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

Uterine Fibroid Clinical Trial

Official title:

LIBERTY 2: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co-Administered With and Without Low-Dose Estradiol and Norethindrone Acetate in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03103087
• Other study ID #: MVT-601-3002
• Secondary ID: 2016-005113-50
• Status: Completed
• Phase: Phase 3
• Start date: June 14, 2017
• Est. completion date: September 16, 2020

Study information

• Verified date: September 2021
• Source: Myovant Sciences GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 382
• Est. completion date: September 16, 2020
• Est. primary completion date: July 10, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

Key Inclusion Criteria:

1. Premenopausal female aged 18 to 50 years old (inclusive) on the day of signing and dating the informed consent form.

2. Has regularly occurring menstrual periods of = 14 days duration with a cycle of 21 to 38 days from the start of 1 menstrual period until the start of the next, by participant history for at least 3 months prior to the first screening visit.

3. Has a diagnosis of uterine fibroids that is confirmed by a transvaginal and/or transabdominal ultrasound performed during the screening period.

4. Has heavy menstrual bleeding associated with uterine fibroids as evidenced by an MBL of = 160 milliliter (mL) during 1 cycle or = 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method during the screening period.

Key Exclusion Criteria:

1. Has transvaginal and/or transabdominal ultrasound during the screening period demonstrating pathology other than uterine fibroids that could be responsible for or contributing to the participant's heavy menstrual bleeding.

2. Has known rapidly enlarging uterine fibroids in the opinion of the investigator.

3. Has a weight that exceeds the weight limit of the DXA scanner or has a condition that precludes an adequate DXA measurement at the lumbar spine and proximal femur.

4. Has a history of or currently has osteoporosis, or other metabolic bone disease, hyperparathyroidism, hyperprolactinemia, hyperthyroidism, anorexia nervosa, or low traumatic (from the standing position) or atraumatic fracture (toe, finger, skull, face and ankle fractures are allowed). A history of successfully treated hyperparathyroidism, hyperprolactinemia, or hyperthyroidism is allowed if the participant's bone mineral density is within normal limits.

5. Has a history of the use of bisphosphonates, calcitonin, calcitriol, ipriflavone, teriparatide, denosumab, or any medication other than calcium and vitamin D preparations to treat bone mineral density loss.

6. Has been a participant in an investigational drug or device study within the 1 month prior to the first screening visit.

Related Conditions & MeSH terms

• Heavy Menstrual Bleeding
• Hemorrhage
• Leiomyoma
• Menorrhagia
• Uterine Fibroid

Intervention

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

Locations

Country	Name	City	State
Belgium	Brussels	Brussels
Belgium	Brussels	Brussels
Belgium	Ghent	Ghent
Belgium	Jette	Jette
Belgium	La Louvière	La Louvière
Brazil	Botucatu	Botucatu
Brazil	Porto Alegre	Porto Alegre
Brazil	Porto Alegre	Porto Alegre
Brazil	São Paulo	São Paulo
Chile	San Ramon	San Ramón
Chile	Santiago	Santiago
Chile	Santiago	Santiago
Chile	Santiago	Santiago	Providencia
Czechia	Ceské Budejovice	Ceské Budejovice
Czechia	Jihlava	Jihlava
Czechia	Nachod	Náchod
Czechia	Olomouc	Olomouc
Czechia	Ostrava	Ostrava
Czechia	Pisek	Písek
Hungary	Budapest	Budapest
Hungary	Debrecen	Debrecen
Hungary	Debrecen	Debrecen	Hajdu
Hungary	Gyula	Gyula
Hungary	Kecskemét	Kecskemét
Hungary	Nyíregyháza	Nyíregyháza	Szabolcs-Szatmar-Bereg
Hungary	Pecs	Pécs
Hungary	Szentes	Szentes
Poland	Bialystok	Bialystok	Podlaskie
Poland	Bialystok	Bialystok	Podlaskie
Poland	Gdansk	Gdansk
Poland	Katowice	Katowice	Slaskie
Poland	Krakow	Krakow	Malopolskie
Poland	Poznan	Poznan	Wielkopolskie
Poland	Rzeszów	Rzeszów	Mazowieckie
South Africa	Bloemfontein	Bloemfontein
South Africa	Cape Town	Cape Town	Western Cape
South Africa	Centurion	Centurion
South Africa	Parow	Parow
United States	Albuquerque	Albuquerque	New Mexico
United States	Atlanta	Atlanta	Georgia
United States	Aventura	Aventura	Florida
United States	Avon	Avon	Indiana
United States	Baltimore	Baltimore	Maryland
United States	Bay City	Bay City	Michigan
United States	Beaumont	Beaumont	Texas
United States	Birmingham	Birmingham	Alabama
United States	Brooklyn	Brooklyn	New York
United States	Canoga Park	Canoga Park	California
United States	Canton	Canton	Michigan
United States	Champaign	Champaign	Illinois
United States	Charleston	Charleston	South Carolina
United States	Chicago	Chicago	Illinois
United States	Cincinnati	Cincinnati	Ohio
United States	Columbus	Columbus	Ohio
United States	Covington	Covington	Washington
United States	Dallas	Dallas	Texas
United States	Dallas	Dallas	Texas
United States	Decatur	Decatur	Georgia
United States	DeLand	DeLand	Florida
United States	Denver	Denver	Colorado
United States	Detroit	Detroit	Michigan
United States	Duluth	Duluth	Georgia
United States	Durham	Durham	North Carolina
United States	Ft. Lauderdale	Fort Lauderdale	Florida
United States	Fort Worth	Fort Worth	Texas
United States	Frisco	Frisco	Texas
United States	Houston	Houston	Texas
United States	Houston	Houston	Texas
United States	Huntington Beach	Huntington Beach	California
United States	Idaho Falls	Idaho Falls	Idaho
United States	Jupiter	Jupiter	Florida
United States	Lake City	Lake City	Florida
United States	Lakewood	Lakewood	Colorado
United States	Las Vegas	Las Vegas	Nevada
United States	Las Vegas	Las Vegas	Nevada
United States	Las Vegas	Las Vegas	Nevada
United States	Long Beach	Long Beach	California
United States	Longview	Longview	Texas
United States	Los Angeles	Los Angeles	California
United States	Los Angeles	Los Angeles	California
United States	Loxahachee	Loxahatchee Groves	Florida
United States	Marrero	Marrero	Louisiana
United States	Mesa	Mesa	Arizona
United States	Metairie	Metairie	Louisiana
United States	Miami	Miami	Florida
United States	Miami	Miami	Florida
United States	Miami Springs	Miami Springs	Florida
United States	Nampa	Nampa	Idaho
United States	Naperville	Naperville	Illinois
United States	New Brunswick	New Brunswick	New Jersey
United States	New Orleans	New Orleans	Louisiana
United States	New Port Richey	New Port Richey	Florida
United States	New York	New York	New York
United States	New York	New York	New York
United States	Norcross	Norcross	Georgia
United States	Norfolk	Norfolk	Nebraska
United States	Virginia Beach	Norfolk	Virginia
United States	North Miami	North Miami	Florida
United States	Oakbrook	Oak Brook	Illinois
United States	Oviedo	Oviedo	Florida
United States	Panorama	Panorama City	California
United States	Plantation	Plantation	Florida
United States	Port St. Lucie	Port Saint Lucie	Florida
United States	Puyallup	Puyallup	Washington
United States	Raleigh	Raleigh	North Carolina
United States	Richmond	Richmond	Virginia
United States	Rochester	Rochester	New York
United States	Saginaw	Saginaw	Michigan
United States	Saint Cloud	Saint Cloud	Florida
United States	San Antonio	San Antonio	Texas
United States	San Diego	San Diego	California
United States	Sandy Springs	Sandy Springs	Georgia
United States	Sarasota	Sarasota	Florida
United States	Savannah	Savannah	Georgia
United States	Shawnee	Shawnee Mission	Kansas
United States	Spokane	Spokane	Washington
United States	Stuart	Stuart	Florida
United States	Tampa	Tampa	Florida
United States	Towson	Towson	Maryland
United States	Tucson	Tucson	Arizona
United States	Tuscon	Tucson	Arizona
United States	Upland	Upland	California
United States	Washington	Washington	District of Columbia
United States	Wellington	Wellington	Florida
United States	West Palm Beach	West Palm Beach	Florida
United States	West Reading	West Reading	Pennsylvania
United States	Winston Salem	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Myovant Sciences GmbH

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Chile,  Czechia,  Hungary,  Poland,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	From Baseline up to the last 35 days of treatment (up to Week 24)
Secondary	Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment	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.	From Baseline up to last 35 days of treatment (up to Week 24)
Secondary	Percent Change From Baseline At Week 24 In MBL Volume	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.	Baseline, Week 24
Secondary	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	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.	From Baseline up to Week 24
Secondary	Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score = 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment	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.	From Baseline up to Week 24
Secondary	Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume	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.	Baseline Week 24
Secondary	Percent Change From Baseline At Week 24 In Uterine Volume	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.	From Baseline up to Week 24
Secondary	Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)	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	Baseline Week 24
Secondary	Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 to L4) As Assessed By DXA	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.	From Baseline up to Week 12
Secondary	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	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	Baseline through Week 24
Secondary	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12	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.	Baseline through Week 12
Secondary	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24	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.	Baseline through Week 24
Secondary	Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24	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.	Week 24
Secondary	Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24	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.	Week 24
Secondary	Change From Baseline At Week 24 In Predose Concentrations Of E2 In The Relugolix Plus E2/NETA Group	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.	Baseline, Week 24
Secondary	Time To MBL Response	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.	From Baseline through Week 24
Secondary	Sustained Amenorrhea Rate (No Or Negligible Bleeding)	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.	Week 24
Secondary	Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)	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.	From Baseline through Week 24
Secondary	Time To Achieving Amenorrhea (No Or Negligible Bleeding)	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.	From Baseline through Week 24
Secondary	Number Of Participants With Hemoglobin = 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL 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.	From Baseline through Week 24
Secondary	Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration = 10.5 g/dL At Baseline	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.	Baseline, Week 24
Secondary	Number Of Participants With Hemoglobin Increase Of = 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal	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.	Week 24
Secondary	Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score	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.	Baseline, Week 24
Secondary	Change From Baseline In UFS-QoL Score by Health-Related Quality of Life Total Score	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.	Baseline, Week 24
Secondary	Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale 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.	From Baseline through Week 24
Secondary	Change From Baseline in UFS-QoL Bleeding and Pelvic Discomfort Scale Score	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.	Baseline, Week 24
Secondary	Number Of Responders With At Least 20 Points Decrease in UFS-QoL Bleeding And Pelvic Discomfort Scale Score	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire	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.	Baseline, Week 24
Secondary	Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24	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.	From Baseline through Week 24
Secondary	Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24	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.	From Baseline through Week 24
Secondary	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities	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.	Baseline, Week 24
Secondary	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities	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.	Baseline, Week 24
Secondary	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	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.	From Baseline up to the last 35 days of treatment (up to 24 weeks)
Secondary	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	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.	Baseline, Week 24
Secondary	Change From Baseline In Luteinizing Serum Concentration 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.	Baseline, Week 24
Secondary	Change From Baseline In Follicle Stimulating Serum Concentration 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.	Baseline, Week 24
Secondary	Change From Baseline In E2 Serum Concentration 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.	Baseline, Week 24
Secondary	Change From Baseline In Progesterone Serum Concentration 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.	Baseline, Week 24