A Phase 3 Study to Evaluate the Efficacy and Safety of Relugolix (TAK-385) 40 mg Compared With Leuprorelin in the Treatment of Uterine Fibroids

A Multicenter, Randomized, Double-Blind, Parallel-Group, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-385 40 mg Compared With Leuprorelin in the Treatment of Uterine Fibroids

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02655237

Enrollment

281

Registered

2016-01-13

Start date

2016-03-05

Completion date

2017-09-25

Last updated

2019-03-22

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

Conditions

Uterine Fibroids

Keywords

Drug Therapy

Brief summary

The purpose of this study is to evaluate the efficacy of Relugolix (TAK-385) 40 mg administered orally once daily for 12 weeks, compared with leuprorelin injection (once every 4 weeks, 1.88 mg or 3.75 mg subcutaneously \[SC\]/time) in patients with uterine fibroids.

Detailed description

The drug tested in this study was called Relugolix (TAK-385). Relugolix was tested to treat people who had uterine fibroids. The study enrolled 281 patients. Participants received relugolix placebo and leuprorelin acetate placebo in run in period for 3 to 6 weeks. After run-in period, participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups in 1:1 ratio: * Relugolix 40 mg * Leuprorelin 1.88 or 3.75 mg Participants received relugolix tablets once daily along with leuprorelin 1.88 mg or 3.75 mg subcutaneous injection once in 4 weeks for 24 weeks in treatment period. This multi-center trial was conducted in Japan. The overall time to participate in this study was approximately 32 to 40 weeks including run-in period of 3 to 6 weeks and a treatment period of 24 weeks. Participants will make multiple visits to the clinic, and a final visit 4 weeks after last dose of study drug for a follow-up assessment.

Interventions

DRUGRelugolix

Relugolix tablets

DRUGRelugolix Placebo

Relugolix placebo-matching tablets

DRUGLeuprorelin

Leuprorelin injection

DRUGLeuprorelin Placebo

Leuprorelin placebo-matching injections

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

Inclusion Criteria for Entering the Screening (at VISIT 1) 1. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant signs and dates a written, informed consent form prior to the initiation of any study procedures. 3. Prior to VISIT 1, the participant has a diagnosis of uterine fibroids confirmed by transvaginal ultrasound, abdominal ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), or laparoscopy, and has never received any surgical treatment for the myoma (measurable noncalcified myoma with the longest diameter of ≥ 3 cm). 4. The participant is a premenopausal Japanese woman. 5. The participant is aged 20 years or older on the day of signing and dating the informed consent form. 6. The participant has 1 or more measurable noncalcified myomas with the longest diameter of ≥ 3 cm confirmed by transvaginal ultrasound. 7. The participant has experienced 1 or more regular menstrual cycles (25 to 38 days) immediately prior to VISIT 1 and that should include menstrual bleeding for at least 3 consecutive days. 8. The participant who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the study. Inclusion Criteria for Entering the Run-in (at VISIT 2) 9. The participant has experienced regular menstrual cycles (25 to 38 days) immediately prior to VISIT 2 that should include menstrual bleeding of at least 3 consecutive days (at least 2 regular menstruation cycles to be confirmed by Inclusion criteria #7 and #9). Inclusion Criteria for Entering the Treatment (at VISIT 3) 10. The participant has 1 or more measurable noncalcified myomas, with a longest diameter of ≥ 3 cm confirmed by transvaginal ultrasound (the same myoma should be measured as in Inclusion criterion #6). 11. The participant has a diagnosis of menorrhagia with a total Pictorial Blood loss Assessment Chart (PBAC) score of ≥ 120 in 1 menstrual cycle just before VISIT 3. 12. The participant has experienced regular menstrual cycles (25 to 38 days) after VISIT 1 that should include menstrual bleeding for at least 3 consecutive days (at least 3 regular menstruation cycles to be confirmed by Inclusion criteria #7, #9 and #12).

Exclusion criteria

1. The participant has received any investigational compound within 24 weeks prior to the start of the administration of the study medication for the Run-in (VISIT 2). 2. The participant has received relugolix (including placebo) in a previous clinical study. 3. The participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 4. The participant has a previous or current history of blood disorders (eg, thalassemia, sickle cells anemia, folic-acid deficiency, and coagulopathy), excluding (latent) iron-deficiency anemia. 5. The participant has a known history of severe hypersensitivity or severe allergy to sanitary goods. 6. The participant has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis. 7. The participant has a current history of thyroid gland disorder with irregular menstruation, or has a potential for irregular menstruation due to thyroid gland disorder, as determined by the investigator or subinvestigator. 8. The participant has a previous or current history of pelvic inflammatory disease within 8 weeks prior to VISIT 1. 9. The participant has a positive Pap smear test result obtained within 1 year prior to VISIT 1 (if there are no previous test results, those who were judged positive in the test conducted before VISIT 2). 10. The participant has a history of panhysterectomy or bilateral oophorectomy. 11. The participant has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the investigator or subinvestigator. 12. The participant has a malignant tumor or a history of a malignant tumor within 5 years prior to VISIT 1. 13. The participant has been treated with any of the following drugs (excluding drugs for external use and dietary supplements) within 4 weeks prior to VISIT 2: anti-coagulant drugs, anti-platelet drugs, tranexamic acid, selective estrogen receptor modulators (SERMs), activated vitamin D preparations, other vitamin D preparations, calcitonin, ipriflavone, steroid hormones, vitamin K preparations, teriparatide, or denosumab. 14. The participant has been treated with any of the following drugs within 8 weeks prior to VISIT 2: oral contraceptive or sex hormone preparations (norethindrone, norethisterone, medroxyprogesterone, estrogen, or other progestins), and within 16 weeks prior to VISIT 2: gonadotropin-releasing hormone (GnRH) analogues, dienogest, danazol, or aromatase inhibitors (for 1- and 3-month sustained-release preparations, within 20 and 28 weeks prior to VISIT 2, respectively). 15. The participant has been treated with a bisphosphonate preparation within 24 weeks prior to VISIT 2. 16. The participant has a previous or current history of hypersensitivity or allergies to leuprorelin, synthetic GnRH, GnRH agonists or GnRH antagonists, or has a previous or current history of severe hypersensitivity or severe allergy to other drugs. 17. The participant has nondiagnosable abnormal genital bleeding. 18. Female participant who is pregnant, lactating, or intending to become pregnant or to donate ova prior to the signing of informed consent, during the study period, or within 1 month after the end of the study. 19. The participant has a previous or current history of osteoporosis, osteopenia, or other metabolic bone diseases. 20. The participant has clinically significant cardiovascular disease (eg, myocardial infarction or unstable angina pectoris within 24 weeks prior to VISIT 1) or uncontrollable hypertension (eg, resting systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg at Screening and Run-in). 21. The participant is inappropriate for participation in this study based on standard 12-lead electrocardiogram (ECG) findings, as determined by the investigator or subinvestigator. 22. The participant has active liver disease or jaundice, or with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin (total bilirubin) \> 1.5 times the upper limit of normal (ULN) in the clinical laboratory tests at VISITs 1 and 2. 23. The participant has previous or current history of diseases considered to be inappropriate for participation in this study, including severe hepatic impairment, jaundice, renal impairment, cardiovascular disease, endocrine system disease, metabolic disorder, pulmonary disease, gastrointestinal disease, neurological disease, urological disease, immune disease, or mental disorder (especially depression-like symptoms) or suicide attempt resulting from a mental disorder. 24. The participant has a previous or current history of drug abuse (defined as any illicit drug use) or alcohol abuse. 25. The participant is inappropriate for participation in this study for other reasons, as determined by the investigator or subinvestigator.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12	Week 6 to 12	PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.

Secondary

Measure	Time frame	Description
Percentage of Participants With Total PBAC Score of <10 From Week 2 to 6	Week 2 to 6	PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.
Percentage of Participants With Total PBAC Score of <10 From Week 18 to 24	Week 18 to 24	PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.
Percentage of Participants With Total PBAC Score of <10 for 6 Weeks Before the Final Dose of Study Drug	For 6 weeks before the final dose of study drug (up to Week 24)	PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.
Percent Change From Baseline in Myoma Volumes at Weeks 2, 4, 8, 12 and 24	Baseline, Weeks 2, 4, 8, 12 and 24	A transvaginal ultrasound was performed to determine myoma volumes. Only the largest myoma among those measurable at visit 1 was measured throughout the study. On the assumption that the myoma was spheroids, the myoma volumes were calculated using 3 diameters (D1, D2, and D3). D1: the longest diameter of the myoma; D2: the longest diameter of the myoma which was perpendicular to D1; D3: the diameter of the myoma which crossed the intersection of D1 and D2 (intersection Z) and was perpendicular to D1/D2 plane. The formula used for calculation is Myoma volume= D1\D2\D3\*π/6.
Percent Change From Baseline in Uterine Volumes at Weeks 2, 4, 8, 12 and 24	Baseline, Weeks 2, 4, 8, 12 and 24	A transvaginal ultrasound was performed for determination of uterine volumes. On the assumption that the uterus was spheroids, the uterine volumes were calculated using 3 diameters (D1, D2, and D3) measured as shown below: D1: the longest diameter of the uterus (unit of length: cm); D2: the longest diameter of the uterus which was perpendicular to D1 (unit of length: cm); D3: the diameter of the uterus which crossed the intersection of D1 and D2 (intersection Z) and was perpendicular to D1/D2 plane (unit of length: cm). The formula used for calculation is Uterine volume=D1\D2\D3\*π/6.
Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow up (up to Week 28)	Anemia-related measurements consisted of hemoglobin, which were determined at the central laboratory.
Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)	UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total symptom severity score is ranging from 0 to 100. The higher scores indicate greater severity.
Numerical Rating Scale (NRS) Score	From Week 6 to 12, from Week 2 to 6, from Week 18 to 24, and for 6 weeks before the final dose (up to Week 24)	Pain symptoms were evaluated using the NRS score. NRS score is a self-reported instrument assessing pain from 0 to 10. Higher scores reflect greater level of pain.
Number of Participants Who Had One or More Treatment Emergent Adverse Event (TEAE)	Up to Week 28	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Number of Participants With Markedly Abnormal Values of Vital Signs	Up to Week 28	Vital signs included sitting blood pressure (after the participant has rested for at least 5 minutes), body temperature (oral or tympanic measurement) (degree Celsius \[°C\]) and pulse (beats per minute \[bpm\]) is reported.
Number of Participants With TEAE Related to Weight	Up to Week 28	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to weight was reported.
Number of Participants With TEAE Related to Standard 12-Lead ECGs	Up to Week 28	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to ECG was reported.
Number of Participants With Markedly Abnormal Values of Laboratory Test	Up to Week 28	Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. WBC = White blood cells, AST = Aspartate Aminotransferase, ALT = Alanine Aminotransferase, GGT = gamma-glutamyl transferase, ULN = upper limit of normal or upper reference limit.
Number of Participants With TEAE (Bone Density Decreased) Related to Bone Mineral Density	Up to Week 28	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to bone mineral density was reported.
Number of Participants With TEAE Related to Biochemical Bone Metabolism Markers	Up to Week 28	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to biochemical bone metabolism markers was reported.
Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)	UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total HRQL score is ranging from 0 to 100. The higher scores indicate better QOL.

Countries

Japan

Participant flow

Recruitment details

Participants took part in the study at 34 investigative sites in Japan from 05 March 2016 to 25 September 2017.

Pre-assignment details

Participants with a diagnosis of uterine fibroids were enrolled in 1 of 2 (Relugolix once daily and Leuprorelin once in 4 weeks) treatment groups.

Participants by arm

Arm	Count
Relugolix 40 mg Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, subcutaneously (SC), once in 4 weeks for 3 to 6 weeks in run-in period followed by relugolix 40 mg, tablets, orally, once daily and leuprorelin acetate placebo matching injection, SC, once in 4 weeks for 24 weeks in treatment period.	139
Leuprorelin 1.88 mg or 3.75 mg Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, subcutaneously (SC), once in 4 weeks for 3 to 6 weeks in run-in period followed by leuprorelin acetate 1.88 mg or 3.75 mg, injection, SC, once in 4 weeks and relugolix placebo matching tablets, orally, once daily for 24 weeks in treatment period.	142
Total	281

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	10	7
Overall Study	Lack of Efficacy	0	1
Overall Study	Protocol Deviation	2	0
Overall Study	Randomized but Not Treated	1	0
Overall Study	Recovery Leading to Surgery	2	1
Overall Study	Reduction of Hemoglobin Concentration	1	0
Overall Study	Withdrawal by Participant	1	2

Baseline characteristics

Characteristic	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg	Total
Age, Continuous	43.2 years STANDARD_DEVIATION 4.98	42.6 years STANDARD_DEVIATION 5.27	42.9 years STANDARD_DEVIATION 5.13
Any Surgery for Uterine Fibroids Had Any Surgery for Uterine Fibroids	18 Participants	11 Participants	29 Participants
Any Surgery for Uterine Fibroids Had Not Any Surgery for Uterine Fibroids	121 Participants	131 Participants	252 Participants
Birth Experience Had Birth Experience	74 Participants	75 Participants	149 Participants
Birth Experience Had No Birth Experience	65 Participants	67 Participants	132 Participants
Body Mass Index (BMI)	22.78 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.506	23.43 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.657	23.11 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.592
Dosage of Leuprorelin Vial 1.88 mg	121 Participants	124 Participants	245 Participants
Dosage of Leuprorelin Vial 3.75 mg	17 Participants	18 Participants	35 Participants
Height	159.8 centimeter (cm) STANDARD_DEVIATION 5.29	159.4 centimeter (cm) STANDARD_DEVIATION 5.23	159.6 centimeter (cm) STANDARD_DEVIATION 5.25
Hemoglobin	11.49 Gram per deciliter (g/dL) STANDARD_DEVIATION 1.368	11.62 Gram per deciliter (g/dL) STANDARD_DEVIATION 1.377	11.56 Gram per deciliter (g/dL) STANDARD_DEVIATION 1.372
Numerical Rating Scale (NRS) Score	0.63 score on a scale STANDARD_DEVIATION 0.79	0.56 score on a scale STANDARD_DEVIATION 0.559	0.59 score on a scale STANDARD_DEVIATION 0.682
Pictorial Blood Loss Assessment Chart (PBAC) Score	254.3 score on a scale STANDARD_DEVIATION 155.28	263.7 score on a scale STANDARD_DEVIATION 171.33	259.1 score on a scale STANDARD_DEVIATION 163.39
Race and Ethnicity Not Collected	—	—	0 Participants
Region of Enrollment Japan	139 Participants	142 Participants	281 Participants
Sex: Female, Male Female	139 Participants	142 Participants	281 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants
Smoking Classification Current Smoker	19 Participants	26 Participants	45 Participants
Smoking Classification Ex-Smoker	24 Participants	27 Participants	51 Participants
Smoking Classification Never Smoked	96 Participants	89 Participants	185 Participants
Stopped Any Medications for Uterine Fibroids Had Not Stopped Any Medications	109 Participants	105 Participants	214 Participants
Stopped Any Medications for Uterine Fibroids Had Stopped Any Medications	30 Participants	37 Participants	67 Participants
Type of Uterine Fibroid Intramural Fibroid	117 Participants	112 Participants	229 Participants
Type of Uterine Fibroid Submucosal Fibroid	13 Participants	20 Participants	33 Participants
Type of Uterine Fibroid Subserosal Fibroid	54 Participants	53 Participants	107 Participants
UFS-QOL Score: Health Related Quality of Life (HRQL) Total	80.2 score on a scale STANDARD_DEVIATION 16.73	76.8 score on a scale STANDARD_DEVIATION 19.57	78.5 score on a scale STANDARD_DEVIATION 18.27
Uterine Fibroid Symptom and Quality of Life (UFS-QOL) Score: Symptom Severity	28.4 score on scale STANDARD_DEVIATION 14.38	29.7 score on scale STANDARD_DEVIATION 15.18	29.1 score on scale STANDARD_DEVIATION 14.78
Volume of Myoma	117.41 cm^3 STANDARD_DEVIATION 126.533	122.25 cm^3 STANDARD_DEVIATION 124.27	119.87 cm^3 STANDARD_DEVIATION 125.184
Volume of Uterus	406.25 cm^3 STANDARD_DEVIATION 392.354	379.07 cm^3 STANDARD_DEVIATION 331.568	392.51 cm^3 STANDARD_DEVIATION 362.495
Weight	58.16 kilogram (kg) STANDARD_DEVIATION 9.167	59.53 kilogram (kg) STANDARD_DEVIATION 9.907	58.85 kilogram (kg) STANDARD_DEVIATION 9.557

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 138	0 / 142
other Total, other adverse events	123 / 138	134 / 142
serious Total, serious adverse events	0 / 138	2 / 142

Outcome results

Primary

Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12

PBAC score was used to measure volume of menstrual blood loss. Participants used sanitary products designated by sponsor and recorded the numbers of tampons or towels used, clots and flooding in patient diary. Three diagrams used which represented a lightly, moderately stained or completely saturated pad/tampon. Following scores assigned: 1) 1, 5, or 20 points for each pad; 2) 1, 5, or 10 points for each tampon; 3) 1 or 5 points for each blood clot of \<1 cm/=1 cm/\>1 in longest diameter; 4) 5 points for each episode of flooding. The total PBAC score (sum of points) ranges from 0 to \>500.

Time frame: Week 6 to 12

Population: Full analysis set (FAS) included all participants who were randomized and received at least 1 dose of the study drug for the treatment period. The number analyzed is the number of participants with data available for analysis at the given time-point.

Arm	Measure	Value (NUMBER)
Relugolix 40 mg	Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12	82.2 percentage of participants
Leuprorelin 1.88 mg or 3.75 mg	Percentage of Participants With Total PBAC Score of <10 From Week 6 to 12	83.1 percentage of participants

p-value: 0.001395% CI: [-10.098, 8.346]Farrington and Manning (FM)

Secondary

Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up

Anemia-related measurements consisted of hemoglobin, which were determined at the central laboratory.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow up (up to Week 28)

Population: FAS included all participants who were randomized and received at least 1 dose of the study drug for the treatment period. The number analyzed is the number of participants with data available for analysis at the given time-point.

Arm	Measure	Group	Value (MEAN)	Dispersion
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 12	1.38 g/dL	Standard Deviation 1.134
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 20	1.47 g/dL	Standard Deviation 1.264
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 4	0.79 g/dL	Standard Deviation 0.763
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 24	1.56 g/dL	Standard Deviation 1.281
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 16	1.40 g/dL	Standard Deviation 1.19
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Follow-Up (up to Week 28)	1.25 g/dL	Standard Deviation 1.301
Relugolix 40 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 8	1.20 g/dL	Standard Deviation 1.043
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Follow-Up (up to Week 28)	1.75 g/dL	Standard Deviation 1.182
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 4	0.60 g/dL	Standard Deviation 0.789
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 8	1.10 g/dL	Standard Deviation 0.925
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 12	1.31 g/dL	Standard Deviation 1
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 16	1.42 g/dL	Standard Deviation 0.978
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 20	1.58 g/dL	Standard Deviation 1.033
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Hemoglobin at Weeks 4, 8, 12, 16, 20, 24 and Follow up	Change at Week 24	1.65 g/dL	Standard Deviation 1.116

Comparison: Week 2495% CI: [-0.385, 0.209]

Comparison: Follow up (up to Week 28)95% CI: [-0.787, -0.199]

Comparison: Week 495% CI: [0.015, 0.381]

Comparison: Week 895% CI: [-0.135, 0.333]

Comparison: Week 1295% CI: [-0.189, 0.323]

Comparison: Week 1695% CI: [-0.275, 0.251]

Comparison: Week 2095% CI: [-0.386, 0.18]

Secondary

Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up

UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total HRQL score is ranging from 0 to 100. The higher scores indicate better QOL.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)

Arm	Measure	Group	Value (MEAN)	Dispersion
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 12	10.4 score on a scale	Standard Deviation 15.01
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 20	11.5 score on a scale	Standard Deviation 14.65
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 8	8.1 score on a scale	Standard Deviation 14.48
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 24	12.0 score on a scale	Standard Deviation 14.91
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 16	10.9 score on a scale	Standard Deviation 14.43
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Follow-Up (up to Week 28)	10.9 score on a scale	Standard Deviation 16.53
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 4	2.4 score on a scale	Standard Deviation 12.42
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Follow-Up (up to Week 28)	15.7 score on a scale	Standard Deviation 18.08
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 4	3.5 score on a scale	Standard Deviation 12.89
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 8	9.5 score on a scale	Standard Deviation 16.78
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 12	13.3 score on a scale	Standard Deviation 17.99
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 16	14.3 score on a scale	Standard Deviation 18.31
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 20	14.5 score on a scale	Standard Deviation 17.59
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- HRQL Total Scores at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 24	15.8 score on a scale	Standard Deviation 18.13

Comparison: Week 495% CI: [-1.66, 6.34]

Comparison: Week 895% CI: [-0.37, 5.77]

Comparison: Week 1295% CI: [-1.84, 3.61]

Comparison: Week 1695% CI: [-2.61, 2.79]

Comparison: Week 2095% CI: [-1.74, 3.41]

Comparison: Week 2495% CI: [-2.07, 2.71]

Comparison: Follow-Up (up to Week 28)95% CI: [-3.96, 1.09]

Secondary

Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up

UFS-QOL was a 37-item self-reporting tool for evaluating QOL in participants with uterine fibroid. It includes eight symptom-related questions and 29 HRQL questions across six subscales (concern, activities, energy/mood, control, self-consciousness, sexual function). The total symptom severity score is ranging from 0 to 100. The higher scores indicate greater severity.

Time frame: Baseline, Weeks 4, 8, 12, 16, 20, 24 and Follow-up (up to Week 28)

Arm	Measure	Group	Value (MEAN)	Dispersion
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 12	-21.0 score on a scale	Standard Deviation 14.93
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 20	-21.9 score on a scale	Standard Deviation 14.97
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 8	-19.5 score on a scale	Standard Deviation 14.47
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 24	-22.5 score on a scale	Standard Deviation 15.17
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 16	-21.4 score on a scale	Standard Deviation 14.76
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Follow-Up (up to Week 28)	-20.6 score on a scale	Standard Deviation 16.83
Relugolix 40 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 4	-5.5 score on a scale	Standard Deviation 14.11
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Follow-Up (up to Week 28)	-25.4 score on a scale	Standard Deviation 14.04
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 4	-4.5 score on a scale	Standard Deviation 16.09
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 8	-17.2 score on a scale	Standard Deviation 16.91
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 12	-23.0 score on a scale	Standard Deviation 14.66
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 16	-24.4 score on a scale	Standard Deviation 14.04
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 20	-24.3 score on a scale	Standard Deviation 14.87
Leuprorelin 1.88 mg or 3.75 mg	Change From Baseline in Uterine Fibroid Symptom and Quality of Life (UFS-QOL)- Symptom Severity Score at Weeks 4, 8, 12, 16, 20, 24 and Follow-up	Change at Week 24	-25.3 score on a scale	Standard Deviation 14.52

Comparison: Week 495% CI: [-6.39, 1.43]

Comparison: Week 895% CI: [-6.68, -1.31]

Comparison: Week 1295% CI: [-1.99, 2.36]

Comparison: Week 1695% CI: [-0.68, 3.28]

Comparison: Week 2095% CI: [-1.8, 2.32]

Comparison: Week 2495% CI: [-1.48, 2.52]

Comparison: Follow-Up (up to Week 28)95% CI: [1.08, 5.77]

Secondary

Number of Participants Who Had One or More Treatment Emergent Adverse Event (TEAE)

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Time frame: Up to Week 28