Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer (NCT NCT03085095)

NCT ID: NCT03085095

Last Updated: 2022-01-18

Results Overview

Sustained castration rate defined as the cumulative probability of testosterone suppression to \< 50 nanogram (ng)/deciliter (dL). The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants. The lower bound of the 95% confidence interval (CI) for the cumulative probability of sustained testosterone suppression in the relugolix treatment group must have been ≥ 90% to meet evaluation criteria for efficacy.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1134 participants
• Primary outcome timeframe: From Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337)
• Results posted on: 2022-01-18

Participant Flow

To support registration in China, the study continued to enroll additional nonmetastatic or metastatic participants from China after the final analysis to reach the target enrollment of approximately 90 participants.

The primary analysis of efficacy and safety included 934 participants. The primary analysis excluded additional participants with metastatic disease and a cohort of participants enrolled in China and Taiwan who will be included in the final analysis of the study (N=200).

Participant milestones

Measure	Relugolix Relugolix 120-milligram (mg) tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Overall Study STARTED	624	310
Overall Study Received at Least 1 Dose of Study Drug	622	308
Overall Study COMPLETED	563	276
Overall Study NOT COMPLETED	61	34

Reasons for withdrawal

Measure	Relugolix Relugolix 120-milligram (mg) tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Overall Study Adverse Event	23	8
Overall Study Protocol Violation	0	1
Overall Study Lost to Follow-up	2	1
Overall Study Withdrawal by Subject	17	6
Overall Study Physician Decision	9	3
Overall Study Testosterone Suppression Level Not Met	7	13
Overall Study Did not Receive Study Drug	2	2
Overall Study Dosing Interruption (Logistical Reason)	1	0

Baseline Characteristics

A Study to Evaluate the Safety and Efficacy of Relugolix in Men With Advanced Prostate Cancer

Baseline characteristics by cohort

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.	Total n=930 Participants Total of all reporting groups
Age, Continuous	71.2 years STANDARD_DEVIATION 7.75 • n=5 Participants	71.0 years STANDARD_DEVIATION 8.03 • n=7 Participants	71.1 years STANDARD_DEVIATION 7.84 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	622 Participants n=5 Participants	308 Participants n=7 Participants	930 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	52 Participants n=5 Participants	31 Participants n=7 Participants	83 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	558 Participants n=5 Participants	269 Participants n=7 Participants	827 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	12 Participants n=5 Participants	8 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	127 Participants n=5 Participants	71 Participants n=7 Participants	198 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	30 Participants n=5 Participants	16 Participants n=7 Participants	46 Participants n=5 Participants
Race (NIH/OMB) White	434 Participants n=5 Participants	202 Participants n=7 Participants	636 Participants n=5 Participants
Race (NIH/OMB) More than one race	11 Participants n=5 Participants	4 Participants n=7 Participants	15 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	20 Participants n=5 Participants	15 Participants n=7 Participants	35 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Sustained castration rate defined as the cumulative probability of testosterone suppression to < 50 nanogram (ng)/deciliter (dL). The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

The lower bound of the 95% confidence interval (CI) for the cumulative probability of sustained testosterone suppression in the relugolix treatment group must have been ≥ 90% to meet evaluation criteria for efficacy.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Sustained Castration Rate	96.7 percentage of participants Interval 94.9 to 97.9	88.8 percentage of participants Interval 84.6 to 91.8

SECONDARY outcome

Timeframe: Week 1 Day 4 (Day 4)

Population: All randomized participants who received at least 1 dose of study drug.

Castration rate was defined as the cumulative probability of testosterone suppression to < 50 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Castration Rate At Week 1 Day 4	56.04 percentage of participants Interval 52.18 to 59.97	0.00 percentage of participants Not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: Week 3 Day 1 (Day 15)

Population: All randomized participants who received at least 1 dose of study drug.

Castration rate was defined as the cumulative probability of testosterone suppression to < 50 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Castration Rate At Week 3 Day 1	98.71 percentage of participants Interval 97.56 to 99.39	12.05 percentage of participants Interval 8.88 to 16.25

SECONDARY outcome

Timeframe: Week 3 Day 1 (Day 15) and Week 5 Day 1 (Day 29)

Population: All randomized participants who received at least 1 dose of study drug.

Confirmed PSA response defined as > 50% reduction in PSA from baseline at Week 3 Day 1 followed with confirmation at Week 5 Day 1.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Confirmed Prostate-specific Antigen (PSA) Response Rate	79.4 percentage of participants Interval 76.03 to 82.53	19.8 percentage of participants Interval 15.5 to 24.7

SECONDARY outcome

Timeframe: Week 3 Day 1 (Day 15)

Population: All randomized participants who received at least 1 dose of study drug.

Castration rate defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Profound Castration Rate At Week 3 Day 1 (Day 15)	78.38 percentage of participants Interval 75.06 to 81.53	0.98 percentage of participants Interval 0.32 to 3.0

SECONDARY outcome

Timeframe: Week 25 Day 1 (Day 169)

Population: All randomized participants who received at least 1 dose of study drug.

To evaluate the effect of relugolix and leuprolide acetate on FSH suppression.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Follicle-stimulating Hormone (FSH) Level	1.72 IU/L Standard Deviation 1.376	5.95 IU/L Standard Deviation 3.071

SECONDARY outcome

Timeframe: Week 3 Day 1 (Day 15)

Population: All randomized participants who received at least 1 dose of study drug.

PSA response defined as > 50% reduction in PSA from baseline. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
PSA Response Rate At Week 3 Day 1	80.1 percentage of participants Interval 76.7 to 83.14	20.1 percentage of participants Interval 15.8 to 25.05

SECONDARY outcome

Timeframe: Week 5 Day 1 (Day 29)

Population: All randomized participants who received at least 1 dose of study drug.

PSA response defined as > 50% reduction in PSA from baseline. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
PSA Response Rate At Week 5 Day 1	94.5 percentage of participants Interval 92.44 to 96.19	79.2 percentage of participants Interval 74.26 to 83.61

SECONDARY outcome

Timeframe: Day 90 follow-up

Population: All randomized participants who received at least 1 dose of study drug and were followed in the testosterone recovery phase.

The cumulative probability of testosterone recovery back to > 280 ng/dL (lower limit of the normal range), back to ≥ 50 ng/dL (definition of castration), and back to > 280 ng/dL or baseline at 90 days after drug discontinuation was assessed. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Testosterone Recovery Rate ≥ 50 ng/dL	93.01 percentage of participants Interval 87.82 to 96.54	10.12 percentage of participants Interval 3.84 to 25.24
Testosterone Recovery Rate > 280 ng/dL	53.93 percentage of participants Interval 45.2 to 63.16	3.23 percentage of participants Interval 0.46 to 20.77
Testosterone Recovery Rate > Baseline level or 280 ng/dL	54.73 percentage of participants Interval 45.97 to 63.94	3.23 percentage of participants Interval 0.46 to 20.77

SECONDARY outcome

Timeframe: Week 5 Day 1 (Day 29) through Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Sustained profound castration rate was defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated by the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Sustained Profound Castration Rate From Week 5 Day 1 Through Week 49 Day 1	81.6 percentage of participants Interval 78.1 to 84.5	68.6 percentage of participants Interval 63.0 to 73.5

SECONDARY outcome

Timeframe: At Week 1 Day 4 (Day 4)

Population: All randomized participants who received at least 1 dose of study drug.

Castration rate defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated for each treatment group using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Profound Castration Rate At Week 1 Day 4 (Day 4)	6.92 percentage of participants Interval 5.18 to 9.22	0.0 percentage of participants Not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: Week 25 Day 1 (Day 169) through Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Sustained profound castration rate was defined as the cumulative probability of testosterone suppression to < 20 ng/dL. The rate was estimated by the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Sustained Profound Castration Rate From Week 25 Day 1 Through Week 49 Day 1	84.6 percentage of participants Interval 81.3 to 87.3	87.5 percentage of participants Interval 83.0 to 90.8

SECONDARY outcome

Timeframe: Week 25 Day 1 (Day 169)

Population: All randomized participants who received at least 1 dose of study drug.

Defined as the proportion of participants with PSA concentration < 0.02 ng/milliliter (mL).The rate was estimated by the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Undetectable PSA Rate	20.7 percentage of participants Interval 17.62 to 24.14	20.8 percentage of participants Interval 16.39 to 25.74

SECONDARY outcome

Timeframe: Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

PSA progression was defined as the first increase in PSA of 25% or greater and 2 ng/mL or greater above the nadir with confirmation by a second consecutive PSA measurement at least 3 weeks later. For participants without declining PSA from baseline, a PSA increase of ≥ 25% and ≥ 2 ng/mL from baseline beyond 12 weeks was considered PSA progression. The rate of progression-free survival was estimated using the Kaplan-Meier method and reported as percentage of participants.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Rate Of PSA Progression-free Survival	89.31 percentage of participants Interval 86.52 to 91.55	89.50 percentage of participants Interval 85.39 to 92.5

SECONDARY outcome

Timeframe: Baseline, Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The EORTC QLQ-C30 core measurement was used to capture distal outcomes, including physical, social functioning, and overall health-related quality of life. The questionnaire incorporates 30 questions comprising nine multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality of life scale. All raw domain scores are linearly transformed to a 0-100 scale. The global health and quality of life domain is presented. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems).

Outcome measures

Measure	Relugolix n=543 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=257 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Change From Baseline In Quality Of Life (QoL) Total Score As Assessed By The Global Health Domain Of The European Organisation Of Research And Treatment Of Cancer (EORTC)-Quality Of Life Questionnaire (QLQ)-C30	-3.8 score on a scale Standard Deviation 18.13	-3.6 score on a scale Standard Deviation 15.70

SECONDARY outcome

Timeframe: Baseline, Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The EORTC QLQ-C30 core measurement was used to capture distal outcomes, including physical, social functioning, and overall health-related quality of life. The questionnaire incorporates 30 questions comprising nine multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality of life scale. All raw domain scores are linearly transformed to a 0-100 scale. All domains except for the global health and quality are presented. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems).

Outcome measures

Measure	Relugolix n=543 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=257 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Nausea and vomiting	0.2 score on a scale Standard Deviation 7.12	0.8 score on a scale Standard Deviation 6.02
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Physical functioning	-4.6 score on a scale Standard Deviation 13.09	-4.4 score on a scale Standard Deviation 12.29
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Role functioning	-6.2 score on a scale Standard Deviation 19.92	-5.6 score on a scale Standard Deviation 17.84
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Emotional functioning	0.5 score on a scale Standard Deviation 16.12	-0.5 score on a scale Standard Deviation 13.23
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Cognitive functioning	-3.7 score on a scale Standard Deviation 16.77	-3.8 score on a scale Standard Deviation 16.37
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Social functioning	-2.7 score on a scale Standard Deviation 18.31	-4.0 score on a scale Standard Deviation 18.18
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Fatigue	6.1 score on a scale Standard Deviation 19.46	7.0 score on a scale Standard Deviation 18.40
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Pain	1.7 score on a scale Standard Deviation 20.19	4.0 score on a scale Standard Deviation 21.96
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Dyspnoea	5.3 score on a scale Standard Deviation 19.16	7.9 score on a scale Standard Deviation 20.25
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Insomnia	4.8 score on a scale Standard Deviation 25.88	4.8 score on a scale Standard Deviation 21.82
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Appetite loss	-0.6 score on a scale Standard Deviation 17.82	-0.6 score on a scale Standard Deviation 14.86
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Constipation	1.4 score on a scale Standard Deviation 23.26	3.5 score on a scale Standard Deviation 18.88
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Diarrhoea	2.0 score on a scale Standard Deviation 16.70	1.4 score on a scale Standard Deviation 19.60
Change From Baseline In QoL Total Score For Remaining Domain Scores As Assessed By The EORTC-QLQ-C30 Financial difficulties	0.2 score on a scale Standard Deviation 18.28	0.1 score on a scale Standard Deviation 19.21

SECONDARY outcome

Timeframe: Baseline, Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Subscales for assessment of hormonal treatment-related symptoms (6 items) and sexual activity and function (6 items) from the EORTC-QLQ-PR25 25-item prostate cancer module of the EORTC are presented. Questions used 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale. An increase in activity or functioning scores indicates improvement (higher/healthier level of functioning) and a decrease in symptom scores indicates improvement (lower level of symptoms/problems).

Outcome measures

Measure	Relugolix n=537 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=256 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains Sexual activity	13.9 score on a scale Standard Deviation 26.51	10.8 score on a scale Standard Deviation 27.90
Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains Sexual functioning	-9.0 score on a scale Standard Deviation 23.37	-10.4 score on a scale Standard Deviation 21.10
Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains Hormonal treatment-related symptoms	10.6 score on a scale Standard Deviation 12.25	11.4 score on a scale Standard Deviation 13.30

SECONDARY outcome

Timeframe: Baseline, Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

Subscale assessments of urinary symptoms (9 items) and bowel symptoms (4 items) from the EORTC-QLQ-PR25 25-item prostate cancer module of the EORTC are presented. Questions used 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale. A decrease in symptom scores indicates improvement (lower level of symptoms/problems).

Outcome measures

Measure	Relugolix n=537 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=256 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTC-QLQ-PR25 Urinary symptoms	1.1 score on a scale Standard Deviation 15.29	-0.4 score on a scale Standard Deviation 13.78
Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTC-QLQ-PR25 Incontinence aid use	1.0 score on a scale Standard Deviation 15.41	0.0 score on a scale Standard Deviation 19.80
Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTC-QLQ-PR25 Bowel symptoms	1.2 score on a scale Standard Deviation 8.92	2.0 score on a scale Standard Deviation 9.51

SECONDARY outcome

Timeframe: Baseline, Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug and had analyzable data at the specified timepoint.

The EuroQoL EQ-5D-5L comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 levels: no problems (1 as numerical score), slight problems (2 as numerical score), moderate problems (3 as numerical score), severe problems (4 as numerical score), and extreme problems (5 as numerical score). The total score ranges from 0 to 100. A decrease in score indicates improvement.

Outcome measures

Measure	Relugolix n=549 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=259 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Change From Baseline In QoL Total Score As Assessed By The European Quality Of Life 5-Dimension 5-Level Questionnaire (EuroQoL EQ-5D-5L)	-1.5 score on a scale Standard Deviation 14.36	-2.7 score on a scale Standard Deviation 14.57

SECONDARY outcome

Timeframe: Week 1 Day 4 (Day 4), Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Blood samples were collected from participants for hormonal measurements.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone Week 1 Day 4 (Day 4)	-88.25 Percent change Standard Deviation 20.696	147.71 Percent change Standard Deviation 122.735
Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone Week 5 Day 1 (Day 29)	-94.54 Percent change Standard Deviation 8.500	-82.67 Percent change Standard Deviation 27.146
Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone Week 25 Day 1 (Day 169)	-93.93 Percent change Standard Deviation 7.242	-93.45 Percent change Standard Deviation 13.202
Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone Week 49 Day 1 (Day 337)	-91.54 Percent change Standard Deviation 16.779	-95.14 Percent change Standard Deviation 4.507

SECONDARY outcome

Timeframe: Week 1 Day 4 (Day 4), Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Blood samples were collected from participants for hormonal measurements.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Percent Change From Baseline In Serum Concentrations Of FSH Week 1 Day 4 (Day 4)	-62.59 percent change Standard Deviation 9.051	-4.74 percent change Standard Deviation 36.121
Percent Change From Baseline In Serum Concentrations Of FSH Week 5 Day 1 (Day 29)	-90.80 percent change Standard Deviation 8.151	-67.73 percent change Standard Deviation 27.311
Percent Change From Baseline In Serum Concentrations Of FSH Week 25 Day 1 (Day 169)	-86.32 percent change Standard Deviation 10.699	-47.53 percent change Standard Deviation 32.560
Percent Change From Baseline In Serum Concentrations Of FSH Week 49 Day 1 (Day 337)	-79.39 percent change Standard Deviation 21.987	-47.23 percent change Standard Deviation 30.112

SECONDARY outcome

Timeframe: Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Blood samples were collected from participants for hormonal measurements.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone Week 5 Day 1 (Day 29)	-87.61 percent change Standard Deviation 12.225	-81.95 percent change Standard Deviation 23.733
Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone Week 25 Day 1 (Day 169)	-88.06 percent change Standard Deviation 11.810	-85.45 percent change Standard Deviation 32.261
Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone Week 49 Day 1 (Day 337)	-88.23 percent change Standard Deviation 11.235	-87.56 percent change Standard Deviation 12.088

SECONDARY outcome

Timeframe: Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

Blood samples were collected from participants for hormonal measurements.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin Week 5 Day 1 (Day 29)	1.08 percent change Standard Deviation 22.068	-1.21 percent change Standard Deviation 20.430
Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin Week 25 Day 1 (Day 169)	7.24 percent change Standard Deviation 28.265	3.59 percent change Standard Deviation 24.947
Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin Week 49 Day 1 (Day 337)	6.54 percent change Standard Deviation 28.787	2.59 percent change Standard Deviation 27.051

SECONDARY outcome

Timeframe: Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2

Population: A subset of Japanese participants enrolled in study were included in the PK analysis.

The Cmax of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose pharmacokinetics (PK) was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks.

Outcome measures

Measure	Relugolix n=7 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=7 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Maximum Observed Plasma Concentration (Cmax) Of Relugolix	125 ng/mL Geometric Coefficient of Variation 220	46.4 ng/mL Geometric Coefficient of Variation 141

SECONDARY outcome

Timeframe: Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2

Population: A subset of Japanese participants enrolled in study were included in the PK analysis.

The AUC0-τ of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose PK was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks.

Outcome measures

Measure	Relugolix n=7 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=7 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Area Under The Concentration-Time Curve (AUC0-τ) Of Relugolix	663 ng⸳hr/mL Geometric Coefficient of Variation 151	373 ng⸳hr/mL Geometric Coefficient of Variation 51

SECONDARY outcome

Timeframe: Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2

Population: A subset of Japanese participants enrolled in study were included in the PK analysis.

The Tmax of relugolix was determined for single and repeat doses in subsets of participants from Japan. Single dose PK was assessed on Day 1 following an initial 360 mg dose of relugolix. Repeat dose PK was assessed following repeat dosing of relugolix 120 mg once daily for 2 weeks.

Outcome measures

Measure	Relugolix n=7 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=7 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Time To Maximum Observed Plasma Concentration (Tmax) Of Relugolix	1.03 hours Interval 0.4 to 4.05	0.983 hours Interval 0.433 to 4.08

OTHER_PRE_SPECIFIED outcome

Timeframe: From Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337)

Population: All randomized participants who received at least 1 dose of study drug.

MACE were defined as nonfatal myocardial infarction, nonfatal stroke, and death from any cause.

Outcome measures

Measure	Relugolix n=622 Participants Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 Participants Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
Percentage of Participants Who Experienced Major Adverse Cardiovascular Events (MACE)	2.9 percentage of participants	6.2 percentage of participants

Adverse Events

Relugolix

Serious events: 76 serious events

Other events: 493 other events

Deaths: 7 deaths

Leuprolide Acetate

Serious events: 47 serious events

Other events: 239 other events

Deaths: 9 deaths

Serious adverse events

Measure	Relugolix n=622 participants at risk Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 participants at risk Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, and Taiwan), every 3 months by subcutaneous injection.
Blood and lymphatic system disorders Anaemia	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.97% 3/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Acute myocardial infarction	0.80% 5/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Atrial fibrillation	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Acute coronary syndrome	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Acute left ventricular failure	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Aortic valve stenosis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Atrioventricular block complete	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Atrioventricular block second degree	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Cardiac failure	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Cardiac failure congestive	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Angina unstable	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Cardiac failure acute	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.97% 3/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Cardiopulmonary failure	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Sinus arrest	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Cardiac disorders Sinus node dysfunction	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Ear and labyrinth disorders Vertigo	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Endocrine disorders Hypercalcaemia of malignancy	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Abdominal pain	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Abdominal incarcerated hernia	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Small intestinal obstruction	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Vomiting	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Dysphagia	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Inguinal hernia	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Chest discomfort	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Chest pain	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Gait disturbance	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Multiple organ dysfunction syndrome	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Hepatobiliary disorders Cholecystitis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Urinary tract infection	0.48% 3/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Appendicitis perforated	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Bronchitis	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Cellulitis	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Pneumonia	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Endocarditis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Gastroenteritis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Pyelonephritis acute	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Septic shock	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Tooth abscess	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Upper respiratory tract infection	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Osteomyelitis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Urosepsis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Fall	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Pulmonary contusion	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Alcohol poisoning	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Brachial plexus injury	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Cystitis radiation	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Femoral neck fracture	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Hip fracture	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Rib fracture	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Road traffic accident	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Shunt aneurysm	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Spinal compression fracture	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Traumatic fracture	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Injury, poisoning and procedural complications Subcutaneous haematoma	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Investigations Blood sodium decreased	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Investigations Troponin increased	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Investigations Liver function test abnormal	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Metabolism and nutrition disorders Dehydration	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Metabolism and nutrition disorders Diabetes mellitus inadequate control	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Metabolism and nutrition disorders Hyponatraemia	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Pathological fracture	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Arthropathy	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Intervertebral disc compression	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Pain in extremity	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma stage II	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma stage I	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer metastatic	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Schwannoma	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer metastatic	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell cancer of the renal pelvis and ureter	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to spine	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Ischaemic stroke	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Encephalopathy	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Haemorrhagic stroke	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Hemiparesis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Lacunar infarction	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Spinal cord compression	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Cerebral haemorrhage	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Cerebrovascular accident	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Dizziness	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Haemorrhage intracranial	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Presyncope	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Syncope	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.65% 2/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Transient ischaemic attack	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.97% 3/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Psychiatric disorders Mental disorder	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Psychiatric disorders Suicidal ideation	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Acute kidney injury	0.64% 4/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Bladder obstruction	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Bladder neck obstruction	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Bladder outlet obstruction	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Calculus bladder	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Chronic kidney disease	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Lower urinary tract symptoms	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Renal failure	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Tubulointerstitial nephritis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Urethral stenosis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Urinary bladder polyp	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Urinary retention	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Haematuria	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Hydronephrosis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Micturition urgency	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Urinary tract obstruction	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.32% 2/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.00% 0/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Social circumstances Homicide	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Vascular disorders Aortic stenosis	0.16% 1/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Vascular disorders Aortic aneurysm	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Vascular disorders Deep vein thrombosis	0.00% 0/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	0.32% 1/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.

Other adverse events

Measure	Relugolix n=622 participants at risk Relugolix 120-mg tablet administered orally once daily for 48 weeks following an oral loading dose of 360 mg (3 x 120-mg tablets) on Day 1.	Leuprolide Acetate n=308 participants at risk Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, and Taiwan), every 3 months by subcutaneous injection.
Gastrointestinal disorders Constipation	12.2% 76/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	9.7% 30/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Diarrhoea	12.2% 76/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.8% 21/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Gastrointestinal disorders Nausea	5.8% 36/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	4.2% 13/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Asthenia	5.1% 32/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.8% 21/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
General disorders Fatigue	21.5% 134/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	18.5% 57/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Infections and infestations Nasopharyngitis	9.5% 59/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	9.4% 29/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Investigations Weight increased	7.9% 49/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.5% 20/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Arthralgia	12.1% 75/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	9.1% 28/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Back pain	8.0% 50/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	9.1% 28/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Musculoskeletal and connective tissue disorders Pain in extremity	5.1% 32/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.2% 19/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Dizziness	5.6% 35/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	5.5% 17/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Nervous system disorders Headache	5.6% 35/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	4.2% 13/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Psychiatric disorders Insomnia	6.9% 43/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	4.5% 14/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Nocturia	5.8% 36/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.2% 19/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Pollakiuria	5.9% 37/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	6.5% 20/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Renal and urinary disorders Urinary incontinence	4.8% 30/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	5.2% 16/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Skin and subcutaneous tissue disorders Hyperhidrosis	2.4% 15/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	5.2% 16/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Vascular disorders Hot flush	54.3% 338/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	51.6% 159/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
Vascular disorders Hypertension	7.9% 49/622 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.	11.7% 36/308 • Day 1 (after dosing) through up to 52 weeks All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.

Additional Information

Clinical Trials at Myovant

Myovant Sciences GmbH

Phone: 650-278-8743

Email: ClinicalTrials@Myovant.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place