LIBERTY 1: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03049735

Enrollment

388

Registered

2017-02-10

Start date

2017-04-26

Completion date

2020-08-24

Last updated

2022-04-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heavy Menstrual Bleeding, Uterine Fibroid

Keywords

Uterine Fibroid, Heavy Menstrual Bleeding, Menstrual Blood Volume

Brief summary

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

Detailed description

This study is an international phase 3 randomized, double-blind, placebo-controlled efficacy and safety study to evaluate 24 weeks of oral daily relugolix 40 mg co-administered with low-dose E2 and NETA (Group A) and 12 weeks of daily oral relugolix 40 mg alone followed by 12 weeks of daily oral relugolix 40 mg co-administered with low-dose E2 and NETA (Group B) compared with 24 weeks of placebo (Group C). All participants completing the Week 24 visit, including women randomized to placebo, were offered the opportunity to enroll in an open-label extension study in which all eligible participants will receive relugolix co-administered with low-dose E2 and NETA. Participants who did not enroll into the extension study had a follow-up visit approximately 30 days after the end of treatment (that is, after the participant's last dose of study medication). Safety will be assessed throughout the study by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and assessments of bone mineral density.

Interventions

DRUGRelugolix

Relugolix (40 mg) tablet administered orally once daily.

DRUGEstradiol/norethindrone acetate

E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily.

DRUGEstradiol/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.

DRUGRelugolix placebo

Relugolix (0 mg) placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 50 Years

Healthy volunteers

Inclusion criteria

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 patient'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.

Design outcomes

Primary

Measure	Time frame	Description
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	From Baseline up to last 35 days of treatment (up to Week 24)	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.

Secondary

Measure	Time frame	Description
Percent Change From Baseline At Week 24 In MBL Volume	Baseline, Week 24	MBL volume was measured using 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.
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	From Baseline up to 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.
Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment	From Baseline up to Week 24	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.
Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume	Baseline, Week 24	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.
Percent Change From Baseline At Week 24 In Uterine Volume	Baseline, Week 24	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.
Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)	Baseline, Week 24	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 maximum symptom severity. As per the study objective, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only these two arms are presented.
Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 To L4), As Assessed By DXA	Baseline, Week 12	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. As per the objective of the study, the pre-specified secondary analyses compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12 and are presented below.
Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Baseline, Week 24	BMD was assessed by DXA at the lumbar spine (L1, L2, L3, and L4), total hip, and femoral neck 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. 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.
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12	Baseline 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 CI based on exact binomial 95% CI (Clopper-Pearson). As per the objective of the study, this secondary analysis compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12 and are presented below.
Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24	Baseline 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.
Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24	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.
Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24	Week 24	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.
Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group	Baseline, Week 24	Blood samples for determination of 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 To MBL Response	From Baseline through Week 24	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. MBL volume was measured using 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.
Sustained Amenorrhea Rate (No Or Negligible Bleeding)	Week 24	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 To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)	From Baseline through Week 24	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 To Achieving Amenorrhea (No Or Negligible Bleeding)	From Baseline through Week 24	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.
Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24	From Baseline through 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.
Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline	Week 24	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. 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.
Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal	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.
Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score	Baseline, Week 24	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.
Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score	Baseline, Week 24	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. 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.
Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score	Baseline, Week 24	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. 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.
Change From Baseline In UFS-QoL Score By Health-Related Quality Of Life Total Score	Baseline, Week 24	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.
Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score	From Baseline through 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.
Change From Baseline In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	Baseline, Week 24	The Bleeding and Pelvic Discomfort Scale consists of 3 items proximal to uterine fibroids that are experienced by most patients (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.
Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	Baseline, Week 24	A 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.
Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11	Baseline, Week 24	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.
Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20	Baseline, Week 24	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.
Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29	Baseline, Week 24	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.
Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire	Baseline, 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 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.
Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire	Baseline, 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 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.
Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	From Baseline through 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.
Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	From Baseline through 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.
Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities	Baseline, Week 24	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.
Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities	Baseline, Week 24	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.
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	From Baseline up to the last 35 days of treatment (up to 24 weeks)	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.
Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment	From Baseline up to last 35 days of treatment (up to Week 24)	Amenorrhea was defined as meeting 1 of the following criteria for 2 consecutive visits: 1. No feminine product returned due to reported amenorrhea; 2. No feminine product returned due to reports of spotting/negligible bleeding coupled with electronic diary (eDiary) data indicating infrequent non-cyclic bleeding/spotting; 3. Feminine product collection with a negligible observed MBL volume coupled with eDiary 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.
Change From Baseline In Luteinizing Serum Concentration At Week 24	Baseline, 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.
Change From Baseline In Follicle Stimulating Serum Concentration At Week 24	Baseline, 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.
Change From Baseline In E2 Serum Concentration At Week 24	Baseline, 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.
Change From Baseline In Progesterone Serum Concentration At Week 24	Baseline, 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.
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	Baseline, Week 24	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.

Countries

Brazil, Italy, Poland, South Africa, United Kingdom, United States

Participant flow

Recruitment details

A total of 80 study centers globally were initiated in this study, including centers in the United States, Brazil, Italy, Poland, South Africa, and the United Kingdom.

Pre-assignment details

A total of 388 premenopausal women aged 18 to 50 years with heavy menstrual bleeding (≥ 80 milliliters \[mL\] per cycle for 2 cycles or ≥ 160 mL during 1 cycle documented by the alkaline hematin method) associated with uterine fibroids were randomized. One placebo participant was randomized and not treated due to a serious adverse event.

Participants by arm

Arm	Count
Relugolix Plus E2/NETA (Group A) Relugolix 40 mg co-administered with E2 (1.0 mg) and NETA (0.5 mg) for 24 weeks.	128
Relugolix Plus Delayed E2/NETA (Group B) Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks.	132
Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks.	128
Total	388

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	7	18	5
Overall Study	Discontinued due to AE (not dosed)	0	0	1
Overall Study	Lack of Efficacy	4	0	3
Overall Study	Lost to Follow-up	1	5	5
Overall Study	Other	5	3	1
Overall Study	Pregnancy	0	0	1
Overall Study	Protocol deviation	1	0	0
Overall Study	Withdrawal by Subject	10	3	7

Baseline characteristics

Characteristic	Relugolix Plus E2/NETA (Group A)	Total	Relugolix Plus Delayed E2/NETA (Group B)	Placebo (Group C)
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	128 Participants	388 Participants	132 Participants	128 Participants
Age, Continuous	42.5 years STANDARD_DEVIATION 4.99	42.0 years STANDARD_DEVIATION 5.38	41.3 years STANDARD_DEVIATION 5.39	42.2 years STANDARD_DEVIATION 5.7
Race/Ethnicity, Customized American Indian or Alaska Native	2 Participants	8 Participants	5 Participants	1 Participants
Race/Ethnicity, Customized Asian	0 Participants	4 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	59 Participants	192 Participants	67 Participants	66 Participants
Race/Ethnicity, Customized Ethnicity Not reported	2 Participants	3 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Hispanic or Latino	34 Participants	90 Participants	33 Participants	23 Participants
Race/Ethnicity, Customized Multiple Race	1 Participants	7 Participants	4 Participants	2 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	92 Participants	295 Participants	99 Participants	104 Participants
Race/Ethnicity, Customized Other Race	2 Participants	4 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Race Not reported	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized White	64 Participants	173 Participants	53 Participants	56 Participants
Region of Enrollment Brazil	3 participants	11 participants	5 participants	3 participants
Region of Enrollment Italy	10 participants	20 participants	7 participants	3 participants
Region of Enrollment Poland	12 participants	50 participants	16 participants	22 participants
Region of Enrollment South Africa	4 participants	7 participants	3 participants	0 participants
Region of Enrollment United Kingdom	1 participants	2 participants	0 participants	1 participants
Region of Enrollment United States	98 participants	298 participants	101 participants	99 participants
Sex: Female, Male Female	128 Participants	388 Participants	132 Participants	128 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 128	0 / 132	0 / 127
other Total, other adverse events	32 / 128	62 / 132	33 / 127
serious Total, serious adverse events	7 / 128	3 / 132	2 / 127

Outcome results

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.

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

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

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	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	73.4 Percentage of participants
Placebo (Group C)	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	18.9 Percentage of participants

Comparison: The primary efficacy analysis was the comparison of the relugolix + E2/NETA group with the placebo group with respect to responder rate.p-value: <0.000195% CI: [44.3, 64.78]Cochran-Mantel-Haenszel

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29	-1.5 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29	-0.4 score on a scale	Standard Error 0.14

Secondary

Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire

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 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

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire	-1.6 score on a scale	Standard Error 0.16
Placebo (Group C)	Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire	-0.5 score on a scale	Standard Error 0.15

Secondary

Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group

Blood samples for determination of 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

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group	-22.95 pg/mL	Standard Deviation 84.005

Secondary

Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire	-2.1 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire	-0.8 score on a scale	Standard Error 0.13

p-value: <0.0001Mixed Models Analysis

Secondary

Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11	-2.1 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11	-0.6 score on a scale	Standard Error 0.13

p-value: <0.0001Mixed Models Analysis

Secondary

Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20	-1.7 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20	-0.7 score on a scale	Standard Error 0.14

p-value: <0.0001Mixed Models Analysis

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities	-2.0 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities	-0.9 score on a scale	Standard Error 0.14

Secondary

Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities	-1.9 score on a scale	Standard Error 0.14
Placebo (Group C)	Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities	-0.8 score on a scale	Standard Error 0.14

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). Lower score indicates minimal symptom severity and higher score indicates maximum 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 are presented.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score	44.4 score on a scale	Standard Error 3.06
Placebo (Group C)	Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score	14.6 score on a scale	Standard Error 2.99

p-value: <0.0001Mixed Models Analysis

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). Lower score indicates minimal symptom severity and higher score indicates maximum 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 are presented.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score	45.8 units on a scale	Standard Error 3.19
Placebo (Group C)	Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score	15.1 units on a scale	Standard Error 3.12

p-value: <0.0001Mixed Models Analysis

Secondary

Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score	-30.9 score on a scale	Standard Error 2.61
Placebo (Group C)	Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score	-10.5 score on a scale	Standard Error 2.55

p-value: <0.0001Mixed Models Analysis

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

Time frame: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data for UFS-QoL BPD scores at the specified timepoints.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Relugolix Plus E2/NETA (Group A)	Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)	-45.0 units on a scale
Placebo (Group C)	Change From Baseline At Week 24 In UFS-QoL Bleeding And Pelvic Discomfort Scale Score As Measured By The UFS-QoL (Q1, Q2, Q5)	-16.1 units on a scale

p-value: <0.000195% CI: [-36.3, -21.5]Mixed Models Analysis

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In E2 Serum Concentration At Week 24	-22.95 pg/mL	Standard Deviation 84.005
Placebo (Group C)	Change From Baseline In E2 Serum Concentration At Week 24	51.72 pg/mL	Standard Deviation 145.346

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In Follicle Stimulating Serum Concentration At Week 24	-6.25 IU/L	Standard Deviation 14.779
Placebo (Group C)	Change From Baseline In Follicle Stimulating Serum Concentration At Week 24	0.10 IU/L	Standard Deviation 11.024

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In Luteinizing Serum Concentration At Week 24	-1.90 IU/L	Standard Deviation 20.496
Placebo (Group C)	Change From Baseline In Luteinizing Serum Concentration At Week 24	3.62 IU/L	Standard Deviation 12.524

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In Progesterone Serum Concentration At Week 24	-0.05 ng/mL	Standard Deviation 2.262
Placebo (Group C)	Change From Baseline In Progesterone Serum Concentration At Week 24	3.00 ng/mL	Standard Deviation 4.802

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 patients (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

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	-45.0 score on a scale	Standard Error 2.88
Placebo (Group C)	Change From Baseline In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	-16.1 score on a scale	Standard Error 2.81

p-value: <0.0001Mixed Models Analysis

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Change From Baseline In UFS-QoL Score By Health-Related Quality Of Life Total Score	38.0 units on a scale	Standard Error 2.8
Placebo (Group C)	Change From Baseline In UFS-QoL Score By Health-Related Quality Of Life Total Score	12.8 units on a scale	Standard Error 2.73

p-value: <0.0001Mixed Models Analysis

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.

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

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	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	33 Participants
Placebo (Group C)	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	11 Participants

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

Time frame: Baseline, Week 24

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	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	42 Participants
Placebo (Group C)	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	27 Participants

p-value: 0.0002Cochran-Mantel-Haenszel

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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24	15 Participants
Placebo (Group C)	Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24	5 Participants

p-value: 0.0377Cochran-Mantel-Haenszel

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.

Time frame: Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had hemoglobin below lower normal limit of normal at baseline.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal	34 Participants
Placebo (Group C)	Number Of Participants With Hemoglobin Increase Of ≥ 1 g/dL From Baseline To Week 24 Among Those With Below Lower Limit Of Normal	17 Participants

p-value: 0.0084Cochran-Mantel-Haenszel

Secondary

Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score

A 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

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	79 Participants
Placebo (Group C)	Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score	35 Participants

p-value: <0.0001Cochran-Mantel-Haenszel

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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score	78 Participants
Placebo (Group C)	Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score	45 Participants

p-value: <0.0001Cochran-Mantel-Haenszel

Secondary

Participants Achieving Improvement From Baseline In The 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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	1 Category improvement (-1)	14 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	2 Category improvement (-2)	29 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	3 Category improvement (-3)	22 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	4 Category improvement (-4)	8 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	4 Category improvement (-4)	5 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	1 Category improvement (-1)	28 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	3 Category improvement (-3)	1 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24	2 Category improvement (-2)	14 Participants

Secondary

Participants Achieving Improvement From Baseline In The PGA Questionnaire 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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	1 Category improvement (-1)	21 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	2 Category improvement (-2)	18 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	3 Category improvement (-3)	23 Participants
Relugolix Plus E2/NETA (Group A)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	4 Category improvement (-4)	2 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	4 Category improvement (-4)	4 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	1 Category improvement (-1)	16 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	3 Category improvement (-3)	4 Participants
Placebo (Group C)	Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24	2 Category improvement (-2)	9 Participants

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 CI based on exact binomial 95% CI (Clopper-Pearson). As per the objective of the study, this 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

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

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12	10.94 percentage of participants
Placebo (Group C)	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12	36.36 percentage of participants

p-value: <0.0001Fisher Exact

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.

Time frame: Baseline through Week 24

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

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24	14.8 percentage of participants
Placebo (Group C)	Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24	9.4 percentage of participants

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.

Time frame: From Baseline up to Week 24

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

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	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	50.0 Percentage of participants
Placebo (Group C)	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	21.74 Percentage of participants

p-value: =0.037795% CI: [3.68, 52.84]Cochran-Mantel-Haenszel

Secondary

Percentage Of Participants With A Maximum 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.

Time frame: From Baseline up to Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data for uterine fibroid-associated pain at the specified timepoints.

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment	43.10 Percentage of participants
Placebo (Group C)	Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment	10.14 Percentage of participants

p-value: <0.000195% CI: [18.36, 47.56]Cochran-Mantel-Haenszel

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: 1. No feminine product returned due to reported amenorrhea; 2. No feminine product returned due to reports of spotting/negligible bleeding coupled with electronic diary (eDiary) data indicating infrequent non-cyclic bleeding/spotting; 3. Feminine product collection with a negligible observed MBL volume coupled with eDiary 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)

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

Arm	Measure	Value (NUMBER)
Relugolix Plus E2/NETA (Group A)	Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment	52.34 percentage of participants
Placebo (Group C)	Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment	5.51 percentage of participants

p-value: <0.000195% CI: [37.31, 56.35]Cochran-Mantel-Haenszel

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. As per the objective of the study, the pre-specified secondary analyses compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12 and are presented below.

Time frame: Baseline, Week 12

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data for BMD at lumbar spine (L1 to L4) at the specified timepoints.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 To L4), As Assessed By DXA	-0.470 percent change	Standard Error 0.2915
Placebo (Group C)	Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 To L4), As Assessed By DXA	-1.995 percent change	Standard Error 0.2848

Secondary

Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck

BMD was assessed by DXA at the lumbar spine (L1, L2, L3, and L4), total hip, and femoral neck 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. 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

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data for BMD at the lumbar spine (L1 to L4), total hip, and femoral neck at the specified timepoints.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Lumbar Spine (L1 to L4)	-0.356 percent change	Standard Error 0.2929
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Total Hip	0.023 percent change	Standard Error 0.2461
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Femoral Neck	-0.262 percent change	Standard Error 0.4466
Placebo (Group C)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Lumbar Spine (L1 to L4)	0.052 percent change	Standard Error 0.2896
Placebo (Group C)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Total Hip	0.549 percent change	Standard Error 0.2407
Placebo (Group C)	Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck	Femoral Neck	0.307 percent change	Standard Error 0.4395

Secondary

Percent Change From Baseline At Week 24 In MBL Volume

MBL volume was measured using 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: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In MBL Volume	-84.3 percent change
Placebo (Group C)	Percent Change From Baseline At Week 24 In MBL Volume	-23.2 percent change

p-value: <0.000195% CI: [-73.5, -48.6]Mixed Models Analysis

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.

Time frame: Baseline, Week 24

Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had analyzable data for primary uterine fibroid volume at the specified timepoints.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume	-12.4 Percent change
Placebo (Group C)	Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume	-0.3 Percent change

p-value: 0.092195% CI: [-26.3, 2]ANCOVA

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.

Time frame: Baseline, Week 24

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline At Week 24 In Uterine Volume	-12.9 percent change
Placebo (Group C)	Percent Change From Baseline At Week 24 In Uterine Volume	2.2 percent change

p-value: 0.000295% CI: [-23, -7.3]ANCOVA

Secondary

Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline

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. 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

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

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline	20.8 percent change	Standard Error 3.05
Placebo (Group C)	Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline	10.0 percent change	Standard Error 3.53

p-value: 0.0117Mixed Models Analysis

Secondary

Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24

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: Week 24

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

Arm	Measure	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24	48.34 pg/mL	Standard Deviation 59.66

Secondary

Predose Trough Concentrations Of Relugolix And Norethindrone (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.

Time frame: Week 24

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

Arm	Measure	Group	Value (MEAN)	Dispersion
Relugolix Plus E2/NETA (Group A)	Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24	Relugolix	2.13 ng/mL	Standard Deviation 2.144
Relugolix Plus E2/NETA (Group A)	Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24	NET	0.33 ng/mL	Standard Deviation 0.369

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.

Time frame: Week 24

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Relugolix Plus E2/NETA (Group A)	Sustained Amenorrhea Rate (No Or Negligible Bleeding)	67 Participants
Placebo (Group C)	Sustained Amenorrhea Rate (No Or Negligible Bleeding)	7 Participants

p-value: <0.0001Cochran-Mantel-Haenszel

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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Value (MEDIAN)
Relugolix Plus E2/NETA (Group A)	Time To Achieving Amenorrhea (No Or Negligible Bleeding)	5.3 weeks
Placebo (Group C)	Time To Achieving Amenorrhea (No Or Negligible Bleeding)	NA weeks

p-value: <0.0001Log Rank

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.

Time frame: From Baseline through Week 24

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

Arm	Measure	Value (MEDIAN)
Relugolix Plus E2/NETA (Group A)	Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)	11.3 weeks
Placebo (Group C)	Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)	NA weeks

p-value: <0.0001Log Rank

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. MBL volume was measured using 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

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

Arm	Measure	Value (MEDIAN)
Relugolix Plus E2/NETA (Group A)	Time To MBL Response	8.3 weeks
Placebo (Group C)	Time To MBL Response	25.1 weeks

p-value: <0.0001Log Rank

Source: ClinicalTrials.gov · Data processed: Feb 22, 2026

LIBERTY 1: Efficacy & Safety Study of Relugolix in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids

Conditions

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Brief summary

Detailed description

Related papers

Interventions

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Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

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

Change From Baseline At Week 24 In Embarrassment Caused By Uterine Fibroids Based On UFS-QoL Question 29

Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire

Change From Baseline At Week 24 In Predose Concentrations Of Estradiol In The Relugolix Plus E2/NETA Group

Change From Baseline At Week 24 In Symptoms Assessed Using The Patient Global Assessment (PGA) Questionnaire

Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11

Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20

Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Physical Activities

Change From Baseline At Week 24 In The Menorrhagia Impact Questionnaire Score For Social Activities

Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score

Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score

Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score

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

Change From Baseline In E2 Serum Concentration At Week 24

Change From Baseline In Follicle Stimulating Serum Concentration At Week 24

Change From Baseline In Luteinizing Serum Concentration At Week 24

Change From Baseline In Progesterone Serum Concentration At Week 24

Change From Baseline In UFS-QoL Bleeding And Pelvic Discomfort Scale Score

Change From Baseline In UFS-QoL Score By Health-Related Quality Of Life Total Score

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

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

Number Of Participants With Hemoglobin ≤ 10.5 g/dL At Baseline And Achieved An Increase Of > 2 g/dL At Week 24

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

Number Of Responders With At Least 20 Points Decrease In UFS-QoL Bleeding And Pelvic Discomfort Scale Score

Number Of Responders With At Least 20 Points Increase From Baseline At Week 24 In UFS-QoL Revised Activities Scale Score

Participants Achieving Improvement From Baseline In The PGA Questionnaire For Symptoms From Baseline At Week 24

Participants Achieving Improvement From Baseline In The PGA Questionnaire For Uterine Fibroid-related Function From Baseline At Week 24

Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12

Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24

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

Percentage Of Participants With A Maximum NRS Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment

Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment

Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 To L4), As Assessed By DXA

Percent Change From Baseline At Week 24 In Bone Mineral Density At The Lumbar Spine (L1 To L4), Total Hip, And Femoral Neck

Percent Change From Baseline At Week 24 In MBL Volume

Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume

Percent Change From Baseline At Week 24 In Uterine Volume

Percent Change From Baseline In Hemoglobin For Women With a Hemoglobin ≤ 10.5 g/dL At Baseline

Predose Trough Concentrations Of E2 In The Relugolix Plus E2/NETA Group At Week 24

Predose Trough Concentrations Of Relugolix And Norethindrone (NET) In The Relugolix Plus E2/NETA Group At Week 24

Sustained Amenorrhea Rate (No Or Negligible Bleeding)

Time To Achieving Amenorrhea (No Or Negligible Bleeding)

Time To Achieving Sustained Amenorrhea (No Or Negligible Bleeding)

Time To MBL Response