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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02655237
• Collaborator: (none)
• Enrollment: 281
• Locations: 25
• Arms: 2
• Actual Duration (Months): 18.7
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Uterine Fibroids	Drug: Relugolix; Drug: Relugolix Placebo; Drug: Leuprorelin; Drug: Leuprorelin Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 281 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 5, 2016
• Actual Primary Completion Date: May 17, 2017
• Actual Study Completion Date: Sep 25, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Relugolix 40 mg Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, 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.	Drug: Relugolix; Relugolix tablets; Other Names: TAK-385 ; Drug: Relugolix Placebo; Relugolix placebo-matching tablets; Drug: Leuprorelin Placebo; Leuprorelin placebo-matching injections
Active Comparator: Leuprorelin 1.88 mg or 3.75 mg Relugolix placebo matching tablets, orally, once daily along with leuprorelin acetate placebo matching injection, 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.	Drug: Relugolix Placebo; Relugolix placebo-matching tablets; Drug: Leuprorelin; Leuprorelin injection; Drug: Leuprorelin Placebo; Leuprorelin placebo-matching injections

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

1. 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)

1. 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).

2. 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.

3. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya	Aichi	Japan
2		Matsudo	Chiba	Japan
3		Kouriyama	Fukushima	Japan
4		Ebetsu	Hokkaido	Japan
5		Sapporo	Hokkaido	Japan
6		Kako-gun	Hyogo	Japan
7		Nishinomiya	Hyogo	Japan
8		Kawasaki	Kanagawa	Japan
9		Yamato	Kanagawa	Japan
10		Yokohama	Kanagawa	Japan
11		Ibaraki	Osaka	Japan
12		Sakai	Osaka	Japan
13		Suita	Osaka	Japan
14		Yao	Osaka	Japan
15		Bunkyo-ku	Tokyo	Japan
16		Chiyoda-ku	Tokyo	Japan
17		Chuou-ku	Tokyo	Japan
18		Minato-ku	Tokyo	Japan
19		Setagaya-ku	Tokyo	Japan
20		Suginami-ku	Tokyo	Japan
21		Taitou-ku	Tokyo	Japan
22		Kagoshima		Japan
23		Kyoto		Japan
24		Osaka		Japan
25		Saitama		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Nov 24, 2015
• Statistical Analysis Plan - Aug 1, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02655237
• Other Study ID Numbers: TAK-385/CCT-002; U1111-1178-0989; JapicCTI-163128
• First Posted: Jan 13, 2016
• Last Update Posted: Mar 22, 2019
• Last Verified: Dec 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Leiomyoma; Myofibroma; Leuprolide; Relugolix

Study Results

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

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	139	142
COMPLETED	122	131
NOT COMPLETED	17	11

Baseline Characteristics

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	139	142	281
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.2 (4.98)	42.6 (5.27)	42.9 (5.13)
Sex: Female, Male (Count of Participants)
Female	139 100%	142 100%	281 100%
Male	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
Japan	139 100%	142 100%	281 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	159.8 (5.29)	159.4 (5.23)	159.6 (5.25)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	58.16 (9.167)	59.53 (9.907)	58.85 (9.557)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	22.78 (3.506)	23.43 (3.657)	23.11 (3.592)
Smoking Classification (Count of Participants)
Never Smoked	96 69.1%	89 62.7%	185 65.8%
Current Smoker	19 13.7%	26 18.3%	45 16%
Ex-Smoker	24 17.3%	27 19%	51 18.1%
Birth Experience (Count of Participants)
Had Birth Experience	74 53.2%	75 52.8%	149 53%
Had No Birth Experience	65 46.8%	67 47.2%	132 47%
Type of Uterine Fibroid (Count of Participants)
Subserosal Fibroid	54 38.8%	53 37.3%	107 38.1%
Intramural Fibroid	117 84.2%	112 78.9%	229 81.5%
Submucosal Fibroid	13 9.4%	20 14.1%	33 11.7%
Stopped Any Medications for Uterine Fibroids (Count of Participants)
Had Stopped Any Medications	30 21.6%	37 26.1%	67 23.8%
Had Not Stopped Any Medications	109 78.4%	105 73.9%	214 76.2%
Any Surgery for Uterine Fibroids (Count of Participants)
Had Any Surgery for Uterine Fibroids	18 12.9%	11 7.7%	29 10.3%
Had Not Any Surgery for Uterine Fibroids	121 87.1%	131 92.3%	252 89.7%
Volume of Myoma (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	117.41 (126.533)	122.25 (124.270)	119.87 (125.184)
Volume of Uterus (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	406.25 (392.354)	379.07 (331.568)	392.51 (362.495)
Pictorial Blood Loss Assessment Chart (PBAC) Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	254.3 (155.28)	263.7 (171.33)	259.1 (163.39)
Numerical Rating Scale (NRS) Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	0.63 (0.790)	0.56 (0.559)	0.59 (0.682)
Uterine Fibroid Symptom and Quality of Life (UFS-QOL) Score: Symptom Severity (score on scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on scale]	28.4 (14.38)	29.7 (15.18)	29.1 (14.78)
UFS-QOL Score: Health Related Quality of Life (HRQL) Total (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	80.2 (16.73)	76.8 (19.57)	78.5 (18.27)
Hemoglobin (Gram per deciliter (g/dL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Gram per deciliter (g/dL)]	11.49 (1.368)	11.62 (1.377)	11.56 (1.372)
Dosage of Leuprorelin Vial (Count of Participants)
1.88 mg	121 87.1%	124 87.3%	245 87.2%
3.75 mg	17 12.2%	18 12.7%	35 12.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Number [percentage of participants]	82.2 59.1%	83.1 58.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The point estimate and 2-sided 95% confidence interval of the difference in the percentage were calculated between Relugolix 40 mg group and leuprorelin group (Relugolix 40 mg group - leuprorelin group), using Farrington and Manning (FM) method. If the lower boundary of the 95% CI was greater or equal to the non-inferiority margin of -15%, then the non-inferiority of Relugolix 40 mg to leuprorelin was concluded.
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	Farrington and Manning (FM)
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	-0.9
	Confidence Interval	(2-Sided) 95%; -10.098 to 8.346
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

2. Secondary Outcome

Title	Percentage of Participants With Total PBAC Score of <10 From Week 2 to 6
Description	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 2 to 6

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Number [percentage of participants]	64.2 46.2%	31.7 22.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of the difference in the percentage were calculated between relugolix 40 mg group and leuprorelin group, using FM method with the non-inferiority margin of -15%. The confidence interval was presented in a descriptive manner and not for the purpose of statistical inference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	32.5
	Confidence Interval	(2-Sided) 95%; 20.953 to 44.134
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

3. Secondary Outcome

Title	Percentage of Participants With Total PBAC Score of <10 From Week 18 to 24
Description	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 18 to 24

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Number [percentage of participants]	84.1 60.5%	94.7 66.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of the difference in the percentage were calculated between relugolix 40 mg group and leuprorelin group, using FM method with the non-inferiority margin of -15%. The confidence interval was presented in a descriptive manner and not for the purpose of statistical inference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	-10.6
	Confidence Interval	(2-Sided) 95%; -18.337 to -2.883
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

4. Secondary Outcome

Title	Percentage of Participants With Total PBAC Score of <10 for 6 Weeks Before the Final Dose of Study Drug
Description	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	For 6 weeks before the final dose of study drug (up to Week 24)

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Number [percentage of participants]	79.0 56.8%	92.3 65%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of the difference in the percentage were calculated between relugolix 40 mg group and leuprorelin group, using FM method with the non-inferiority margin of -15%. The confidence interval was presented in a descriptive manner and not for the purpose of statistical inference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	-13.3
	Confidence Interval	(2-Sided) 95%; -21.418 to -5.118
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

5. Secondary Outcome

Title	Percent Change From Baseline in Myoma Volumes at Weeks 2, 4, 8, 12 and 24
Description	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.
Time Frame	Baseline, Weeks 2, 4, 8, 12 and 24

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Change at Week 2	-18.74 (31.849)	-6.68 (33.377)
Change at Week 4	-24.99 (46.374)	-22.44 (31.935)
Change at Week 8	-35.92 (39.546)	-40.62 (25.036)
Change at Week 12	-43.28 (33.849)	-46.87 (24.067)
Change at Week 24	-49.75 (34.331)	-53.71 (24.257)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 2
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-12.05
	Confidence Interval	(2-Sided) 95%; -19.778 to -4.330
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-2.55
	Confidence Interval	(2-Sided) 95%; -11.916 to 6.819
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 8
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	4.69
	Confidence Interval	(2-Sided) 95%; -3.141 to 12.529
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	3.59
	Confidence Interval	(2-Sided) 95%; -3.433 to 10.605
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 24
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	3.96
	Confidence Interval	(2-Sided) 95%; -3.319 to 11.245
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

6. Secondary Outcome

Title	Percent Change From Baseline in Uterine Volumes at Weeks 2, 4, 8, 12 and 24
Description	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.
Time Frame	Baseline, Weeks 2, 4, 8, 12 and 24

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Change at Week 2	-22.05 (17.870)	-6.90 (27.984)
Change at Week 4	-28.07 (23.965)	-17.80 (34.058)
Change at Week 8	-34.73 (22.507)	-33.83 (27.882)
Change at Week 12	-39.79 (24.454)	-38.85 (25.157)
Change at Week 24	-44.87 (29.214)	-45.73 (27.778)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 2
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-15.15
	Confidence Interval	(2-Sided) 95%; -20.786 to -9.509
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-10.27
	Confidence Interval	(2-Sided) 95%; -17.291 to -3.246
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 8
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.89
	Confidence Interval	(2-Sided) 95%; -6.996 to 5.209
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.94
	Confidence Interval	(2-Sided) 95%; -6.964 to 5.076
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 24
	Type of Statistical Test	Other
	Comments	The mean differences in the percent changes from baseline between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; -6.206 to 7.935
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Change at Week 4	0.79 (0.763)	0.60 (0.789)
Change at Week 8	1.20 (1.043)	1.10 (0.925)
Change at Week 12	1.38 (1.134)	1.31 (1.000)
Change at Week 16	1.40 (1.190)	1.42 (0.978)
Change at Week 20	1.47 (1.264)	1.58 (1.033)
Change at Week 24	1.56 (1.281)	1.65 (1.116)
Change at Follow-Up (up to Week 28)	1.25 (1.301)	1.75 (1.182)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.381
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 8
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.135 to 0.333
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.189 to 0.323
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 16
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.275 to 0.251
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 20
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.386 to 0.180
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 24
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.385 to 0.209
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Follow up (up to Week 28)
	Type of Statistical Test	Other
	Comments	The mean differences in the change from baseline between relugolix 40 mg and leuprorelin groups and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.787 to -0.199
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

8. Secondary Outcome

Title	Numerical Rating Scale (NRS) Score
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Week 6 to 12	0.21 (0.500)	0.14 (0.363)
Week 2 to 6	0.32 (0.707)	0.27 (0.489)
Week 18 to 24	0.12 (0.308)	0.11 (0.289)
For 6 weeks before the final dose (up to Week 24)	0.14 (0.359)	0.12 (0.327)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 6 to 12
	Type of Statistical Test	Other
	Comments	Two-sided 95% confidence interval of the difference was calculated between relugolix 40 mg and leuprorelin group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.032 to 0.174
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 2 to 6
	Type of Statistical Test	Other
	Comments	Two-sided 95% confidence interval of the difference was calculated between relugolix 40 mg and leuprorelin group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.089 to 0.197
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 18 to 24
	Type of Statistical Test	Other
	Comments	Two-sided 95% confidence interval of the difference was calculated between relugolix 40 mg and leuprorelin group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.060 to 0.086
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	For 6 Weeks Before the Final Dose (up to Week 24)
	Type of Statistical Test	Other
	Comments	Two-sided 95% confidence interval of the difference was calculated between relugolix 40 mg and leuprorelin group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.063 to 0.099
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

9. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Change at Week 4	-5.5 (14.11)	-4.5 (16.09)
Change at Week 8	-19.5 (14.47)	-17.2 (16.91)
Change at Week 12	-21.0 (14.93)	-23.0 (14.66)
Change at Week 16	-21.4 (14.76)	-24.4 (14.04)
Change at Week 20	-21.9 (14.97)	-24.3 (14.87)
Change at Week 24	-22.5 (15.17)	-25.3 (14.52)
Change at Follow-Up (up to Week 28)	-20.6 (16.83)	-25.4 (14.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -6.39 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 8
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-4.0
	Confidence Interval	(2-Sided) 95%; -6.68 to -1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -1.99 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 16
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; -0.68 to 3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 20
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -1.80 to 2.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 24
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -1.48 to 2.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Follow-Up (up to Week 28)
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 1.08 to 5.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

10. Secondary Outcome

Title	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
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Change at Week 4	2.4 (12.42)	3.5 (12.89)
Change at Week 8	8.1 (14.48)	9.5 (16.78)
Change at Week 12	10.4 (15.01)	13.3 (17.99)
Change at Week 16	10.9 (14.43)	14.3 (18.31)
Change at Week 20	11.5 (14.65)	14.5 (17.59)
Change at Week 24	12.0 (14.91)	15.8 (18.13)
Change at Follow-Up (up to Week 28)	10.9 (16.53)	15.7 (18.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 4
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -1.66 to 6.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 8
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; -0.37 to 5.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 12
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; -1.84 to 3.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 16
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -2.61 to 2.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 20
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; -1.74 to 3.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Week 24
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -2.07 to 2.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Leuprorelin 1.88 mg or 3.75 mg
	Comments	Follow-Up (up to Week 28)
	Type of Statistical Test	Other
	Comments	The mean differences in the observed values between relugolix 40 mg and leuprorelin group and the two-sided 95% confidence intervals were calculated for each visit.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Each Visit)
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -3.96 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Leuprorelin

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Count of Participants [Participants]	131 94.2%	139 97.9%

12. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Values of Vital Signs
Description	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.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Systolic Blood Pressure Lower (<85 mmHg)	3 2.2%	2 1.4%
Systolic Blood Pressure Upper (>180 mmHg)	0 0%	1 0.7%
Diastolic Blood Pressure Lower (<50 mmHg)	5 3.6%	5 3.5%
Diastolic Blood Pressure Upper (>110 mmHg)	2 1.4%	3 2.1%
Pulse Rate Lower (<50 bpm)	0 0%	1 0.7%
Body temperature Lower (<35.6 °C)	23 16.5%	23 16.2%
Body temperature Upper (>37.7 °C)	1 0.7%	0 0%

13. Secondary Outcome

Title	Number of Participants With TEAE Related to Weight
Description	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to weight was reported.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Count of Participants [Participants]	0 0%	0 0%

14. Secondary Outcome

Title	Number of Participants With TEAE Related to Standard 12-Lead ECGs
Description	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to ECG was reported.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Count of Participants [Participants]	0 0%	0 0%

15. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Values of Laboratory Test
Description	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.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
WBC Upper (>1.5×ULN×10^3 cells/μL)	1 0.7%	0 0%
Eosinophils Upper (>2×ULN×10^3 cells/μL)	3 2.2%	4 2.8%
Total cholesterol Upper (>300 mg/dL)	6 4.3%	4 2.8%
Triglycerides Upper (>2.5×ULN mg/dL)	4 2.9%	12 8.5%
Creatine kinase Upper (>5×ULN U/L)	1 0.7%	0 0%
AST Upper (>3×ULN U/L)	2 1.4%	0 0%
ALT Upper (>3×ULN U/L)	3 2.2%	2 1.4%
GGT Upper (>3×ULN U/L)	10 7.2%	6 4.2%
Hemoglobin A1c Upper (>7%)	0 0%	2 1.4%

16. Secondary Outcome

Title	Number of Participants With TEAE (Bone Density Decreased) Related to Bone Mineral Density
Description	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to bone mineral density was reported.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Count of Participants [Participants]	6 4.3%	8 5.6%

17. Secondary Outcome

Title	Number of Participants With TEAE Related to Biochemical Bone Metabolism Markers
Description	Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to biochemical bone metabolism markers was reported.
Time Frame	Up to Week 28

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of the study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.	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.
Measure Participants	138	142
Bone Resorption Test Abnormal	7 5%	7 4.9%
Resorption Bone Increased	7 5%	8 5.6%

Adverse Events

Time Frame	Up to Week 28
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Relugolix 40 mg		Leuprorelin 1.88 mg or 3.75 mg
Arm/Group Description	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.		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.
All Cause Mortality
	Relugolix 40 mg		Leuprorelin 1.88 mg or 3.75 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/138 (0%)		0/142 (0%)
Serious Adverse Events
	Relugolix 40 mg		Leuprorelin 1.88 mg or 3.75 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/138 (0%)		2/142 (1.4%)
Gastrointestinal disorders
Large intestine polyp	0/138 (0%)		1/142 (0.7%)
Injury, poisoning and procedural complications
Ulna fracture	0/138 (0%)		1/142 (0.7%)
Other (Not Including Serious) Adverse Events
	Relugolix 40 mg		Leuprorelin 1.88 mg or 3.75 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	123/138 (89.1%)		134/142 (94.4%)
General disorders
Malaise	8/138 (5.8%)		5/142 (3.5%)
Infections and infestations
Viral upper respiratory tract infection	39/138 (28.3%)		46/142 (32.4%)
Investigations
Gamma-glutamyltransferase increased	7/138 (5.1%)		9/142 (6.3%)
Bone density decreased	6/138 (4.3%)		8/142 (5.6%)
Bone resorption test abnormal	7/138 (5.1%)		7/142 (4.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/138 (5.8%)		9/142 (6.3%)
Resorption bone increased	7/138 (5.1%)		8/142 (5.6%)
Nervous system disorders
Headache	21/138 (15.2%)		14/142 (9.9%)
Dizziness	9/138 (6.5%)		7/142 (4.9%)
Somnolence	7/138 (5.1%)		6/142 (4.2%)
Reproductive system and breast disorders
Metrorrhagia	68/138 (49.3%)		93/142 (65.5%)
Menorrhagia	34/138 (24.6%)		22/142 (15.5%)
Genital haemorrhage	7/138 (5.1%)		7/142 (4.9%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	13/138 (9.4%)		15/142 (10.6%)
Vascular disorders
Hot flush	59/138 (42.8%)		75/142 (52.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.