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

• ClinicalTrials.gov Identifier: NCT03103087
• Recruitment Status: Completed
• First Posted: April 6, 2017
• Results First Posted: April 20, 2022
• Last Update Posted: April 20, 2022
• Sponsor: Myovant Sciences GmbH
• Information provided by (Responsible Party): Myovant Sciences GmbH

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Conditions: Heavy Menstrual Bleeding; Uterine Fibroid
• Interventions: Drug: Relugolix; Drug: Estradiol/norethindrone acetate; Drug: Relugolix placebo; Drug: Estradiol/norethindrone acetate placebo
• Enrollment: 382

Participant Flow

Recruitment Details	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.
Pre-assignment Details	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.

Arm/Group Title	Relugolix Plus Estradiol (E2])/Norethindrone Acetate (NETA) (Group A)	Relugolix Plus Delayed E2/NETA (Group B)	Placebo (Group C)
Arm/Group Description	Relugolix 40 milligrams (mg) co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	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 for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Period Title: Overall Study
Started	126	127	129
Completed	102	98	102
Not Completed	24	29	27
Reason Not Completed
Did not receive any study drug	1	0	0
Protocol Violation	1	2	1
Lack of Efficacy	2	1	1
Pregnancy	0	0	1
Adverse Event	2	15	6
Withdrawal by Subject	13	6	6
Lost to Follow-up	4	2	7
Other reason not reported	1	3	5

Baseline Characteristics

Arm/Group Title		Relugolix Plus E2/NETA (Group A)	Relugolix Plus Delayed E2/NETA (Group B)	Placebo (Group C)	Total
Arm/Group Description		Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	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 for relugolix co-administered with placebo for E2/NETA for 24 weeks	Total of all reporting groups
Overall Number of Baseline Participants		126	127	129	382
Baseline Analysis Population Description		All participants who were enrolled and randomized in the study.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	126 100.0%	127 100.0%	129 100.0%	382 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
		42.4 (5.37)	42.1 (5.25)	41.8 (5.26)	42.1 (5.29)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
	Female	126 100.0%	127 100.0%	129 100.0%	382 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
	Hispanic or Latino	18 14.3%	34 26.8%	32 24.8%	84 22.0%
	Not Hispanic or Latino	106 84.1%	91 71.7%	96 74.4%	293 76.7%
	Unknown or Not Reported	2 1.6%	2 1.6%	1 0.8%	5 1.3%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
	American Indian or Alaska Native	0 0.0%	2 1.6%	1 0.8%	3 0.8%
	Asian	0 0.0%	3 2.4%	1 0.8%	4 1.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	63 50.0%	66 52.0%	74 57.4%	203 53.1%
	White	58 46.0%	50 39.4%	49 38.0%	157 41.1%
	More than one race	1 0.8%	1 0.8%	0 0.0%	2 0.5%
	Unknown or Not Reported	4 3.2%	5 3.9%	4 3.1%	13 3.4%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	126 participants	127 participants	129 participants	382 participants
Hungary		7	7	8	22
Belgium		0	3	1	4
United States		94	94	96	284
Czechia		4	2	3	9
Poland		7	6	4	17
Brazil		1	3	1	5
South Africa		7	3	7	17
Chile		6	9	9	24
Mean MBL Volume; Mean (Standard Deviation); Unit of measure: mL
	Number Analyzed	126 participants	127 participants	129 participants	382 participants
		247.62 (185.553)	227.41 (34.350)	211.75 (129.903)	228.45 (152.205)

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	From Baseline up to the last 35 days of treatment (up to Week 24)

Outcome Measure Data

Analysis Population Description

All randomized participants who received any amount of study drug.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	125	129
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	71.2; (62.42 to 78.95)	14.73; (9.11 to 22.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was stratified by baseline MBL volume (< 225 mL or ≥ 225 mL) and geographic region (North America or Rest of World). Assessed at a 2-sided α = 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	56.47
	Confidence Interval	(2-Sided) 95%; 46.45 to 66.49
	Estimation Comments	Treatment difference is relugolix plus E2/NETA minus placebo.

2. Secondary Outcome

Title	Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment
Description	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.
Time Frame	From Baseline up to last 35 days of treatment (up to Week 24)

Outcome Measure Data

Analysis Population Description

All randomized participants who received any amount of study drug.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	125	129
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	50.40; (41.32 to 59.46)	3.10; (0.85 to 7.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America or Rest of World). Assessed at a 2-sided α = 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments	Treatment difference was relugolix plus E2/NETA minus placebo. 95% confidence interval (CI) for the difference is based on the normal approximation.
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	47.3
	Confidence Interval	(2-Sided) 95%; 38.04 to 56.56
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Percent Change From Baseline At Week 24 In MBL Volume
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received any amount of study drug.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	125	129
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-84.3; (-95.0 to -73.6)	-15.1; (-25.8 to -4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects. Assessed at a 2-sided α = 0.05 significance.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-69.2
	Confidence Interval	(2-Sided) 95%; -84.1 to -54.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.58
	Estimation Comments	Treatment difference was relugolix plus E2/NETA minus placebo.

4. Secondary Outcome

Title	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
Description	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.
Time Frame	From Baseline up to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	31	37
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	61.29; (42.19 to 78.15)	5.41; (0.66 to 18.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL). Assessed at a 2-sided α = 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	55.88
	Confidence Interval	(2-Sided) 95%; 37.25 to 74.52
	Estimation Comments	Treatment difference is relugolix plus E2/NETA minus placebo. 95% CI for difference is based on the normal approximation.

5. Secondary Outcome

Title	Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment
Description	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.
Time Frame	From Baseline up to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received any amount of study drug.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.
Overall Number of Participants Analyzed	68	82
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	47.06; (34.83 to 59.55)	17.07; (9.66 to 26.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL). Assessed at a 2-sided α = 0.05 significance level.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	29.99
	Confidence Interval	(2-Sided) 95%; 15.6 to 44.38
	Estimation Comments	Treatment difference is relugolix plus E2/NETA minus placebo. 95% CI for difference is based on the normal approximation.

6. Secondary Outcome

Title	Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume
Description	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.
Time Frame	Baseline Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	95	98
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-17.4; (-29.1 to -5.7)	-7.4; (-19.1 to 4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.2153
	Comments	LS Means based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95%; -25.8 to 5.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.03
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percent Change From Baseline At Week 24 In Uterine Volume
Description	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.
Time Frame	From Baseline up to Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	95	100
Least Squares Mean (95% Confidence Interval); Unit of Measure: percent change
	-13.8; (-20.4 to -7.1)	-1.5; (-8.2 to 5.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.0078
	Comments	LS Means based on analysis of covariance model including treatment, randomization stratification factors, Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World), and Baseline values as covariate.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-12.2
	Confidence Interval	(2-Sided) 95%; -21.3 to -3.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.57
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)
Description	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
Time Frame	Baseline Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received any amount of study drug.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.
Overall Number of Participants Analyzed	96	95
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	-51.7; (-57.4 to -46.0)	-18.3; (-24.1 to -12.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Assessed at a 2-sided α = 0.05 significance level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-33.4
	Confidence Interval	(2-Sided) 95%; -41.2 to -25.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.98
	Estimation Comments	Relugolix plus E2/NETA minus placebo. Treatment, visit, region, Baseline MBL and treatment by visit interaction as fixed effects.

9. Secondary Outcome

Title	Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 to L4) As Assessed By DXA
Description	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.
Time Frame	From Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Relugolix Plus Delayed E2/NETA (Group B)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	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.
Overall Number of Participants Analyzed	103	95
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-0.819 (0.2686)	-1.919 (0.2767)

10. Secondary Outcome

Title	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
Description	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
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	98	95
Least Squares Mean (Standard Error); Unit of Measure: percent change
Lumbar Spine (L1-L4)	-0.126 (0.2971)	0.315 (0.2909)
Total Hip	-0.173 (0.2221)	-0.044 (0.2200)
Femoral Neck	-0.684 (0.3730)	0.019 (0.3697)

11. Secondary Outcome

Title	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12
Description	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.
Time Frame	Baseline through Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Relugolix Plus Delayed E2/NETA (Group B)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	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.
Overall Number of Participants Analyzed	126	126
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	5.56; (2.26 to 11.11)	35.71; (27.38 to 44.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Relugolix Plus Delayed E2/NETA (Group B)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.33
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24
Description	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.
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	126	129
Measure Type: Number; Unit of Measure: percentage of participants
	6.3	3.9

13. Secondary Outcome

Title	Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.
Overall Number of Participants Analyzed	93
Mean (Standard Deviation); Unit of Measure: ng/mL
Relugolix	1.96 (2.025)
NET	0.28 (0.285)

14. Secondary Outcome

Title	Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.
Overall Number of Participants Analyzed	88
Mean (Standard Deviation); Unit of Measure: pg/mL
	45.34 (46.330)

15. Secondary Outcome

Title	Change From Baseline At Week 24 In Predose Concentrations Of E2 In The Relugolix Plus E2/NETA Group
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.
Overall Number of Participants Analyzed	93
Mean (Standard Deviation); Unit of Measure: pg/mL
	-22.30 (66.552)

16. Secondary Outcome

Title	Time To MBL Response
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	104	34
Median (97.5% Confidence Interval); Unit of Measure: weeks
	8.4; (8.1 to 9.0)	27.1; (25.0 to 27.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-value is based on Log-rank test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World) from the proportional hazard regression model comparing relugolix plus E2/NETA with placebo.
	Method	Log Rank
	Comments	[Not Specified]

17. Secondary Outcome

Title	Sustained Amenorrhea Rate (No Or Negligible Bleeding)
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	125	129
Measure Type: Count of Participants; Unit of Measure: Participants
	63 50.4%	4 3.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value for testing difference between relugolix plus E2/NETA and placebo is based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

18. Secondary Outcome

Title	Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	63	4
Median (95% Confidence Interval); Unit of Measure: weeks
	16.3 [1]; (8.1 to NA)	NA [2]; (NA to NA)

[1]

Not evaluable.

[2]

Sustained amenorrhea was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on Log-rank test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World) from the proportional hazard regression model comparing relugolix plus E2/NETA with placebo.
	Method	Log Rank
	Comments	[Not Specified]

19. Secondary Outcome

Title	Time To Achieving Amenorrhea (No Or Negligible Bleeding)
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Relugolix placebo co-administered with E2/NETA placebo for 24 weeks.
Overall Number of Participants Analyzed	71	11
Median (95% Confidence Interval); Unit of Measure: weeks
	8.9; (5.3 to 16.3)	NA [1]; (NA to NA)

[1]

Amenorrhea was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	P-value is based on Log-rank test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World) from the proportional hazard regression model comparing relugolix plus E2/NETA with placebo.
	Method	Log Rank
	Comments	[Not Specified]

20. Secondary Outcome

Title	Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	31	37
Measure Type: Count of Participants; Unit of Measure: Participants
	19 61.3%	2 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

21. Secondary Outcome

Title	Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	31	37
Least Squares Mean (Standard Error); Unit of Measure: percent change
	24.3 (3.02)	4.3 (2.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

22. Secondary Outcome

Title	Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	69	75
Measure Type: Count of Participants; Unit of Measure: Participants
	35 50.7%	18 24.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World). Lower limit of normal is Hgb < 11.6 g/dL.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

23. Secondary Outcome

Title	Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-36.1 (2.59)	-13.7 (2.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

24. Secondary Outcome

Title	Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	43.6 (2.77)	17.1 (2.80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

25. Secondary Outcome

Title	Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	44.4 (2.90)	16.5 (2.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

26. Secondary Outcome

Title	Change From Baseline In UFS-QoL Score by Health-Related Quality of Life Total Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	37.8 (2.49)	13.8 (2.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

27. Secondary Outcome

Title	Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	125	129
Measure Type: Count of Participants; Unit of Measure: Participants
	78 62.4%	42 32.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

28. Secondary Outcome

Title	Change From Baseline in UFS-QoL Bleeding and Pelvic Discomfort Scale Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-51.7 (2.91)	-18.3 (2.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

29. Secondary Outcome

Title	Number Of Responders With At Least 20 Points Decrease in UFS-QoL Bleeding And Pelvic Discomfort Scale Score
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	125	129
Measure Type: Count of Participants; Unit of Measure: Participants
	79 63.2%	37 28.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

30. Secondary Outcome

Title	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-2.0 (0.14)	-0.7 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

31. Secondary Outcome

Title	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.8 (0.13)	-0.6 (0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

32. Secondary Outcome

Title	Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	96	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.4 (0.14)	-0.7 (0.14)

33. Secondary Outcome

Title	Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	80	84
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-2.0 (0.14)	-0.8 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	LS means and p-value 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.
	Method	Mixed Models Analysis
	Comments	[Not Specified]

34. Secondary Outcome

Title	Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	80	84
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.7 (0.15)	-0.8 (0.15)

35. Secondary Outcome

Title	Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	80	84
Measure Type: Count of Participants; Unit of Measure: Participants
1 Category improvement (-1)	7 8.8%	21 25.0%
3 Category improvement (-3)	22 27.5%	8 9.5%
2 Category improvement (-2)	29 36.3%	18 21.4%
4 Category improvement (-4)	10 12.5%	2 2.4%

36. Secondary Outcome

Title	Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24
Description	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.
Time Frame	From Baseline through Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	80	84
Measure Type: Count of Participants; Unit of Measure: Participants
1 Category improvement (-1)	13 16.3%	19 22.6%
2 Category improvement (-2)	30 37.5%	13 15.5%
3 Category improvement (-3)	18 22.5%	10 11.9%
4 Category improvement (-4)	4 5.0%	2 2.4%

37. Secondary Outcome

Title	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	94	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.8 (0.14)	-0.9 (0.14)

38. Secondary Outcome

Title	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	94	95
Least Squares Mean (Standard Error); Unit of Measure: score on a scale
	-1.8 (0.14)	-1.0 (0.14)

39. Secondary Outcome

Title	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
Description	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.
Time Frame	From Baseline up to the last 35 days of treatment (up to 24 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	93	95
Measure Type: Count of Participants; Unit of Measure: Participants
	34 36.6%	17 17.9%

40. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	68	82
Measure Type: Count of Participants; Unit of Measure: Participants
	48 70.6%	34 41.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix Plus E2/NETA (Group A), Placebo (Group C)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0004
	Comments	P-value was based on Cochran-Mantel-Haenszel test stratified by Baseline MBL volume (< 225 mL, ≥ 225 mL) and geographic region (North America, Rest of World).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

41. Secondary Outcome

Title	Change From Baseline In Luteinizing Serum Concentration At Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	92	93
Mean (Standard Deviation); Unit of Measure: IU/L
	-3.10 (4.807)	3.04 (13.162)

42. Secondary Outcome

Title	Change From Baseline In Follicle Stimulating Serum Concentration At Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	92	93
Mean (Standard Deviation); Unit of Measure: IU/L
	-5.47 (9.049)	-0.67 (7.422)

43. Secondary Outcome

Title	Change From Baseline In E2 Serum Concentration At Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	93	90
Mean (Standard Deviation); Unit of Measure: pg/mL
	-22.30 (66.552)	39.85 (99.578)

44. Secondary Outcome

Title	Change From Baseline In Progesterone Serum Concentration At Week 24
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Relugolix Plus E2/NETA (Group A)	Placebo (Group C)
Arm/Group Description:	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks
Overall Number of Participants Analyzed	92	93
Mean (Standard Deviation); Unit of Measure: ng/mL
	0.12 (3.963)	3.48 (5.415)

Adverse Events

Time Frame	From Day 1 to End of Study (24 Weeks)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Relugolix Plus E2/NETA (Group A)		Relugolix Plus Delayed E2/NETA (Group B)		Placebo (Group C)
Arm/Group Description	Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.		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 for relugolix co-administered with placebo for E2/NETA for 24 weeks
All-Cause Mortality
	Relugolix Plus E2/NETA (Group A)		Relugolix Plus Delayed E2/NETA (Group B)		Placebo (Group C)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/126 (0.00%)		0/126 (0.00%)		0/129 (0.00%)
Serious Adverse Events
	Relugolix Plus E2/NETA (Group A)		Relugolix Plus Delayed E2/NETA (Group B)		Placebo (Group C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/126 (0.79%)		2/126 (1.59%)		4/129 (3.10%)
Blood and lymphatic system disorders
Anaemia † 1	0/126 (0.00%)	0	0/126 (0.00%)	0	1/129 (0.78%)	1
Hepatobiliary disorders
Cholecystitis † 1	1/126 (0.79%)	1	0/126 (0.00%)	0	0/129 (0.00%)	0
Cholecystitis acute † 1	0/126 (0.00%)	0	1/126 (0.79%)	1	0/129 (0.00%)	0
Infections and infestations
Necrotising fasciitis † 1	0/126 (0.00%)	0	0/126 (0.00%)	0	1/129 (0.78%)	1
Injury, poisoning and procedural complications
Radius fracture † 1	0/126 (0.00%)	0	0/126 (0.00%)	0	1/129 (0.78%)	1
Road traffic accident † 1	0/126 (0.00%)	0	0/126 (0.00%)	0	1/129 (0.78%)	1
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration † 1	0/126 (0.00%)	0	1/126 (0.79%)	1	0/129 (0.00%)	0
Intervertebral disc protrusion † 1	0/126 (0.00%)	0	1/126 (0.79%)	1	0/129 (0.00%)	0
Nervous system disorders
Syncope † 1	0/126 (0.00%)	0	0/126 (0.00%)	0	1/129 (0.78%)	1
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Relugolix Plus E2/NETA (Group A)		Relugolix Plus Delayed E2/NETA (Group B)		Placebo (Group C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/126 (24.60%)		67/126 (53.17%)		42/129 (32.56%)
Blood and lymphatic system disorders
Anaemia † 1	2/126 (1.59%)	2	2/126 (1.59%)	2	7/129 (5.43%)	7
Gastrointestinal disorders
Nausea † 1	6/126 (4.76%)	6	4/126 (3.17%)	4	10/129 (7.75%)	11
General disorders
Fatigue † 1	1/126 (0.79%)	1	7/126 (5.56%)	7	2/129 (1.55%)	2
Infections and infestations
Upper respiratory tract infection † 1	6/126 (4.76%)	6	3/126 (2.38%)	3	7/129 (5.43%)	7
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/126 (0.79%)	1	8/126 (6.35%)	11	4/129 (3.10%)	6
Nervous system disorders
Headache † 1	11/126 (8.73%)	15	28/126 (22.22%)	34	15/129 (11.63%)	21
Vascular disorders
Hot flush † 1	7/126 (5.56%)	7	44/126 (34.92%)	46	5/129 (3.88%)	5
Hypertension † 1	5/126 (3.97%)	5	7/126 (5.56%)	7	4/129 (3.10%)	4
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

None reported

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Clinical Trials at Myovant
• Organization: Myovant Sciences GmbH
• Phone: +1 650 238 0250
• EMail: clinicaltrials@myovant.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Al-Hendy A, Lukes AS, Poindexter AN 3rd, Venturella R, Villarroel C, McKain L, Li Y, Wagman RB, Stewart EA. Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas. Obstet Gynecol. 2022 Dec 1;140(6):920-930. doi: 10.1097/AOG.0000000000004988. Epub 2022 Nov 2.

Stewart EA, Lukes AS, Venturella R, Arjona Ferreira JC, Li Y, Hunsche E, Wagman RB, Al-Hendy A. Relugolix Combination Therapy for Uterine Leiomyoma-Associated Pain in the LIBERTY Randomized Trials. Obstet Gynecol. 2022 Jun 1;139(6):1070-1081. doi: 10.1097/AOG.0000000000004787. Epub 2022 May 2. Erratum In: Obstet Gynecol. 2022 Jul 1;140(1):138.

Hunsche E, Rakov V, Scippa K, Witherspoon B, McKain L. The Burden of Uterine Fibroids from the Perspective of US Women Participating in Open-Ended Interviews. Womens Health Rep (New Rochelle). 2022 Mar 4;3(1):286-296. doi: 10.1089/whr.2021.0086. eCollection 2022.

Al-Hendy A, Lukes AS, Poindexter AN 3rd, Venturella R, Villarroel C, Critchley HOD, Li Y, McKain L, Arjona Ferreira JC, Langenberg AGM, Wagman RB, Stewart EA. Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy. N Engl J Med. 2021 Feb 18;384(7):630-642. doi: 10.1056/NEJMoa2008283.

• Responsible Party: Myovant Sciences GmbH
• ClinicalTrials.gov Identifier: NCT03103087
• Other Study ID Numbers: MVT-601-3002; 2016-005113-50 ( EudraCT Number )
• First Submitted: February 8, 2017
• First Posted: April 6, 2017
• Results First Submitted: March 23, 2022
• Results First Posted: April 20, 2022
• Last Update Posted: April 20, 2022