Heavy Menstrual Bleeding, Uterine Fibroid
Conditions
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 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.
Interventions
DRUGRelugolix
Relugolix (40 mg) tablet administered orally once daily.
E2 (1.0 mg)/NETA (0.5 mg) co-formulated capsule administered orally once daily.
Relugolix (0 mg) placebo tablet administered orally once daily and manufactured to match the relugolix tablet in size, shape, color, and odor.
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.
Sponsors
Myovant Sciences GmbH
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
No
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 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.
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 the 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. 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. |
| 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 Numerical Rating Scale (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 | From Baseline up to 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 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 |
| Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 to L4) As Assessed By DXA | From Baseline up to 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. 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. |
| 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 | Baseline through Week 24 | 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 |
| 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. |
| 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 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. |
| 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 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 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. |
| Change From Baseline At Week 24 In Predose Concentrations Of E2 In The Relugolix Plus E2/NETA Group | Baseline, 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 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. 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. |
| Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline | 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 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 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). 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. |
| 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). 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. |
| 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 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. |
| Number Of Responders With At Least 20 Points Decrease in UFS-QoL Bleeding And Pelvic Discomfort Scale Score | Baseline, Week 24 | 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 | 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 | 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 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 PGA 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: * 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. |
| 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
Belgium, Brazil, Chile, Czechia, Hungary, Poland, South Africa, United States
Participant flow
Recruitment details
The study was conducted at 99 study centers throughout the world, including centers in the United States, Belgium, Brazil, Chile, Czech Republic, Hungary, Poland, and South Africa.
Pre-assignment details
A total of 382 premenopausal women aged 18 to 50 years old (inclusive) with heavy menstrual bleeding (≥ 160 milliliters \[mL\] during 1 cycle or ≥ 80 mL per cycle for 2 menstrual cycles as measured by the alkaline hematin method) associated with uterine fibroids were randomized. One participant was randomized in error before eligibility confirmed.
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. | 126 |
| Relugolix Plus Delayed E2/NETA (Group B) Relugolix 40 mg co-administered with placebo for E2/NETA for 12 weeks followed by relugolix 40 mg co-administered with E2/NETA (1.0/0.5 mg) for 12 weeks. | 127 |
| Placebo (Group C) Placebo for relugolix co-administered with placebo for E2/NETA for 24 weeks | 129 |
| Total | 382 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 15 | 6 |
| Overall Study | Did not receive any study drug | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 2 | 7 |
| Overall Study | Other reason not reported | 1 | 3 | 5 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 6 | 6 |
Baseline characteristics
| Characteristic | Relugolix Plus E2/NETA (Group A) | Total | Placebo (Group C) | Relugolix Plus Delayed E2/NETA (Group B) |
|---|---|---|---|---|
| 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 | 126 Participants | 382 Participants | 129 Participants | 127 Participants |
| Age, Continuous | 42.4 years STANDARD_DEVIATION 5.37 | 42.1 years STANDARD_DEVIATION 5.29 | 41.8 years STANDARD_DEVIATION 5.26 | 42.1 years STANDARD_DEVIATION 5.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 84 Participants | 32 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 106 Participants | 293 Participants | 96 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Mean MBL Volume | 247.62 mL STANDARD_DEVIATION 185.553 | 228.45 mL STANDARD_DEVIATION 152.205 | 211.75 mL STANDARD_DEVIATION 129.903 | 227.41 mL STANDARD_DEVIATION 34.35 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 63 Participants | 203 Participants | 74 Participants | 66 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 13 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) White | 58 Participants | 157 Participants | 49 Participants | 50 Participants |
| Region of Enrollment Belgium | 0 participants | 4 participants | 1 participants | 3 participants |
| Region of Enrollment Brazil | 1 participants | 5 participants | 1 participants | 3 participants |
| Region of Enrollment Chile | 6 participants | 24 participants | 9 participants | 9 participants |
| Region of Enrollment Czechia | 4 participants | 9 participants | 3 participants | 2 participants |
| Region of Enrollment Hungary | 7 participants | 22 participants | 8 participants | 7 participants |
| Region of Enrollment Poland | 7 participants | 17 participants | 4 participants | 6 participants |
| Region of Enrollment South Africa | 7 participants | 17 participants | 7 participants | 3 participants |
| Region of Enrollment United States | 94 participants | 284 participants | 96 participants | 94 participants |
| Sex: Female, Male Female | 126 Participants | 382 Participants | 129 Participants | 127 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 / 126 | 0 / 126 | 0 / 129 |
| other Total, other adverse events | 31 / 126 | 67 / 126 | 42 / 129 |
| serious Total, serious adverse events | 1 / 126 | 2 / 126 | 4 / 129 |
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 the last 35 days of treatment (up to Week 24)
Population: All randomized participants who received any amount 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 | 71.2 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 | 14.73 Percentage of participants |
p-value: <0.000195% CI: [46.45, 66.49]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 | -1.4 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 | -0.7 score on a scale | Standard Error 0.14 |
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.
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 | -1.7 score on a scale | Standard Error 0.15 |
| Placebo (Group C) | Change From Baseline At Week 24 In Function Assessed Using The PGA Questionnaire | -0.8 score on a scale | Standard Error 0.15 |
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.
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 (MEAN) | Dispersion |
|---|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Change From Baseline At Week 24 In Predose Concentrations Of E2 In The Relugolix Plus E2/NETA Group | -22.30 pg/mL | Standard Deviation 66.552 |
Secondary
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.
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 | -2.0 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 0.14 |
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
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 The Interference Of Uterine Fibroids With Physical Activities Based On UFS-QoL Question 11 | -2.0 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 | -0.7 score on a scale | Standard Error 0.14 |
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
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 The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20 | -1.8 score on a scale | Standard Error 0.13 |
| Placebo (Group C) | Change From Baseline At Week 24 In The Interference Of Uterine Fibroids With Social Activities Based On UFS-QoL Question 20 | -0.6 score on a scale | Standard Error 0.13 |
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 | -1.8 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
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 Social Activities | -1.8 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 | -1.0 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). Higher scores are indicative of better health-related quality of life (high score = good). As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
Time frame: Baseline, Week 24
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 | 43.6 score on a scale | Standard Error 2.77 |
| Placebo (Group C) | Change From Baseline At Week 24 In The UFS-QoL Activities Scale Score | 17.1 score on a scale | Standard Error 2.8 |
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). Higher scores are indicative of better health-related quality of life (high score = good). LS means and p-value for test of difference was relugolix plus E2/NETA minus placebo based on mixed-effect model with treatment, visit, region, Baseline MBL and treatment by visit interaction included as fixed effects. As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
Time frame: Baseline, Week 24
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 | 44.4 units on a scale | Standard Error 2.9 |
| Placebo (Group C) | Change From Baseline At Week 24 In The UFS-QoL Revised Activities Scale Score | 16.5 units on a scale | Standard Error 2.94 |
p-value: <0.0001Mixed Models Analysis
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.
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 | -36.1 score on a scale | Standard Error 2.59 |
| Placebo (Group C) | Change From Baseline At Week 24 In The UFS-QoL Symptom Severity Scale Score | -13.7 score on a scale | Standard Error 2.61 |
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 symptom severity. As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms
Time frame: Baseline Week 24
Population: All randomized participants who received any amount of study drug.
| 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) | -51.7 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) | -18.3 units on a scale |
p-value: <0.000195% CI: [-41.2, -25.5]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 | -22.30 pg/mL | Standard Deviation 66.552 |
| Placebo (Group C) | Change From Baseline In E2 Serum Concentration At Week 24 | 39.85 pg/mL | Standard Deviation 99.578 |
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 | -5.47 IU/L | Standard Deviation 9.049 |
| Placebo (Group C) | Change From Baseline In Follicle Stimulating Serum Concentration At Week 24 | -0.67 IU/L | Standard Deviation 7.422 |
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 | -3.10 IU/L | Standard Deviation 4.807 |
| Placebo (Group C) | Change From Baseline In Luteinizing Serum Concentration At Week 24 | 3.04 IU/L | Standard Deviation 13.162 |
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 | 0.12 ng/mL | Standard Deviation 3.963 |
| Placebo (Group C) | Change From Baseline In Progesterone Serum Concentration At Week 24 | 3.48 ng/mL | Standard Deviation 5.415 |
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.
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 | -51.7 score on a scale | Standard Error 2.91 |
| Placebo (Group C) | Change From Baseline in UFS-QoL Bleeding and Pelvic Discomfort Scale Score | -18.3 score on a scale | Standard Error 2.95 |
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 | 37.8 units on a scale | Standard Error 2.49 |
| Placebo (Group C) | Change From Baseline In UFS-QoL Score by Health-Related Quality of Life Total Score | 13.8 units on a scale | Standard Error 2.51 |
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 | 34 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 | 17 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
Uterine fibroid-associated pain was assessed by a pain NRS. The pain NRS is a validated, single-item, self-reported measure, which asks respondents to rank their pain on an 11-point scale as follows: 0 (no pain), 1 to 3 (mild pain), 4 to 6 (moderate pain), and 7 to 10 (severe pain). As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
Time frame: Baseline, Week 24
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 | 48 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 | 34 Participants |
p-value: 0.0004Cochran-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 | 19 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 | 2 Participants |
p-value: <0.0001Cochran-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 randomized participants who received any amount of study drug and had analyzable data at the specified timeframe.
| 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 | 35 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 | 18 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
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.
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 | 37 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 | 42 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
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.
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 PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 1 Category improvement (-1) | 13 Participants |
| Relugolix Plus E2/NETA (Group A) | Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 2 Category improvement (-2) | 30 Participants |
| Relugolix Plus E2/NETA (Group A) | Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 3 Category improvement (-3) | 18 Participants |
| Relugolix Plus E2/NETA (Group A) | Participants Achieving Improvement From Baseline In PGA 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 PGA 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 PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 1 Category improvement (-1) | 19 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 3 Category improvement (-3) | 10 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA For Uterine Fibroid-related Function From Baseline At Week 24 | 2 Category improvement (-2) | 13 Participants |
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.
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 PGA Questionnaire For Symptoms From Baseline At Week 24 | 1 Category improvement (-1) | 7 Participants |
| Relugolix Plus E2/NETA (Group A) | Participants Achieving Improvement From Baseline In 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 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 PGA Questionnaire For Symptoms From Baseline At Week 24 | 4 Category improvement (-4) | 10 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 | 4 Category improvement (-4) | 2 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 | 1 Category improvement (-1) | 21 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 | 2 Category improvement (-2) | 18 Participants |
| Placebo (Group C) | Participants Achieving Improvement From Baseline In PGA Questionnaire For Symptoms From Baseline At Week 24 | 3 Category improvement (-3) | 8 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 confidence interval (CI) based on exact binomial 95% CI (Clopper-Pearson). As per the objective of the study, the secondary analysis compared relugolix plus E2/NETA with relugolix plus delayed E2/NETA at Week 12 and are presented below.
Time frame: Baseline through Week 12
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 (NUMBER) |
|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12 | 5.56 percentage of participants |
| Placebo (Group C) | Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 12 | 35.71 percentage of participants |
p-value: <0.000195% CI: [0.07, 0.33]Fisher 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 and had evaluable data at the specified timepoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24 | 6.3 percentage of participants |
| Placebo (Group C) | Percentage Of Participants Experiencing Vasomotor Symptoms Through Week 24 | 3.9 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 randomized participants who received any amount of study drug and had analyzable study data at the specified timepoint.
| 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 | 61.29 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 | 5.41 Percentage of participants |
p-value: <0.000195% CI: [37.25, 74.52]Cochran-Mantel-Haenszel
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.
Time frame: From Baseline up to Week 24
Population: All randomized participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment | 47.06 percentage of participants |
| Placebo (Group C) | Percentage Of Participants With A Maximum Numerical Rating Scale (NRS) Score ≤ 1 For Uterine Fibroid-Associated Pain Over The Last 35 Days Of Treatment | 17.07 percentage of participants |
p-value: <0.000195% CI: [15.6, 44.38]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: * No feminine product returned due to reported amenorrhea; * No feminine product returned due to reports of spotting/negligible bleeding coupled with electronic diary (e-Diary) data indicating infrequent non-cyclic bleeding/spotting; * Feminine product collection with a negligible observed MBL volume coupled with e-Diary data indicating infrequent non-cyclic bleeding/spotting. As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
Time frame: From Baseline up to last 35 days of treatment (up to Week 24)
Population: All randomized participants who received any amount 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 | 50.40 Percentage of participants |
| Placebo (Group C) | Percentage Of Participants With Amenorrhea Over The Last 35 Days Of Treatment | 3.10 Percentage of participants |
p-value: <0.000195% CI: [38.04, 56.56]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. The LS means were based on a mixed-effect model with visit, region, Baseline MBL volume, age at Baseline, body mass index at Baseline, BMD at Baseline, race, and treatment by visit interaction included as fixed effects. As per the objective of the study, the pre-specified secondary efficacy analyses compared relugolix plus E2/NETA with placebo. Therefore, only relugolix plus E2/NETA and placebo arms are presented.
Time frame: From Baseline up to Week 12
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) | Percent Change From Baseline At Week 12 In Bone Mineral Density At The Lumbar Spine (L1 to L4) As Assessed By DXA | -0.819 percent change | Standard Error 0.2686 |
| 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 | -1.919 percent change | Standard Error 0.2767 |
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
Time frame: Baseline through Week 24
Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.
| 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 As Assessed By DXA | Lumbar Spine (L1-L4) | -0.126 percent change | Standard Error 0.2971 |
| 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 As Assessed By DXA | Total Hip | -0.173 percent change | Standard Error 0.2221 |
| 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 As Assessed By DXA | Femoral Neck | -0.684 percent change | Standard Error 0.373 |
| 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 As Assessed By DXA | Lumbar Spine (L1-L4) | 0.315 percent change | Standard Error 0.2909 |
| 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 As Assessed By DXA | Total Hip | -0.044 percent change | Standard Error 0.22 |
| 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 As Assessed By DXA | Femoral Neck | 0.019 percent change | Standard Error 0.3697 |
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.
Time frame: Baseline, Week 24
Population: All randomized participants who received any amount of study drug and had analyzable data at the specified timeframe.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline | 24.3 percent change | Standard Error 3.02 |
| Placebo (Group C) | Percent Change From Baseline At Week 24 In Hemoglobin For Women With A Hemoglobin Concentration ≤ 10.5 g/dL At Baseline | 4.3 percent change | Standard Error 2.68 |
p-value: <0.0001Mixed Models Analysis
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.
Time frame: Baseline, Week 24
Population: All randomized participants who received any amount of study drug.
| 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 | -15.1 percent change |
p-value: <0.000195% CI: [-84.1, -54.3]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 randomized participants who received any amount of study drug and had analyzable study data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume | -17.4 percent change |
| Placebo (Group C) | Percent Change From Baseline At Week 24 In Primary Uterine Fibroid Volume | -7.4 percent change |
p-value: =0.215395% CI: [-25.8, 5.8]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: From Baseline up to Week 24
Population: All participants who were randomized to treatment and who received at least 1 dose of study drug and had evaluable data at the specified timepoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Percent Change From Baseline At Week 24 In Uterine Volume | -13.8 percent change |
| Placebo (Group C) | Percent Change From Baseline At Week 24 In Uterine Volume | -1.5 percent change |
p-value: =0.007895% CI: [-21.3, -3.2]ANCOVA
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.
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 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 | 45.34 pg/mL | Standard Deviation 46.33 |
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.
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 timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Relugolix Plus E2/NETA (Group A) | Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24 | Relugolix | 1.96 ng/mL | Standard Deviation 2.025 |
| Relugolix Plus E2/NETA (Group A) | Predose Trough Concentrations Of Relugolix And NET In The Relugolix Plus E2/NETA Group At Week 24 | NET | 0.28 ng/mL | Standard Deviation 0.285 |
Secondary
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) | 63 Participants |
| Placebo (Group C) | Sustained Amenorrhea Rate (No Or Negligible Bleeding) | 4 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) | 8.9 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) | 16.3 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. 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 | 8.4 weeks |
| Placebo (Group C) | Time To MBL Response | 27.1 weeks |
p-value: <0.0001Log Rank