participants at risk Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Vascular disorders Hot flush	5.6% 7/126 • Number of events 7 • From Day 1 to End of Study (24 Weeks)	34.9% 44/126 • Number of events 46 • From Day 1 to End of Study (24 Weeks)	3.9% 5/129 • Number of events 5 • From Day 1 to End of Study (24 Weeks)
Vascular disorders Hypertension	4.0% 5/126 • Number of events 5 • From Day 1 to End of Study (24 Weeks)	5.6% 7/126 • Number of events 7 • From Day 1 to End of Study (24 Weeks)	3.1% 4/129 • Number of events 4 • From Day 1 to End of Study (24 Weeks)
Blood and lymphatic system disorders Anaemia	1.6% 2/126 • Number of events 2 • From Day 1 to End of Study (24 Weeks)	1.6% 2/126 • Number of events 2 • From Day 1 to End of Study (24 Weeks)	5.4% 7/129 • Number of events 7 • From Day 1 to End of Study (24 Weeks)
Nervous system disorders Headache	8.7% 11/126 • Number of events 15 • From Day 1 to End of Study (24 Weeks)	22.2% 28/126 • Number of events 34 • From Day 1 to End of Study (24 Weeks)	11.6% 15/129 • Number of events 21 • From Day 1 to End of Study (24 Weeks)
General disorders Fatigue	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	5.6% 7/126 • Number of events 7 • From Day 1 to End of Study (24 Weeks)	1.6% 2/129 • Number of events 2 • From Day 1 to End of Study (24 Weeks)
Gastrointestinal disorders Nausea	4.8% 6/126 • Number of events 6 • From Day 1 to End of Study (24 Weeks)	3.2% 4/126 • Number of events 4 • From Day 1 to End of Study (24 Weeks)	7.8% 10/129 • Number of events 11 • From Day 1 to End of Study (24 Weeks)
Musculoskeletal and connective tissue disorders Arthralgia	0.79% 1/126 • Number of events 1 • From Day 1 to End of Study (24 Weeks)	6.3% 8/126 • Number of events 11 • From Day 1 to End of Study (24 Weeks)	3.1% 4/129 • Number of events 6 • From Day 1 to End of Study (24 Weeks)
Infections and infestations Upper respiratory tract infection	4.8% 6/126 • Number of events 6 • From Day 1 to End of Study (24 Weeks)	2.4% 3/126 • Number of events 3 • From Day 1 to End of Study (24 Weeks)	5.4% 7/129 • Number of events 7 • From Day 1 to End of Study (24 Weeks)

Additional Information

Clinical Trials at Myovant

Myovant Sciences GmbH

Phone: +1 650 238 0250

Email: clinicaltrials@myovant.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60