A Phase 2 Study to Evaluate the Safety and Efficacy of TAK-385, Together With a Leuprorelin Observational Cohort, in Participants With Prostate Cancer

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02083185
• Collaborator: (none)
• Enrollment: 136
• Locations: 23
• Arms: 3
• Actual Duration (Months): 35
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of TAK 385 for achieving and maintaining testosterone suppression (<50 ng/dL).

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Relugolix; Drug: Leuprorelin	Phase 2

Detailed Description

The drug being tested in this study is called relugolix (TAK-385). Relugolix is being tested to treat people who have prostate cancer. This study will look at achieving and maintaining testosterone suppression (<50 ng/dL).

The study enrolled 136 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):

• Relugolix 80 mg

• Relugolix 120 mg

• Leuprorelin 22.5 mg

Relugolix was administered starting with a 320 mg (loading dose), followed by relugolix 80 mg or 120 mg tablets, for 48 weeks plus an optional 48-week extension at the investigator's discretion. Patients randomized to leuprorelin were administered 22.5 mg subcutaneously on Day 1 and every 12 weeks for 4 injections.

This multicenter trial was conducted in the United States and Canada. The overall time to participate in this study was 114.4 weeks. Participants made multiple visits to the clinic and at 12 weeks after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Open-label, Parallel Group Study to Evaluate the Safety and Efficacy of the Oral GnRH Antagonist TAK-385, Together With a Leuprorelin Observational Cohort, in Patients With Prostate Cancer
• Actual Study Start Date: Mar 26, 2014
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Feb 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Relugolix 80 mg Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion.	Drug: Relugolix; Relugolix tablets; Other Names: TAK-835
Experimental: Relugolix 120 mg Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion.	Drug: Relugolix; Relugolix tablets; Other Names: TAK-835
Active Comparator: Leuprorelin 22.5 mg Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).	Drug: Leuprorelin; Leuprorelin subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Effective Castration Rate Over 24 Weeks [Day 1 of Week 5 to Day 1 of Week 25]

   Effective Castration rate is defined as the observed percentage of participants who have testosterone concentrations less than (<) 50 nanogram per deciliter (ng/dL) (1.73 nanomole per liter [nmol/L]) at all scheduled visits beginning after 4 weeks of treatment.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Related to Vital Signs [From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks]

   Vital signs included oral temperature, pulse rate, supine systolic and diastolic blood pressure, standing systolic and diastolic blood pressure, and weight. Any TEAEs that were associated with vital signs were reported.

2. Number of Participants With TEAEs Related to Physical Examination [From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks]

   Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10) including slit lamp examination of the anterior eye. Any TEAEs Related to physical examination were reported.

3. Number of Participants With TEAEs Related to 12-lead Electrocardiogram (ECG) Findings [From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks]

   A single 12-lead ECG was performed. ECGs were read and interpreted locally and reviewed if indicated by the study monitor. ECG abnormalities were reported as AEs.

4. Number of Participants With TEAES Related to Clinical Laboratory Test Results [From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks]

   Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.

5. Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks]

   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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any AE that results in death, is life threatening, requires hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

6. Percentage of Participants With Prostate-Specific Antigen (PSA) Response of ≥ 50% and ≥ 90% Reduction at 4 Weeks [Week 5, Day 1]

   PSA Response is defined as a reduction in PSA from Baseline and is reported for 2 categories: ≥ 50% reduction and ≥ 90% reduction.

7. Prostate-Specific Antigen Nadir [During Weeks 1 to 24]

   PSA nadir is the lowest PSA achieved after treatment.

8. Serum Prostate-Specific Antigen Concentration at the End of Weeks 12 and 24 [Day 1 of Weeks 13 and 25]

   Blood was collected and serum concentrations of PSA were obtained using a validated laboratory test at a central laboratory facility.

9. Time to Achieve Testosterone Concentrations < 50 ng/dL and < 20 ng/dL [During Weeks 1 to 24]

10. TAK-385 Plasma Concentrations [Day 1 of Weeks 1, 2, 3, 5, 9, 13, 17, 25, 37, 49 pre-dose; Day 4 of Week 1 pre-dose; Day 1 of Weeks 5, 13, 2 hrs post-dose]

11. Serum Luteinizing Hormone (LH) Concentrations [Baseline and Day 4 of Week 1, Day 1 of Weeks 2, 3, 5,13, 25 and 49, End of Treatment (EOT - 106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    Blood was collected and serum concentrations of LH in milli international units per milliliters (mIU/mL) were obtained using a validated laboratory test at a central laboratory facility.

12. Serum Follicle Stimulating Hormone (FSH) Concentrations [Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    Blood was collected and serum concentrations of FSH were obtained using a validated laboratory test at a central laboratory facility.

13. Serum Sex Hormone-binding Globulin (SHBG) Concentrations [Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    Blood was collected and serum concentrations of SHBG were obtained using a validated laboratory test at a central laboratory facility.

14. Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-P25 Score [Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    EORTC QLQ-PR25 is an EORTC module designed to supplement the QLQ-C30 for any application in prostate cancer consisting of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Questions use are answered using a 4-point scale: 1=Not at all to 4 =Very much. All raw domain scores are linearly transformed to a 0 to 100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual). A positive change from Baseline in activity or functioning scales and negative change from Baseline in symptom scales indicates improvement.

15. Percent Change From Baseline of Aging Male Survey (AMS) Total Score [Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    AMS scale is a self-administered questionnaire used to: 1) assess symptoms of aging (independent from those that are disease related) between groups of males under different conditions; 2) evaluate the severity of symptoms over time; and 3) measure changes before and after androgen therapy. Each question was answered between 1=none to 5=extremely severe for 17 items from psychological (5 items), somatic (7 items), and sexual (5 items) categories. Total score is sum of all the item scores and range from 17 (minimum) to 85 (maximum), where high score indicated high level of symptoms.

16. Change From Baseline in EORTC QLQ-C30 [Day 1 of Weeks 5, 13, 25, 37, 49, 73, 97, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)]

    The EORTC QLQ-C30 included 30 questions comprising 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties) and a global health and QOL scale. Most questions used a 4-point scale (1=Not at all to 4=Very much); 2 questions used a 7-point scale (1= Very poor to 7=Excellent). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. A positive change from Baseline in quality og life or functioning scales and negative change from Baseline in symptom or difficulties scales indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

1. Male participant 18 years or older.

2. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma.

3. Candidate for androgen deprivation therapy (ADT) for the management of hormone-sensitive prostate cancer with 1 of the following clinical disease states: 1) advanced localized disease not suitable for primary therapy, 2) evidence of prostate-specific antigen (PSA) biochemical or clinical relapse following primary surgery or radiation therapy of curative intent, or 3) newly diagnosed metastatic disease that is asymptomatic or not threatening to vital organs.

4. Appropriate serum testosterone and serum PSA concentration at screening as specified in the protocol.

5. A body mass index (BMI) ≥ 18.0 at screening and/or baseline.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening and/or baseline.

7. Male participants, even if surgically sterilized, who agree to practice effective barrier contraception or agree to practice true abstinence.

8. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

9. Suitable venous access for the study-required blood sampling, including pharmacokinetic (PK) and pharmacodynamic (PD) Sampling.

Exclusion Criteria

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

1. In participants with advanced, localized M0N1 or M1 disease, the presence of clinically significant symptoms or threat to vital organs requiring immediate gonadotropin-releasing hormone (GnRH) /combined or complete androgen blockade (CAB) therapy, chemotherapy, or radiotherapy.

2. Previously received androgen deprivation therapy (ADT) for more than 8 months total duration (if ADT was received for 8 months or less, then that ADT must have been completed at least 2 years prior to screening).

3. Visceral metastases (liver or lung).

4. Features of the participant's medical condition that may make ADT unnecessary or not indicated.

5. Scheduled for additional surgical or (salvage) radiation therapy within 6 months after baseline evaluations.

6. History of surgical castration.

7. Diagnosis of or treatment for another malignancy within the 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

8. Abnormal screening and/or baseline laboratory values as specified in the protocol.

9. History of any significant cardiac condition within 6 months before receiving the first dose of study drug.

10. Electrocardiogram (ECG) abnormalities as specified in the protocol

11. Congenital long QT syndrome.

12. Current use of Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications.

13. Uncontrolled hypertension despite appropriate medical therapy. Participants may be re-screened after referral and further management of hypertension.

14. Known, previously diagnosed human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C, life-threatening illness unrelated to prostate cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study. Specific screening for chronic viral illness is at the discretion of the site and/or local institutional review board (IRB).

15. Treatment with any investigational products within 3 months before the first dose of study drug.

16. A primary family member (spouse, parent, child, or sibling of the participant) is involved in the conduct of the study or is a study site employee.

17. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-385, including difficulty swallowing tablets.

18. Use of any medication, or food products listed in the excluded medications and dietary products table within 2 weeks before the first dose of study drug. Participant must have no history of amiodarone use in the 6 months before the first dose of TAK-385.

19. Admission or evidence of alcohol or drug abuse or use of illicit drugs.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		San Diego	California	United States
3		Denver	Colorado	United States
4		Daytona Beach	Florida	United States
5		Jeffersonville	Indiana	United States
6		Wichita	Kansas	United States
7		Shreveport	Louisiana	United States
8		Omaha	Nebraska	United States
9		Lawrenceville	New Jersey	United States
10		Garden City	New York	United States
11		Syracuse	New York	United States
12		Cincinnati	Ohio	United States
13		Springfield	Oregon	United States
14		Lancaster	Pennsylvania	United States
15		Myrtle Beach	South Carolina	United States
16		Nashville	Tennessee	United States
17		Dallas	Texas	United States
18		San Antonio	Texas	United States
19		Virginia Beach	Virginia	United States
20		Abbotsford	British Columbia	Canada
21		Vancouver	British Columbia	Canada
22		Montreal	Quebec	Canada
23		Quebec		Canada

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02083185
• Other Study ID Numbers: C27002; U1111-1162-5028; 172837
• First Posted: Mar 11, 2014
• Last Update Posted: May 9, 2018
• Last Verified: Apr 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Prostatic Neoplasms; Leuprolide; Relugolix

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 23 investigative sites in Canada and the United States from 26 March 2014 to 23 February 2017.
Pre-assignment Detail	Participants with a diagnosis of prostate cancer were enrolled in 1 of 2 dose levels of TAK-385 (80 or 120 mg) or leuprorelin 22.5 mg.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Period Title: Overall Study
STARTED	56	56	24
Safety Population	56	54	24
COMPLETED	36	27	17
NOT COMPLETED	20	29	7

Baseline Characteristics

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg	Total
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).	Total of all reporting groups
Overall Participants	56	54	24	134
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	72.3 (9.25)	72.1 (8.06)	68.3 (6.77)	70.9
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	56 100%	54 100%	24 100%	134 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 7.1%	4 7.4%	2 8.3%	10 7.5%
Not Hispanic or Latino	51 91.1%	50 92.6%	22 91.7%	123 91.8%
Unknown or Not Reported	1 1.8%	0 0%	0 0%	1 0.7%
Race/Ethnicity, Customized (Count of Participants)
White	45 80.4%	43 79.6%	24 100%	112 83.6%
Black or African American	9 16.1%	10 18.5%	0 0%	19 14.2%
Asian	2 3.6%	1 1.9%	0 0%	3 2.2%
Region of Enrollment (Count of Participants)
United States	51 91.1%	48 88.9%	23 95.8%	122 91%
Canada	5 8.9%	6 11.1%	1 4.2%	12 9%
Height (cm) [Mean (Full Range) ]
Mean (Full Range) [cm]	176.92 (8.855)	177.83 (8.459)	177.63 (7.580)	177.46
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	90.49 (21.632)	92.16 (17.645)	96.10 (17.297)	92.92
Body Mass Index (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	28.815 (5.9592)	29.077 (4.6509)	30.452 (4.9601)	29.448

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Effective Castration Rate Over 24 Weeks
Description	Effective Castration rate is defined as the observed percentage of participants who have testosterone concentrations less than (<) 50 nanogram per deciliter (ng/dL) (1.73 nanomole per liter [nmol/L]) at all scheduled visits beginning after 4 weeks of treatment.
Time Frame	Day 1 of Week 5 to Day 1 of Week 25

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Number (95% Confidence Interval) [percentage of participants]	91 162.5%	91 168.5%	96 400%

2. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Related to Vital Signs
Description	Vital signs included oral temperature, pulse rate, supine systolic and diastolic blood pressure, standing systolic and diastolic blood pressure, and weight. Any TEAEs that were associated with vital signs were reported.
Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Syncope	3 5.4%	2 3.7%	0 0%
Hypertension	1 1.8%	4 7.4%	1 4.2%
Hypotension	1 1.8%	2 3.7%	0 0%
Arrhythmia	0 0%	1 1.9%	0 0%
Bradycardia	2 3.6%	0 0%	0 0%
Tachycardia	1 1.8%	1 1.9%	1 4.2%
Heart rate irregular	1 1.8%	0 0%	0 0%
Weight increased	4 7.1%	2 3.7%	0 0%
Weight decreased	1 1.8%	0 0%	2 8.3%
Pyrexia	3 5.4%	0 0%	0 0%

3. Secondary Outcome

Title	Number of Participants With TEAEs Related to Physical Examination
Description	Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10) including slit lamp examination of the anterior eye. Any TEAEs Related to physical examination were reported.
Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Weight increased	4 7.1%	2 3.7%	0 0%
Weight decreased	1 1.8%	0 0%	2 8.3%
Ophthalmological examination abnormal	1 1.8%	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants With TEAEs Related to 12-lead Electrocardiogram (ECG) Findings
Description	A single 12-lead ECG was performed. ECGs were read and interpreted locally and reviewed if indicated by the study monitor. ECG abnormalities were reported as AEs.
Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Number [participants]	0 0%	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With TEAES Related to Clinical Laboratory Test Results
Description	Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention.
Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Alanine aminotransferase increased	7 12.5%	3 5.6%	4 16.7%
Aspartate aminotransferase increased	6 10.7%	1 1.9%	3 12.5%
Gamma-glutamyltransferase increased	3 5.4%	1 1.9%	2 8.3%
Blood triglycerides increased	3 5.4%	0 0%	1 4.2%
Blood bilirubin increased	1 1.8%	0 0%	0 0%
Hepatic enzyme increased	0 0%	1 1.9%	0 0%
Prostatic specific antigen increased	1 1.8%	1 1.9%	1 4.2%
Blood cholesterol increased	0 0%	2 3.7%	0 0%
Low density lipoprotein increased	1 1.8%	0 0%	0 0%
Blood glucose increased	1 1.8%	1 1.9%	0 0%
Glycosylated haemoglobin increased	0 0%	1 1.9%	0 0%
Blood creatinine increased	0 0%	1 1.9%	0 0%
Blood lactate dehydrogenase increased	2 3.6%	0 0%	0 0%
Blood alkaline phosphatase increased	1 1.8%	0 0%	0 0%
Blood phosphorus increased	1 1.8%	0 0%	0 0%
Blood potassium increased	1 1.8%	0 0%	0 0%
Blood thyroid stimulating hormone increased	0 0%	1 1.9%	0 0%
Blood testosterone increased	0 0%	0 0%	1 4.2%

6. Secondary Outcome

Title	Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any AE that results in death, is life threatening, requires hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Any Adverse Event	53 94.6%	53 98.1%	23 95.8%
SAEs	10 17.9%	7 13%	2 8.3%

7. Secondary Outcome

Title	Percentage of Participants With Prostate-Specific Antigen (PSA) Response of ≥ 50% and ≥ 90% Reduction at 4 Weeks
Description	PSA Response is defined as a reduction in PSA from Baseline and is reported for 2 categories: ≥ 50% reduction and ≥ 90% reduction.
Time Frame	Week 5, Day 1

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
≥ 50% PSA reduction	75 133.9%	83 153.7%	17 70.8%
≥ 90% PSA reduction	13 23.2%	6 11.1%	0 0%

8. Secondary Outcome

Title	Prostate-Specific Antigen Nadir
Description	PSA nadir is the lowest PSA achieved after treatment.
Time Frame	During Weeks 1 to 24

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here number of participants analyzed are participants evaluable for this outcome measure.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	54	53	24
Mean (Standard Deviation) [micrograms per liter (µg/L)]	1.8 (7.20)	5.2 (26.15)	0.6 (1.03)

9. Secondary Outcome

Title	Serum Prostate-Specific Antigen Concentration at the End of Weeks 12 and 24
Description	Blood was collected and serum concentrations of PSA were obtained using a validated laboratory test at a central laboratory facility.
Time Frame	Day 1 of Weeks 13 and 25

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Week 13, Day 1	2.651 (10.0624)	5.786 (26.4243)	0.916 (1.4478)
Week 25, Day 1	1.936 (7.5731)	2.360 (7.3103)	0.624 (1.0693)

10. Secondary Outcome

Title	Time to Achieve Testosterone Concentrations < 50 ng/dL and < 20 ng/dL
Time Frame	During Weeks 1 to 24

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. If a participant has all post first dose testosterone measurements >= 50 ng/dL, the participant's time to castration was censored at the last testosterone measurement that is >= 50 ng/dL.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Time to Castration (< 50 ng/dL)	4	4	29
Time to Profound Castration (< 20 ng/dL)	15	15	29

11. Secondary Outcome

Title	TAK-385 Plasma Concentrations
Time Frame	Day 1 of Weeks 1, 2, 3, 5, 9, 13, 17, 25, 37, 49 pre-dose; Day 4 of Week 1 pre-dose; Day 1 of Weeks 5, 13, 2 hrs post-dose

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug (TAK-835). Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.
Measure Participants	56	54
Week 1, Day 1 pre-dose	0 (0)	0 (0)
Week 1, Day 4 pre-dose	9.9 (13.63)	14.2 (18.52)
Week 2, Day 1 pre-dose	6.3 (6.32)	8.7 (10.10)
Week 3, Day 1 pre-dose	5.4 (3.24)	10.3 (14.77)
Week 5, Day 1 pre-dose	5.2 (2.79)	8.4 (9.85)
Week 5, Day 1, 2 hours post-dose	25.3 (21.76)	45.4 (42.67)
Week 9, Day 1 pre-dose	4.9 (3.47)	8.0 (5.82)
Week 13, Day 1 pre-dose	5.5 (3.39)	9.0 (7.15)
Week 13, Day 1, 2 hours post-dose	24.1 (23.16)	42.2 (37.04)
Week 17, Day 1 pre-dose	6.3 (8.12)	8.9 (6.80)
Week 25, Day 1 pre-dose	7.3 (11.07)	11.5 (14.15)
Week 37, Day 1 pre-dose	6.3 (7.29)	10.9 (16.94)
Week 49, Day 1 pre-dose	5.9 (4.98)	9.4 (8.32)

12. Secondary Outcome

Title	Serum Luteinizing Hormone (LH) Concentrations
Description	Blood was collected and serum concentrations of LH in milli international units per milliliters (mIU/mL) were obtained using a validated laboratory test at a central laboratory facility.
Time Frame	Baseline and Day 4 of Week 1, Day 1 of Weeks 2, 3, 5,13, 25 and 49, End of Treatment (EOT - 106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Week 1, Day 4	0.665 (0.6982)	0.595 (0.5467)	17.551 (13.1433)
Week 2, Day 1	0.548 (0.6683)	0.638 (1.3988)	8.279 (5.8986)
Week 3, Day 1	0.341 (0.5851)	0.388 (0.7887)	3.171 (2.7636)
Week 5, Day 1	0.424 (1.4941)	0.203 (0.3580)	0.508 (0.4327)
Week 13, Day 1	0.229 (0.6003)	0.183 (0.2542)	0.277 (0.8253)
Week 25, Day 1	0.195 (0.2524)	0.175 (0.1365)	0.134 (0.0992)
Week 49, Day 1	0.341 (0.3948)	0.288 (0.2479)	0.138 (0.1677)
EOT	3.189 (3.6928)	2.704 (2.5312)	0.585 (1.6775)
Follow-Up	8.624 (5.3685)	9.510 (5.2926)	0.525 (1.0187)
End of Study	7.182 (8.0509)	9.306 (7.9054)	1.394 (1.7702)

13. Secondary Outcome

Title	Serum Follicle Stimulating Hormone (FSH) Concentrations
Description	Blood was collected and serum concentrations of FSH were obtained using a validated laboratory test at a central laboratory facility.
Time Frame	Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Week 2, Day 1	3.112 (3.0612)	3.183 (2.8956)	7.650 (5.4542)
Week 5, Day 1	1.248 (2.6737)	1.035 (1.0479)	2.946 (1.4428)
Week 13, Day 1	1.137 (2.4242)	0.908 (0.8104)	4.625 (2.5594)
Week 25, Day 1	1.090 (0.9932)	1.344 (0.9675)	5.043 (2.8221)
Week 49, Day 1	1.802 (1.3956)	1.938 (1.2169)	5.145 (2.8201)
EOT	5.377 (4.1261)	5.691 (2.9528)	5.250 (3.0406)
Follow-Up	16.160 (11.0517)	14.610 (6.1553)	9.200 (0)
End of Study	11.441 (8.7613)	15.768 (12.3329)	5.943 (3.6185)

14. Secondary Outcome

Title	Serum Sex Hormone-binding Globulin (SHBG) Concentrations
Description	Blood was collected and serum concentrations of SHBG were obtained using a validated laboratory test at a central laboratory facility.
Time Frame	Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Week 2, Day 1	50.811 (15.8822)	48.594 (17.7492)	39.029 (16.8910)
Week 5, Day 1	49.641 (16.7048)	49.185 (21.1707)	43.786 (20.0484)
Week 13, Day 1	49.210 (19.3704)	50.538 (23.2109)	41.858 (18.1416)
Week 25, Day 1	47.998 (18.8690)	50.774 (23.3292)	40.839 (16.3732)
Week 49, Day 1	50.607 (18.0377)	54.022 (26.1070)	38.237 (18.6708)
EOT	50.013 (21.5189)	54.105 (20.8439)	23.000 (0)
Follow-Up	45.433 (14.7416)	60.250 (28.1206)
End of Study	51.103 (17.8497)	51.063 (23.1018)	39.014 (13.1876)

15. Secondary Outcome

Title	Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-P25 Score
Description	EORTC QLQ-PR25 is an EORTC module designed to supplement the QLQ-C30 for any application in prostate cancer consisting of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Questions use are answered using a 4-point scale: 1=Not at all to 4 =Very much. All raw domain scores are linearly transformed to a 0 to 100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual). A positive change from Baseline in activity or functioning scales and negative change from Baseline in symptom scales indicates improvement.
Time Frame	Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Sexual Activity: Week 5, Day 1	-6.0 (29.25)	-14.4 (22.39)	-7.6 (20.25)
Sexual Activity: Week 13, Day 1	-9.3 (18.49)	-17.3 (27.28)	-11.1 (19.45)
Sexual Activity: Week 25, Day 1	-9.4 (25.24)	-19.8 (31.82)	-18.8 (20.90)
Sexual Activity: Week 37, Day 1	-12.0 (27.81)	-14.4 (31.70)	-14.3 (21.27)
Sexual Activity: Week 49, Day 1	-13.0 (28.40)	-19.1 (36.24)	-17.5 (31.39)
Sexual Activity: EOT	-15.7 (18.05)	-18.1 (43.79)	-30.8 (27.09)
Sexual Activity: Follow-up	-9.2 (18.32)	-24.6 (32.09)	-14.3 (34.50)
Sexual Activity: End of Study	-7.9 (25.04)	-15.5 (35.89)	-21.9 (24.13)
Sexual Functioning: Week 5, Day 1	-9.9 (24.53)	-2.0 (29.25)	-4.2 (14.43)
Sexual Functioning: Week 13, Day 1	-8.3 (20.89)	-1.4 (29.27)	0.8 (27.34)
Sexual Functioning: Week 25, Day 1	-4.7 (22.97)	-12.5 (33.80)	-16.7 (23.07)
Sexual Functioning: Week 37, Day 1	-10.7 (18.90)	-12.8 (17.55)	-19.8 (17.22)
Sexual Functioning: Week 49, Day 1	-16.7 (23.84)	-13.9 (27.95)	6.0 (23.43)
Sexual Functioning: EOT	-16.7 (25.97)	-10.7 (6.30)	37.5 (53.03)
Sexual Functioning: Follow-up	3.1 (21.33)	-10.4 (18.48)	2.1 (73.40)
Sexual Functioning: End of Study	-11.5 (22.70)	-4.2 (21.96)	-13.9 (12.73)
Urinary Symptoms: Week 5, Day 1	2.0 (12.60)	1.8 (7.84)	4.2 (7.57)
Urinary Symptoms: Week 13, Day 1	1.9 (11.64)	3.8 (7.54)	6.8 (10.70)
Urinary Symptoms: Week 25, Day 1	3.6 (15.46)	5.1 (12.28)	7.2 (10.60)
Urinary Symptoms: Week 37, Day 1	3.4 (14.89)	4.2 (10.24)	12.9 (14.61)
Urinary Symptoms: Week 49, Day 1	4.0 (11.98)	6.5 (11.18)	9.9 (11.45)
Urinary Symptoms: EOT	3.3 (14.00)	7.1 (13.35)	9.0 (12.83)
Urinary Symptoms: Follow-up	-1.0 (11.30)	5.9 (14.52)	9.8 (7.42)
Urinary Symptoms: End of study	2.2 (10.84)	4.5 (14.04)	6.8 (13.08)
Bowel Symptoms: Week 5, Day 1	1.9 (7.24)	1.1 (6.81)	0.3 (5.75)
Bowel Symptoms: Week 13, Day 1	1.0 (4.95)	1.8 (8.55)	2.4 (7.57)
Bowel Symptoms: Week 25, Day 1	3.1 (7.22)	0.3 (6.87)	1.1 (4.57)
Bowel Symptoms: Week 37, Day 1	3.8 (7.80)	1.5 (7.60)	3.2 (7.21)
Bowel Symptoms: Week 49, Day 1	3.0 (6.44)	0.0 (6.97)	2.4 (7.04)
Bowel Symptoms: EOT	2.1 (6.18)	2.4 (7.98)	2.6 (6.26)
Bowel Symptoms: Follow-up	0.0 (4.68)	2.2 (9.95)	2.4 (8.91)
Bowel Symptoms: End of Study	2.1 (5.03)	-0.3 (6.49)	1.0 (9.56)
HTRS: Week 5, Day 1	5.6 (8.98)	5.0 (8.03)	3.5 (8.94)
HTRS: Week 13, Day 1	9.2 (9.95)	10.8 (10.80)	7.2 (9.48)
HTRS: Week 25, Day 1	11.7 (10.07)	11.3 (11.40)	10.9 (9.98)
HTRS: Week 37, Day 1	13.3 (10.51)	12.2 (13.17)	13.2 (13.32)
HTRS: Week 49, Day 1	14.4 (12.39)	9.6 (11.04)	15.9 (12.82)
HTRS: EOT	12.9 (12.33)	14.0 (16.13)	17.9 (12.25)
HTRS: Follow-up	7.5 (8.51)	6.1 (9.05)	15.9 (15.69)
HTRS: End of Study	10.8 (11.03)	9.8 (11.27)	12.5 (12.75)
Incontinence Aid: Week 5, Day 1	0.0 (21.63)	-1.9 (17.98)	-16.7 (19.25)
Incontinence Aid: Week 13, Day 1	0.0 (22.22)	-1.8 (13.49)	-16.7 (19.25)
Incontinence Aid: Week 25, Day 1	3.5 (21.93)	0.0 (15.71)	-16.7 (23.57)
Incontinence Aid: Week 37, Day 1	8.3 (25.82)	-1.8 (13.49)	-16.7 (23.57)
Incontinence Aid: Week 49, Day 1	7.0 (23.78)	-2.2 (15.26)	-22.2 (19.25)
Incontinence Aid: EOT	6.1 (20.10)	6.1 (20.10)	-16.7 (23.57)
Incontinence Aid: Follow-up	0.0 (21.08)	-8.3 (15.43)	-33.3 (0)
Incontinence Aid: End of Study	0.0 (20.10)	-4.8 (22.10)	-33.3 (0)

16. Secondary Outcome

Title	Percent Change From Baseline of Aging Male Survey (AMS) Total Score
Description	AMS scale is a self-administered questionnaire used to: 1) assess symptoms of aging (independent from those that are disease related) between groups of males under different conditions; 2) evaluate the severity of symptoms over time; and 3) measure changes before and after androgen therapy. Each question was answered between 1=none to 5=extremely severe for 17 items from psychological (5 items), somatic (7 items), and sexual (5 items) categories. Total score is sum of all the item scores and range from 17 (minimum) to 85 (maximum), where high score indicated high level of symptoms.
Time Frame	Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Week 5, Day 1	3.914 (24.4749)	10.872 (29.6532)	10.083 (27.1933)
Week 13, Day 1	14.781 (24.0185)	17.259 (33.9921)	21.887 (36.5551)
Week 25, Day 1	20.272 (35.2952)	20.353 (34.2105)	46.995 (55.3558)
Week 37, Day 1	24.136 (33.8595)	24.466 (35.6742)	49.422 (61.1264)
Week 49, Day 1	30.122 (38.1093)	24.377 (33.6078)	59.971 (60.3579)
EOT	18.857 (37.9260)	28.644 (35.6470)	60.952 (63.3615)
Follow-Up	15.754 (21.8158)	13.031 (33.7754)	53.834 (61.6683)
End of Study	16.270 (24.2582)	21.304 (46.0184)	49.879 (54.1540)

17. Secondary Outcome

Title	Change From Baseline in EORTC QLQ-C30
Description	The EORTC QLQ-C30 included 30 questions comprising 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties) and a global health and QOL scale. Most questions used a 4-point scale (1=Not at all to 4=Very much); 2 questions used a 7-point scale (1= Very poor to 7=Excellent). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. A positive change from Baseline in quality og life or functioning scales and negative change from Baseline in symptom or difficulties scales indicates improvement.
Time Frame	Day 1 of Weeks 5, 13, 25, 37, 49, 73, 97, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks)

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here 'n' is the number of participants analyzed at the specific timepoint.

Arm/Group Title	Relugolix 80 mg	Relugolix 120 mg	Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.	Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
Measure Participants	56	54	24
Quality of Life: Week 5, Day 1	-2.7 (14.51)	-4.0 (17.50)	-5.2 (13.64)
Quality of Life: Week 13, Day 1	-2.3 (15.37)	-2.0 (14.87)	-7.3 (15.21)
Quality of Life: Week 25, Day 1	-6.4 (20.21)	-2.3 (15.45)	-6.9 (16.98)
Quality of Life: Week 37, Day 1	-6.0 (20.69)	-7.4 (20.58)	-11.7 (18.84)
Quality of Life: Week 49, Day 1	-7.2 (19.18)	-7.3 (18.18)	-8.3 (17.87)
Quality of Life: Week 73, Day 1	-3.4 (17.18)	-12.0 (13.19)
Quality of Life: Week 97, Day 1	-6.6 (20.71)	-2.2 (18.18)
Quality of Life: EOT	-4.8 (16.82)	-7.1 (15.80)	-13.5 (24.19)
Quality of Life: Follow-Up	-5.4 (12.17)	-8.8 (22.13)	-13.7 (19.50)
Quality of Life: End of Study	-7.9 (18.14)	-10.1 (15.49)	-10.9 (13.85)
Physical Functioning: Week 5, Day 1	0.9 (9.87)	-0.9 (7.70)	-0.8 (8.41)
Physical Functioning: Week 13, Day 1	0.3 (9.23)	-4.4 (8.50)	-0.3 (14.77)
Physical Functioning: Week 25, Day 1	-2.8 (15.24)	-5.3 (10.20)	-2.0 (14.42)
Physical Functioning: Week 37, Day 1	-4.8 (13.60)	-6.2 (12.26)	-4.2 (16.78)
Physical Functioning: Week 49, Day 1	-4.3 (13.79)	-5.2 (9.95)	-7.0 (17.32)
Physical Functioning: Week 73, Day 1	-5.1 (9.20)	-8.5 (8.72)
Physical Functioning: Week 97, Day 1	-8.1 (9.58)	-6.0 (8.86)
Physical Functioning: EOT	-3.4 (15.37)	-9.3 (14.66)	-2.6 (22.20)
Physical Functioning: Follow-Up	-4.0 (9.02)	-6.3 (19.18)	-3.8 (21.52)
Physical Functioning: End of Study	-8.9 (13.52)	-9.0 (13.48)	-2.9 (20.22)
Role Functioning: Week 5, Day 1	0.3 (14.43)	-0.3 (15.30)	2.8 (8.03)
Role Functioning: Week 13, Day 1	-1.0 (17.13)	-3.6 (16.09)	1.4 (21.93)
Role Functioning: Week 25, Day 1	-4.9 (21.18)	-6.3 (19.03)	-2.2 (23.19)
Role Functioning: Week 37, Day 1	-10.9 (23.10)	-10.0 (16.82)	-4.5 (24.22)
Role Functioning: Week 49, Day 1	-8.1 (23.20)	-8.9 (22.70)	-7.1 (19.42)
Role Functioning: Week 73, Day 1	-8.0 (13.08)	-6.7 (14.43)
Role Functioning: Week 97, Day 1	-8.8 (15.08)	-4.4 (12.22)
Role Functioning: EOT	-9.5 (21.88)	-8.6 (20.76)	-5.1 (29.17)
Role Functioning: Follow-Up	-10.0 (16.58)	-10.5 (31.04)	-7.1 (29.75)
Role Functioning: End of Study	-10.6 (12.69)	-13.2 (21.99)	-1.0 (26.15)
Emotional Functioning: Week 5, Day 1	1.9 (8.59)	0.3 (12.45)	1.7 (10.98)
Emotional Functioning: Week 13, Day 1	-0.7 (11.53)	-1.1 (12.70)	-1.4 (12.69)
Emotional Functioning: Week 37, Day 1	-4.3 (12.26)	-1.7 (11.73)	-9.8 (20.35)
Emotional Functioning: Week 49, Day 1	-3.0 (14.01)	-1.4 (12.06)	-4.4 (18.56)
Emotional Functioning: Week 73, Day 1	-2.0 (9.36)	-2.3 (16.578)
Emotional Functioning: Week 97, Day 1	-2.6 (12.44)	2.6 (7.88)
Emotional Functioning: EOT	-3.6 (11.30)	-7.4 (17.12)	-14.1 (24.15)
Emotional Functioning: Follow-Up	-3.3 (8.72)	-1.3 (19.50)	-8.9 (23.22)
Emotional Functioning: End of Study	-5.3 (12.62)	-0.6 (14.42)	-8.3 (17.74)
Cognitive Functioning: Week 5, Day 1	-0.9 (11.97)	-4.2 (14.71)	-2.8 (10.62)
Cognitive Functioning: Week 13, Day 1	-1.0 (13.50)	-7.5 (16.44)	-5.6 (16.05)
Cognitive Functioning: Week 25, Day 1	-0.7 (14.16)	-3.8 (15.08)	-2.9 (11.95)
Cognitive Functioning: Week 37, Day 1	-5.8 (12.28)	-5.6 (16.67)	-9.8 (15.99)
Cognitive Functioning: Week 49, Day 1	-2.6 (12.29)	-6.1 (13.82)	-11.9 (16.79)
Cognitive Functioning: Week 73, Day 1	-5.7 (15.61)	-7.3 (13.68)
Cognitive Functioning: Week 97, Day 1	-6.1 (8.26)	-7.0 (13.96)
Cognitive Functioning: EOT	-2.9 (14.84)	-10.0 (23.64)	-12.8 (21.68)
Cognitive Functioning: Follow-Up	-0.8 (14.78)	-7.0 (21.74)	-10.7 (15.48)
Cognitive Functioning: End of Study	-2.3 (16.01)	-7.5 (18.14)	-3.1 (16.35)
Social Functioning: Week 5, Day 1	0.3 (16.50)	-1.3 (14.33)	4.2 (16.48)
Social Functioning: Week 13, Day 1	1.6 (13.85)	-3.3 (12.48)	-0.7 (18.04)
Social Functioning: Week 25, Day 1	-1.0 (16.98)	-6.3 (20.23)	-202 (22.08)
Social Functioning: Week 37, Day 1	-2.5 (18.58)	-5.9 (16.34)	-7.6 (20.40)
Social Functioning: Week 49, Day 1	-3.7 (15.85)	-9.8 (20.74)	-8.7 (26.15)
Social Functioning: Week 73, Day 1	-2.9 (11.84)	-6.0 (15.12)
Social Functioning: Week 97, Day 1	-5.3 (15.77)	-4.4 (14.53)
Social Functioning: EOT	-5.2 (16.55)	-10.0 (21.08)	-6.4 (30.84)
Social Functioning: Follow-Up	-3.3 (10.26)	-8.8 (25.07)	-4.8 (22.10)
Social Functioning: End of Study	-3.7 (16.48)	-9.2 (19.20)	0.0 (14.91)
Fatigue: Week 5, Day 1	1.9 (13.74)	4.3 (14.95)	3.2 (15.19)
Fatigue: Week 13, Day 1	6.1 (17.40)	8.9 (15.72)	8.3 (11.47)
Fatigue: Week 25, Day 1	6.3 (21.12)	13.2 (15.66)	13.5 (18.94)
Fatigue: Week 37, Day 1	9.7 (21.55)	14.1 (19.30)	16.7 (21.89)
Fatigue: Week 49, Day 1	10.9 (24.33)	11.1 (16.67)	20.1 (23.47)
Fatigue: Week 73, Day 1	10.0 (24.19)	14.7 (13.88)
Fatigue: Week 97, Day 1	5.8 (22.94)	9.9 (18.48)
Fatigue: EOT	12.1 (27.53)	15.9 (20.22)	20.5 (18.62)
Fatigue: Follow-up	7.2 (15.41)	6.4 (19.71)	13.5 (21.87)
Fatigue: End of study	11.4 (17.72)	12.3 (22.88)	8.3 (19.25)
Nausea and Vomiting: Week 5, Day 1	-1.3 (6.41)	0.6 (9.88)	3.5 (6.91)
Nausea and Vomiting: Week 13, Day 1	0.7 (7.42)	0.7 (7.42)	1.4 (4.71)
Nausea and Vomiting: Week 25, Day 1	0.0 (9.10)	0.0 (3.44)	2.9 (6.46)
Nausea and Vomiting: Week 37, Day 1	0.4 (8.95)	1.1 (7.45)	4.5 (9.17)
Nausea and Vomiting: Week 49, Day 1	-1.9 (7.30)	0.8 (6.40)	4.8 (11.95)
Nausea and Vomiting: Week 73, Day 1	0.0 (4.45)	0.7 (3.33)
Nausea and Vomiting: Week 97, Day 1	5.3 (14.75)	1.8 (9.45)
Nausea and Vomiting: Week EOT	-0.5 (8.56)	1.9 (8.83)	7.7 (14.62)
Nausea and Vomiting: Follow-Up	3.3 (16.75)	0.9 (3.82)	0.0 (6.54)
Nausea and Vomiting: End of Study	1.4 (9.24)	-1.1 (4.30)	0.0 (6.09)
Pain: Week 5, Day 1	-1.6 (16.75)	0.6 (16.82)	3.5 (18.38)
Pain: Week 13, Day 1	-1.0 (17.77)	3.3 (18.86)	4.2 (26.12)
Pain: Week 25, Day 1	0.3 (22.67)	2.8 (16.61)	2.9 (22.84)
Pain: Week 37, Day 1	2.9 (23.65)	5.9 (21.37)	11.4 (34.27)
Pain: Week 49, Day 1	3.3 (23.19)	6.5 (18.59)	7.9 (31.46)
Pain: Week 73, Day 1	6.9 (18.64)	7.3 (14.50)
Pain: Week 97, Day 1	5.3 (19.29)	0.0 (14.70)
Pain: EOT	-0.5 (25.08)	6.7 (24.32)	6.4 (35.05)
Pain: Follow-Up	9.2 (21.95)	10.5 (23.05)	1.2 (28.84)
Pain: End of Study	6.5 (17.03)	6.9 (19.17)	-2.1 (30.96)
Dyspnea: Week 5, Day 1	-0.6 (21.17)	2.6 (17.27)	5.6 (18.82)
Dyspnea: Week 13, Day 1	5.9 (22.81)	6.5 (21.10)	8.3 (20.26)
Dyspnea: Week 25, Day 1	4.2 (26.30)	8.3 (22.28)	8.7 (22.96)
Dyspnea: Week 37, Day 1	6.5 (21.80)	11.1 (22.47)	22.7 (26.00)
Dyspnea: Week 49, Day 1	6.7 (22.02)	9.8 (20.06)	17.5 (30.95)
Dyspnea: Week 73, Day 1	8.0 (19.22)	9.3 (18.05)
Dyspnea: Week 97, Day 1	10.5 (19.41)	8.8 (18.73)
Dyspnea: EOT	7.6 (24.37)	14.3 (20.27)	20.5 (32.03)
Dyspnea: Follow-Up	11.7 (22.36)	8.8 (26.86)	14.3 (25.20)
Dyspnea: End of Study	11.1 (19.52)	14.9 (26.10)	8.3 (31.03)
Insomnia: Week 5, Day 1	-1.3 (24.43)	3.2 (17.79)	1.4 (18.33)
Insomnia: Week 13, Day 1	2.6 (20.92)	9.8 (21.39)	6.9 (19.61)
Insomnia: Week 25, Day 1	6.3 (30.49)	12.5 (24.43)	8.7 (22.96)
Insomnia: Week 37, Day 1	2.2 (24.75)	8.1 (22.65)	18.2 (32.08)
Insomnia: Week 49, Day 1	6.7 (29.81)	7.3 (22.99)	6.3 (32.69)
Insomnia: Week 73, Day 1	2.3 (33.25)	10.7 (23.01)
Insomnia: Week 97, Day 1	10.5 (27.34)	10.5 (19.41)
Insomnia: EOT	6.7 (35.97)	7.6 (26.92)	7.7 (24.17)
Insomnia: Follow-Up	5.0 (19.57)	0.0 (27.22)	4.8 (25.68)
Insomnia: End of Study	1.9 (28.67)	5.7 (21.95)	10.4 (29.11)
Appetite Loss: Week 5, Day 1	-3.8 (14.11)	0.6 (21.38)	2.8 (13.61)
Appetite Loss: Week 13, Day 1	-0.7 (18.25)	-0.7 (20.54)	0.0 (13.90)
Appetite Loss: Week 25, Day 1	-3.5 (19.74)	0.0 (19.45)	2.9 (17.15)
Appetite Loss: Week 37, Day 1	-0.7 (17.90)	2.2 (16.51)	0.0 (14.55)
Appetite Loss: Week 49, Day 1	-0.7 (16.65)	0.8 (15.79)	4.8 (15.94)
Appetite Loss: Week 73, Day 1	-2.3 (12.38)	5.3 (18.46)
Appetite Loss: Week 97, Day 1	0.0 (15.71)	3.5 (15.29)
Appetite Loss: EOT	-3.8 (15.70)	8.6 (16.85)	2.6 (16.45)
Appetite Loss: Follow-Up	0.0 (15.29)	3.5 (18.90)	-2.4 (15.82)
Appetite Loss: End of Study	-1.9 (13.67)	3.4 (13.64)	0.0 (24.34)
Constipation: Week 5, Day 1	0.6 (20.14)	1.9 (17.97)	1.4 (6.80)
Constipation: Week 13, Day 1	3.9 (21.75)	5.2 (19.29)	5.6 (12.69)
Constipation: Week 25, Day 1	2.8 (19.25)	6.3 (25.41)	1.4 (15.82)
Constipation: Week 37, Day 1	5.8 (20.25)	8.1 (26.74)	1.5 (12.50)
Constipation: Week 49, Day 1	2.2 (19.33)	7.3 (20.43)	1.6 (7.27)
Constipation: Week 73, Day 1	1.1 (18.86)	1.3 (17.95)
Constipation: Week 97, Day 1	1.8 (26.00)	3.5 (21.93)
Constipation: EOT	3.8 (22.54)	1.9 (17.97)	0.0 (13.61)
Constipation: Follow-Up	5.0 (24.84)	10.5 (24.98)	0.0 (13.07)
Constipation: End Of Study	3.7 (19.15)	5.7 (17.97)	0.0 (17.21)
Diarrhea: Week 5, Day 1	-1.9 (12.08)	1.9 (13.87)	1.4 (11.95)
Diarrhea: Week 13, Day 1	3.9 (18.44)	2.0 (23.49)	0.0 (9.83)
Diarrhea: Week 25, Day 1	2.8 (17.97)	5.6 (19.85)	2.9 (13.90)
Diarrhea: Week 37, Day 1	3.6 (17.54)	0.7 (15.06)	6.1 (13.16)
Diarrhea: Week 49, Day 1	3.0 (17.15)	-1.6 (16.59)	1.6 (16.59)
Diarrhea: Week 73, Day 1	4.6 (17.19)	1.3 (15.15)
Diarrhea: Week 97, Day 1	7.0 (17.84)	0.0 (15.71)
Diarrhea: EOT	4.8 (14.33)	2.9 (16.90)	5.1 (18.49)
Diarrhea: Follow-Up	3.3 (10.26)	0.0 (19.25)	4.8 (12.10)
Diarrhea: End Of Study	1.9 (17.72)	-1.1 (18.86)	2.1 (19.12)
Financial Difficulties:Week 5, Day 1	-1.3 (9.16)	2.6 (21.74)	-1.4 (18.33)
Financial Difficulties:Week 13, Day 1	-2.0 (16.88)	-0.7 (20.54)	2.8 (23.91)
Financial Difficulties:Week 25, Day 1	-3.5 (12.38)	0.7 (20.03)	4.3 (23.15)
Financial Difficulties:Week 37, Day 1	-2.9 (19.66)	1.5 (18.74)	7.6 (20.40)
Financial Difficulties:Week 49, Day 1	-5.2 (20.04)	0.8 (18.99)	3.2 (17.97)
Financial Difficulties:Week 73, Day 1	0.0 (8.91)	2.7 (16.44)
Financial Difficulties: Week 97, Day 1	5.3 (20.07)	1.8 (20.71)
Financial Difficulties: EOT	-3.8 (19.42)	5.7 (20.59)	2.6 (16.45)
Financial Difficulties: Follow-Up	5.0 (12.21)	1.8 (20.71)	11.9 (33.61)
Financial Difficulties: End of Study	-2.8 (18.47)	3.4 (22.44)	0.0 (21.08)

Adverse Events

Time Frame	From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Relugolix 80 mg		Relugolix 120 mg		Leuprorelin 22.5 mg
Arm/Group Description	Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.		Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. Bicalutamide is allowed for firs 4 weeks per investigator's discretion.		Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks).
All Cause Mortality
	Relugolix 80 mg		Relugolix 120 mg		Leuprorelin 22.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Relugolix 80 mg		Relugolix 120 mg		Leuprorelin 22.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/56 (17.9%)		7/54 (13%)		2/24 (8.3%)
Cardiac disorders
Bradycardia	2/56 (3.6%)		0/54 (0%)		0/24 (0%)
Tachycardia	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Acute coronary syndrome	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Myocardial infarction	0/56 (0%)		0/54 (0%)		1/24 (4.2%)
Atrioventricular block first degree	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Atrial flutter	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Cardiac arrest	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Gastrointestinal disorders
Intestinal obstruction	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
General disorders
Death	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Sudden death	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Infections and infestations
Sepsis	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Urinary tract infection	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Nervous system disorders
Cerebral haemorrhage	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Cerebrovascular accident	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Embolic stroke	0/56 (0%)		1/54 (1.9%)		0/24 (0%)
Syncope	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Transient ischaemic attack	1/56 (1.8%)		0/54 (0%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/56 (1.8%)		0/54 (0%)		1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Relugolix 80 mg		Relugolix 120 mg		Leuprorelin 22.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/56 (94.6%)		50/54 (92.6%)		23/24 (95.8%)
Congenital, familial and genetic disorders
Corneal dystrophy	3/56 (5.4%)		0/54 (0%)		0/24 (0%)
Eye disorders
Cataract	7/56 (12.5%)		13/54 (24.1%)		0/24 (0%)
Visual acuity reduced	2/56 (3.6%)		4/54 (7.4%)		0/24 (0%)
Dry eye	3/56 (5.4%)		0/54 (0%)		0/24 (0%)
Gastrointestinal disorders
Constipation	2/56 (3.6%)		5/54 (9.3%)		0/24 (0%)
Diarrhoea	3/56 (5.4%)		3/54 (5.6%)		0/24 (0%)
Nausea	1/56 (1.8%)		4/54 (7.4%)		0/24 (0%)
General disorders
Fatigue	11/56 (19.6%)		19/54 (35.2%)		7/24 (29.2%)
Pyrexia	3/56 (5.4%)		0/54 (0%)		0/24 (0%)
Infections and infestations
Nasopharyngitis	4/56 (7.1%)		5/54 (9.3%)		1/24 (4.2%)
Urinary tract infection	5/56 (8.9%)		2/54 (3.7%)		1/24 (4.2%)
Sinusitis	3/56 (5.4%)		2/54 (3.7%)		1/24 (4.2%)
Gastroenteritis viral	0/56 (0%)		3/54 (5.6%)		0/24 (0%)
Injury, poisoning and procedural complications
Fall	4/56 (7.1%)		2/54 (3.7%)		1/24 (4.2%)
Contusion	0/56 (0%)		3/54 (5.6%)		0/24 (0%)
Investigations
Alanine aminotransferase increased	7/56 (12.5%)		3/54 (5.6%)		4/24 (16.7%)
Aspartate aminotransferase increased	6/56 (10.7%)		1/54 (1.9%)		3/24 (12.5%)
Gamma-glutamyltransferase increased	3/56 (5.4%)		1/54 (1.9%)		2/24 (8.3%)
Weight increased	4/56 (7.1%)		2/54 (3.7%)		0/24 (0%)
Blood triglycerides increased	3/56 (5.4%)		0/54 (0%)		1/24 (4.2%)
Weight decreased	1/56 (1.8%)		0/54 (0%)		2/24 (8.3%)
Metabolism and nutrition disorders
Diabetes mellitus	1/56 (1.8%)		1/54 (1.9%)		3/24 (12.5%)
Hypercholesterolaemia	3/56 (5.4%)		0/54 (0%)		2/24 (8.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/56 (16.1%)		6/54 (11.1%)		2/24 (8.3%)
Back pain	3/56 (5.4%)		2/54 (3.7%)		1/24 (4.2%)
Osteopenia	3/56 (5.4%)		3/54 (5.6%)		0/24 (0%)
Pain in extremity	4/56 (7.1%)		2/54 (3.7%)		0/24 (0%)
Musculoskeletal pain	0/56 (0%)		4/54 (7.4%)		0/24 (0%)
Muscle spasms	1/56 (1.8%)		0/54 (0%)		2/24 (8.3%)
Myalgia	0/56 (0%)		0/54 (0%)		3/24 (12.5%)
Nervous system disorders
Dizziness	2/56 (3.6%)		4/54 (7.4%)		0/24 (0%)
Headache	2/56 (3.6%)		3/54 (5.6%)		1/24 (4.2%)
Psychiatric disorders
Insomnia	1/56 (1.8%)		5/54 (9.3%)		2/24 (8.3%)
Libido decreased	1/56 (1.8%)		3/54 (5.6%)		1/24 (4.2%)
Depression	1/56 (1.8%)		3/54 (5.6%)		0/24 (0%)
Renal and urinary disorders
Pollakiuria	2/56 (3.6%)		0/54 (0%)		3/24 (12.5%)
Reproductive system and breast disorders
Gynaecomastia	3/56 (5.4%)		3/54 (5.6%)		0/24 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/56 (5.4%)		4/54 (7.4%)		1/24 (4.2%)
Nasal congestion	1/56 (1.8%)		2/54 (3.7%)		2/24 (8.3%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/56 (3.6%)		1/54 (1.9%)		3/24 (12.5%)
Vascular disorders
Hot flush	32/56 (57.1%)		35/54 (64.8%)		15/24 (62.5%)
Hypertension	1/56 (1.8%)		4/54 (7.4%)		1/24 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.