A Placebo-Controlled, Phase 3 Study of Relugolix (TAK-385) 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02655224
• Collaborator: (none)
• Enrollment: 65
• Locations: 11
• Arms: 2
• Actual Duration (Months): 13.8
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of Relugolix (TAK-385) in patients having pain symptoms associated with uterine fibroids.

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

Detailed Description

The drug being tested in this study is called relugolix (TAK-385). Relugolix is being tested to treat people who have uterine fibroids.

The study enrolled 65 patients. Participants received relugolix placebo in run in period for 3 to 6 weeks. After run-in period, participants were randomly assigned to one of the two treatment groups in 1:1 ratio:

1. Relugolix 40 mg

2. Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

All participants were asked to take one tablet at the same time each day throughout the study.

This multi-center trial was conducted in Japan. The overall time to participate in this study was 20 to 28 weeks, including run-in period of 3 to 6 weeks and a treatment period of 12 weeks. Participants made multiple visits to the clinic, and 4 weeks after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 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, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Oral TAK-385 40 mg in the Treatment of Pain Symptoms Associated With Uterine Fibroids
• Actual Study Start Date: Mar 26, 2016
• Actual Primary Completion Date: May 16, 2017
• Actual Study Completion Date: May 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Relugolix 40 mg Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Drug: Relugolix; Relugolix Tablets; Other Names: TAK-385
Placebo Comparator: Placebo Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.	Drug: Relugolix placebo; Relugolix placebo-matching tablets

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug [For 28 days before the final dose of study drug (up to Week 12)]

   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. The percentage of participants with a score of 1 or less is reported.

Secondary Outcome Measures

1. Percentage of Participants With a Maximum NRS Score of 0 During the 28 Days Before the Final Dose of Study Drug [For 28 days before the final dose of study drug (up to Week 12)]

   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. The percentage of participants with a score of 0 is reported.

2. Mean NRS Score During the 28 Days Before the Final Dose of Study Drug [For 28 days before the final dose of study drug (up to Week 12)]

   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.

3. Percentage of Days Without Pain Symptoms (NRS = 0) During the 28 Days Before the Final Dose of Study Drug [For 28 days before the final dose of study drug (up to Week 12)]

   Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. 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. Percentage of days without pain symptoms (NRS=0) during the 28 days before the final dose of study drug (%) = [(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)]*100.

4. Percentage of Participants With Maximum NRS Score of 1 or Less From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84 [Day 1 to 28, Day 29 to 56, and Day 57 to 84]

   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. The percentage of participants with a score of 1 or less is reported.

5. Percentage of Participants With a Maximum NRS Score of 0 From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84 [Day 1 to 28, Day 29 to 56, and Day 57 to 84]

   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. The percentage of participants with a score of 0 is reported.

6. Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84 [Day 1 to 28, Day 29 to 56, and Day 57 to 84]

   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.

7. Percentage of Days Without Pain Symptoms (NRS = 0) From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84 [Day 1 to 28, Day 29 to 56, and Day 57 to 84]

   Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. 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. Percentage of days without pain symptoms (NRS=0) (%) = [(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)]*100.

8. Number of Participants Reporting Who Had One or More Treatment-emergent Adverse Event (TEAE) [Up to Week 16]

   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.

9. Number of Participants With Markedly Abnormal Values of Vital Signs [Up to Week 16]

   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]) are reported.

10. Number of Participants With TEAEs Related to Weight [Up to Week 16]

    Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to weight was reported.

11. Number of Participants With TEAEs Related to Standard 12-lead Electrocardiogram (ECG) [Up to Week 16]

    Number of participants with TEAEs of which threshold was 5% or above in either treatment group related to ECG was reported.

12. Number of Participants With Markedly Abnormal Values of Laboratory Tests [Up to Week 16]

    Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. WBC = White blood cells, GGT = gamma-glutamyl transferase, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit.

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 Period (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 a 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 a 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 Period (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 for 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 Period (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 in Inclusion criterion #6).

2. The participant has a maximum Numerical Rating Scale (NRS) score of ≥4 during 1 menstrual cycle just before VISIT 3.

3. The participant has pain symptoms associated with uterine fibroids for at least 2 days during 1 menstrual cycle just before VISIT 3.

4. 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 #13).

Exclusion Criteria:

1. The participant has received any investigational compound within 24 weeks prior to the start of the administration of the study drug for the day of first menstruation after VISIT 1.

2. The participant has received relugolix (including placebo) in a previous clinical study.

3. The participant is an immediate family member or 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, or sibling) or may consent under duress.

4. The participant has lower abdominal pain due to irritable bowel syndrome or severe interstitial cystitis.

5. 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.

6. The participant has a previous or current history of pelvic inflammatory disease within 8 weeks prior to VISIT 1.

7. 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).

8. The participant has a history of panhysterectomy or bilateral oophorectomy.

9. The participant has had markedly abnormal uterine bleeding or anovulatory bleeding, as determined by the investigator or subinvestigator.

10. The participant has a malignant tumor or a history of a malignant tumor within 5 years prior to VISIT 1.

11. The participant has been treated with selective estrogen receptor modulators (SERMs) (excluding drugs for external use and dietary supplements) within 4 weeks prior to VISIT 2.

12. 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).

13. The participant has a previous or current history of severe hypersensitivity or severe allergies to drugs.

14. The participant has nondiagnosable abnormal genital bleeding.

15. 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.

16. 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 Period).

17. The participant is ineligible for this study based on standard 12-lead electrocardiogram (ECG) findings, as determined by the investigator or subinvestigator.

18. 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 VISIT 1 and 2.

19. The participant has a previous or current history of diseases considered to be ineligible for 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, mental disorder (especially depression-like symptoms) and suicide attempt resulting from a mental disorder.

20. The participant has a previous or current history of drug abuse (defined as any illicit drug use) or alcohol abuse.

21. The participant is ineligible for this study for other reasons, as determined by the investigator or subinvestigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Matsudo	Chiba	Japan
2		Ebetsu	Hokkaido	Japan
3		Sapporo	Hokkaido	Japan
4		Nishinomiya	Hyogo	Japan
5		Ibaraki	Osaka	Japan
6		Sakai	Osaka	Japan
7		Bunkyo-ku	Tokyo	Japan
8		Minato-ku	Tokyo	Japan
9		Setagaya-ku	Tokyo	Japan
10		Kagoshima		Japan
11		Osaka		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Dec 3, 2015
• Statistical Analysis Plan - Sep 1, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02655224
• Other Study ID Numbers: TAK-385-3008; U1111-1178-1086; JapicCTI-163127
• 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; Relugolix

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 15 investigative sites in Japan from 26 March 2016 to 19 May 2017.
Pre-assignment Detail	Participants with a diagnosis of uterine fibroids were enrolled in a 1:1 ratio in one of two treatment groups: relugolix 40 mg or placebo.

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Period Title: Overall Study
STARTED	33	32
COMPLETED	32	31
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Relugolix 40 mg	Placebo	Total
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.	Total of all reporting groups
Overall Participants	33	32	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.5 (3.95)	42.6 (5.24)	41.5 (4.72)
Sex: Female, Male (Count of Participants)
Female	33 100%	32 100%	65 100%
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	33 100%	32 100%	65 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	157.5 (6.40)	159.2 (4.25)	158.3 (5.48)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	57.55 (11.775)	57.47 (11.511)	57.51 (11.555)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	23.15 (4.146)	22.56 (3.714)	22.86 (3.919)
Smoking Classification (Count of Participants)
Never Smoked	20 60.6%	21 65.6%	41 63.1%
Current Smoker	6 18.2%	8 25%	14 21.5%
Ex-Smoker	7 21.2%	3 9.4%	10 15.4%
Birth Experience (Count of Participants)
Had Birth Experience	12 36.4%	12 37.5%	24 36.9%
Had No Birth Experience	21 63.6%	20 62.5%	41 63.1%
Type of Uterine Fibroid (Count of Participants)
Subserosal Fibroid	17 51.5%	9 28.1%	26 40%
Intramural Fibroid	22 66.7%	29 90.6%	51 78.5%
Stopped Any Medications for Uterine Fibroids (Count of Participants)
Had Stopped Any Medications	5 15.2%	7 21.9%	12 18.5%
Had not Stopped Any Medications	28 84.8%	25 78.1%	53 81.5%
Number of Participants With No Surgery for Uterine Fibroids (Count of Participants)
Count of Participants [Participants]	33 100%	32 100%	65 100%
Volume of Myoma (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	78.83 (84.189)	101.38 (172.738)	89.94 (134.633)
Volume of Uterus (cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm^3]	252.29 (202.938)	300.09 (295.341)	275.82 (251.837)
Maximum Numerical Rating Scale (NRS) Score (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	6.64 (1.817)	6.28 (1.689)	6.46 (1.751)
Uterine Fibroid Symptom and Quality of Life (UFS-QOL) Score: Symptom Severity (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	25.5 (8.59)	30.3 (13.07)	27.9 (11.20)
UFS-QOL Score: Health Relate Quality of Life (HRQL) Total (score on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [score on a scale]	83.9 (12.47)	80.0 (15.00)	82.0 (13.81)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Maximum NRS Score of 1 or Less During the 28 Days Before the Final Dose of Study Drug
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. The percentage of participants with a score of 1 or less is reported.
Time Frame	For 28 days before the final dose of study drug (up to Week 12)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Number [percentage of participants]	57.6 174.5%	3.1 9.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher's Exact Test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	42.071
	Confidence Interval	(2-Sided) 95%; 5.113 to 346.181
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo

2. Secondary Outcome

Title	Percentage of Participants With a Maximum NRS Score of 0 During the 28 Days Before the Final Dose of Study Drug
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. The percentage of participants with a score of 0 is reported.
Time Frame	For 28 days before the final dose of study drug (up to Week 12)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Number [percentage of participants]	48.5 147%	3.1 9.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	29.176
	Confidence Interval	(2-Sided) 95%; 3.555 to 239.478
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo

3. Secondary Outcome

Title	Mean NRS Score During the 28 Days Before the Final Dose of Study Drug
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	For 28 days before the final dose of study drug (up to Week 12)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Mean (Standard Deviation) [score on a scale]	0.50 (0.967)	0.99 (1.274)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -1.050 to 0.069
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

4. Secondary Outcome

Title	Percentage of Days Without Pain Symptoms (NRS = 0) During the 28 Days Before the Final Dose of Study Drug
Description	Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. 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. Percentage of days without pain symptoms (NRS=0) during the 28 days before the final dose of study drug (%) = [(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)]*100.
Time Frame	For 28 days before the final dose of study drug (up to Week 12)

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of study drug for the treatment period.

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Mean (Standard Deviation) [percentage of days]	76.73 (32.006)	64.78 (29.015)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 (Final Values)
	Estimated Value	11.96
	Confidence Interval	(2-Sided) 95%; -3.201 to 27.112
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

5. Secondary Outcome

Title	Percentage of Participants With Maximum NRS Score of 1 or Less From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84
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. The percentage of participants with a score of 1 or less is reported.
Time Frame	Day 1 to 28, Day 29 to 56, and Day 57 to 84

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of 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	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Day 1 to 28	24.2 73.3%	0.0 0%
Day 29 to 56	45.5 137.9%	12.9 40.3%
Day 57 to 84	59.4 180%	12.9 40.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 29 to 56
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.625
	Confidence Interval	(2-Sided) 95%; 1.605 to 19.709
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo. Statistical analysis for Day 29 to 56 and Day 57 to 84, the odds ratio was calculated. For Day 1 to 28, its ratio was not calculated due to zero cell.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 57 to 84
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	9.865
	Confidence Interval	(2-Sided) 95%; 2.784 to 34.955
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo. Statistical analysis for Day 29 to 56 and Day 57 to 84, the odds ratio was calculated. For Day 1 to 28, its ratio was not calculated due to zero cell.

6. Secondary Outcome

Title	Percentage of Participants With a Maximum NRS Score of 0 From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84
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. The percentage of participants with a score of 0 is reported.
Time Frame	Day 1 to 28, Day 29 to 56, and Day 57 to 84

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of 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	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Day 1 to 28	15.2 46.1%	0.0 0%
Day 29 to 56	27.3 82.7%	6.5 20.3%
Day 57 to 84	46.9 142.1%	6.5 20.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 29 to 56
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.438
	Confidence Interval	(2-Sided) 95%; 1.071 to 27.609
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo. Statistical analysis for Day 29 to 56 and Day 57 to 84, the odds ratio was calculated. For Day 1 to 28, its ratio was not calculated due to zero cell.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 57 to 84
	Type of Statistical Test	Other
	Comments	The point estimate and 2-sided 95% confidence interval of odds ratio were calculated between relugolix 40 mg group and placebo group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	12.794
	Confidence Interval	(2-Sided) 95%; 2.603 to 62.880
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg/Placebo. Statistical analysis for Day 29 to 56 and Day 57 to 84, the odds ratio was calculated. For Day 1 to 28, its ratio was not calculated due to zero cell.

7. Secondary Outcome

Title	Mean NRS Score From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84
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	Day 1 to 28, Day 29 to 56, and Day 57 to 84

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of 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	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Day 1 to 28	1.26 (1.490)	1.17 (1.141)
Day 29 to 56	0.59 (0.991)	1.16 (1.457)
Day 57 to 84	0.43 (0.776)	0.97 (1.279)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 1 to 28
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.574 to 0.745
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 29 to 56
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -1.190 to 0.049
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 57 to 84
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 95%; -1.074 to -0.012
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

8. Secondary Outcome

Title	Percentage of Days Without Pain Symptoms (NRS = 0) From Day 1 to 28, From Day 29 to 56, and From Day 57 to 84
Description	Percentage of day without pain symptoms (NRS = 0) was reported. Number of days without pain symptoms is determined by a zero score on the NRS. 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. Percentage of days without pain symptoms (NRS=0) (%) = [(number of days without pain symptoms (NRS=0) during the last 28 days of the treatment)/(number of days with available data during the last 28 days of the treatment)]*100.
Time Frame	Day 1 to 28, Day 29 to 56, and Day 57 to 84

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of 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	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Day 1 to 28	60.49 (34.043)	56.32 (28.891)
Day 29 to 56	73.98 (31.718)	61.29 (31.459)
Day 57 to 84	77.43 (30.854)	65.84 (29.224)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 1 to 28
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	4.17
	Confidence Interval	(2-Sided) 95%; -11.507 to 19.839
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 29 to 56
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	12.70
	Confidence Interval	(2-Sided) 95%; -3.098 to 28.494
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Relugolix 40 mg, Placebo
	Comments	Day 57 to 84
	Type of Statistical Test	Other
	Comments	The mean differences between relugolix 40 mg group and placebo 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 Period)
	Estimated Value	11.60
	Confidence Interval	(2-Sided) 95%; -3.554 to 26.745
	Parameter Dispersion	Type: Value:
	Estimation Comments	Relugolix 40 mg-Placebo

9. Secondary Outcome

Title	Number of Participants Reporting 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 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Count of Participants [Participants]	29 87.9%	18 56.3%

10. 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]) are reported.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Diastolic Blood Pressure Lower (<50 mmHg)	2 6.1%	1 3.1%
Body temperature Lower (<35.6 °C)	4 12.1%	2 6.3%

11. Secondary Outcome

Title	Number of Participants With TEAEs 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 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Count of Participants [Participants]	0 0%	0 0%

12. Secondary Outcome

Title	Number of Participants With TEAEs Related to Standard 12-lead Electrocardiogram (ECG)
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 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Count of Participants [Participants]	0 0%	0 0%

13. Secondary Outcome

Title	Number of Participants With Markedly Abnormal Values of Laboratory Tests
Description	Number of participants with any markedly abnormal values in laboratory tests collected throughout study is reported. WBC = White blood cells, GGT = gamma-glutamyl transferase, LLN = lower limit of normal or lower reference limit, ULN = upper limit of normal or upper reference limit.
Time Frame	Up to Week 16

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Relugolix 40 mg	Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
Measure Participants	33	32
Hemoglobin Lower (<0.8×LLN g/dL)	0 0%	1 3.1%
WBC Upper (>1.5×ULN × 10^3cells/μL)	0 0%	1 3.1%
Total Cholesterol Upper (>300 mg/dL)	2 6.1%	0 0%
Triglycerides Upper (>2.5×ULN mg/dL)	0 0%	3 9.4%
Total Bilirubin Upper (>2.0 mg/dL)	1 3%	0 0%
GGT Upper (>3×ULN U/L)	1 3%	0 0%

Adverse Events

Time Frame	Up to Week 16
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		Placebo
Arm/Group Description	Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix 40 mg, tablet, orally once daily before breakfast for 12 weeks.		Relugolix placebo-matching tablet, orally, once daily before breakfast for 3 to 6 weeks in the run-in period, followed by relugolix placebo-matching tablet, orally once daily before breakfast for 12 weeks.
All Cause Mortality
	Relugolix 40 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/32 (0%)
Serious Adverse Events
	Relugolix 40 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Relugolix 40 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/33 (81.8%)		14/32 (43.8%)
Infections and infestations
Viral upper respiratory tract infection	7/33 (21.2%)		9/32 (28.1%)
Investigations
Alanine aminotransferase increased	2/33 (6.1%)		0/32 (0%)
Aspartate aminotransferase increased	2/33 (6.1%)		0/32 (0%)
Nervous system disorders
Headache	0/33 (0%)		2/32 (6.3%)
Psychiatric disorders
Insomnia	3/33 (9.1%)		0/32 (0%)
Reproductive system and breast disorders
Metrorrhagia	13/33 (39.4%)		3/32 (9.4%)
Menorrhagia	4/33 (12.1%)		3/32 (9.4%)
Menstruation irregular	1/33 (3%)		3/32 (9.4%)
Genital haemorrhage	2/33 (6.1%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/33 (0%)		2/32 (6.3%)
Oropharyngeal pain	2/33 (6.1%)		0/32 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	5/33 (15.2%)		0/32 (0%)
Vascular disorders
Hot flush	15/33 (45.5%)		0/32 (0%)

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.