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    Clinical Trial Results:
    HERO: A Multinational Phase 3 Randomized, Open-label, Parallel Group Study to Evaluate the Safety and Efficacy of Relugolix in Men with Advanced Prostate Cancer

    Summary
    EudraCT number
    		 2017-000160-15
    Trial protocol
    		 NL   SE   GB   BE   AT   SK   DK   FI   ES   DE   PL   FR   IT  
    Global end of trial date
    26 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2023
    First version publication date
    18 Feb 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MVT-601-3201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03085095
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Myovant Sciences GmbH
    Sponsor organisation address
    Aeschengraben 27, Basel, Switzerland, 4051
    Public contact
    Clinical Trials at Myovant, Myovant Sciences GmbH, 001 6502788749, clinicaltrials@myovant.com
    Scientific contact
    Clinical Trials at Myovant, Myovant Sciences GmbH, 001 6502788743, clinicaltrials@myovant.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the ability of relugolix to achieve and maintain serum testosterone suppression to castrate levels (< 50 ng/dL [1.7 nmol/L]) in men with androgen-sensitive advanced prostate cancer.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 73
    Country: Number of subjects enrolled
    Slovakia: 112
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Denmark: 21
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    China: 12
    Country: Number of subjects enrolled
    Japan: 121
    Country: Number of subjects enrolled
    Korea, Republic of: 84
    Country: Number of subjects enrolled
    New Zealand: 21
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    Brazil: 69
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    United States: 261
    Worldwide total number of subjects
    1078
    EEA total number of subjects
    396
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    203
    From 65 to 84 years
    829
    85 years and over
    46

    Subject disposition

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    Recruitment
    Recruitment details
    		 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.

    Pre-assignment
    Screening details
    		 The primary analysis of efficacy and safety included 934 participants.

    Period 1
    Period 1 title
    Randomized Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Primary Analysis Population - Relugolix
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Relugolix
    Investigational medicinal product code
    Other name
    TAK-385, MVT-601, RVT-601, T-1331285
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loading dose of 360 mg on Day 1 followed by 120 mg once daily

    Arm title
    		 Primary Analysis Population - Leuprolide Acetate
    Arm description
    		 Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Leuprolide acetate
    Investigational medicinal product code
    Other name
    Leuprolide
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Injection
    Dosage and administration details
    22.5 mg (or 11.25 mg in Japan, Taiwan, and China), every 3 months by subcutaneous injection

    Number of subjects in period 1 [1]
    		Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Started
    624
    310
    Completed
    563
    276
    Not completed
    61
    34
         Consent withdrawn by subject
    17
    6
         Physician decision
    9
    3
         Dosing interruption (logistical reason)
    1
    -
         Adverse event
    23
    8
         Did not receive study drug
    2
    2
         Lost to follow-up
    2
    1
         Testosterone suppression level not met
    7
    13
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of four patients were randomized and not treated (two each in the relugolix and leuprolide groups).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Primary Analysis Population - Relugolix
    Reporting group description
    		 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.

    Reporting group title
    Primary Analysis Population - Leuprolide Acetate
    Reporting group description
    		 Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.

    Reporting group values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Total
    Number of subjects
    		 624 310 934
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults (18 years and over)
    		 622 308 930
        Not recorded
    		 2 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.2 ± 7.75 71.0 ± 8.03 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 622 308 930
        Not recorded
    		 2 2 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 52 31 83
        Not Hispanic or Latino
    		 558 269 827
        Unknown or Not Reported
    		 12 8 20
        Not recorded
    		 2 2 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 127 71 198
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 30 16 46
        White
    		 434 202 636
        More than one race
    		 11 4 15
        Unknown or Not Reported
    		 20 15 35
        Not recorded
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Primary Analysis Population - Relugolix
    Reporting group description
    		 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.

    Reporting group title
    Primary Analysis Population - Leuprolide Acetate
    Reporting group description
    		 Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan and Taiwan), every 3 months by subcutaneous injection.

    Subject analysis set title
    Final Analysis Population - Relugolix
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients with or without metastatic disease

    Subject analysis set title
    Final Analysis Population - Leuprolide Acetate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients with or without metastatic disease

    Subject analysis set title
    mITT Metastatic Population - Relugolix
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients with metastatic prostate cancer

    Subject analysis set title
    mITT Metastatic Population - Leuprolide Acetate
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients with metastatic prostate cancer

    Subject analysis set title
    Greater China Patient Population - Relugolix
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To support registration in China, data were analyzed separately for patients enrolled in China and Taiwan.

    Subject analysis set title
    Greater China Patient Population - Leuprolide Acetate
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To support registration in China, data were analyzed separately for patients enrolled in China and Taiwan.

    Primary: Sustained Castration Rate

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    End point title
    		 Sustained Castration Rate
    End point description
    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.
    End point type
    Primary
    End point timeframe
    From Week 5 Day 1 (Day 29) to Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    96.7 (94.9 to 97.9)
    88.8 (84.6 to 91.8)
    98.0 (86.9 to 99.7)
    93.0 (74.7 to 98.2)
    Statistical analysis title
    		 Analysis 1 for Sustained Castration Rate
    Statistical analysis description
    Following statistical analysis of the lower bound of the 95% CI ≥ 90% for the relugolix group, secondary statistical analysis of non-inferiority was conducted.
    Comparison groups
    Primary Analysis Population - Leuprolide Acetate v Primary Analysis Population - Relugolix
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    7.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 11.8
    Notes
    [1] - The lower bound of the 95% CI for the difference in the cumulative probability of sustained profound castration rate between the 2 treatment groups was calculated with a noninferiority margin of -10%.
    Statistical analysis title
    		 Analysis 2 for Sustained Castration Rate
    Statistical analysis description
    Following statistical analysis of the lower bound of the 95% CI ≥ 90% for the relugolix group, secondary statistical analysis of superiority was conducted.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - If non-inferiority was demonstrated, superiority could be claimed if the lower bound of the 95% CI for the difference in the cumulative probability of sustained profound castration rate between the 2 treatment groups also excluded 0%. The p value was calculated post hoc.
    [3] - Two-sided type I error of 0.05.

    Secondary: Castration Rate At Week 1 Day 4

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    End point title
    		 Castration Rate At Week 1 Day 4
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 1 Day 4 (Day 4)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    56.04 (52.18 to 59.97)
    0.00 (0 to 0)
    56.45 (44.63 to 68.93)
    0.00 (0.00 to 0.00)
    Statistical analysis title
    		 Analysis 1 for Castration Rate At Week 1 Day 4
    Statistical analysis description
    Alpha-protected statistical analysis.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - Statistically significance was met if p-value < 0.05. Two-sided type I error rate of 0.05.

    Secondary: Castration Rate At Week 3 Day 1

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    End point title
    		 Castration Rate At Week 3 Day 1
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 3 Day 1 (Day 15)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    98.71 (97.56 to 99.39)
    12.05 (8.88 to 16.25)
    96.77 (90.06 to 99.39)
    17.24 (7.57 to 36.57)
    Statistical analysis title
    		 Analysis 1 for Castration Rate At Week 3 Day 1
    Statistical analysis description
    Alpha-protected statistical analysis.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - Statistically significance was met if p-value < 0.05. Two-sided type I error rate of 0.05.

    Secondary: Confirmed Prostate-specific Antigen (PSA) Response Rate

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    End point title
    		 Confirmed Prostate-specific Antigen (PSA) Response Rate
    End point description
    Confirmed PSA response defined as > 50% reduction in PSA from baseline at Week 3 Day 1 followed with confirmation at Week 5 Day 1.
    End point type
    Secondary
    End point timeframe
    Week 3 Day 1 (Day 15) and Week 5 Day 1 (Day 29)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    79.4 (76.03 to 82.53)
    19.8 (15.50 to 24.70)
    88.9 (78.44 to 95.41)
    55.2 (35.69 to 73.55)
    Statistical analysis title
    		 Analysis 1 for Confirmed PSA Response Rate
    Statistical analysis description
    Alpha-protected statistical analysis.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - Statistically significance was met if p-value < 0.05.

    Secondary: Profound Castration Rate At Week 3 Day 1 (Day 15)

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    End point title
    		 Profound Castration Rate At Week 3 Day 1 (Day 15)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 3 Day 1 (Day 15)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    78.38 (75.06 to 81.53)
    0.98 (0.32 to 3.00)
    72.58 (61.18 to 82.96)
    0.00 (0.00 to 0.00)
    Statistical analysis title
    		 Analysis 1 for Profound Castration Rate
    Statistical analysis description
    Alpha-protected statistical analysis.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Treatment Difference
    Point estimate
    77.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 73.98
         upper limit
    		 80.83
    Notes
    [7] - Statistically significance was met if p-value < 0.05. Two-sided type I error rate of 0.05.

    Secondary: Follicle-stimulating Hormone (FSH) Level

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    End point title
    		 Follicle-stimulating Hormone (FSH) Level
    End point description
    To evaluate the effect of relugolix and leuprolide acetate on FSH suppression.
    End point type
    Secondary
    End point timeframe
    Week 25 Day 1 (Day 169)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    63
    29
    Units: IU/L
        least squares mean (standard deviation)
    1.72 ± 1.376
    5.95 ± 3.071
    1.72 ± 1.455
    6.95 ± 2.768
    Statistical analysis title
    		 Analysis 1 for FSH Level
    Statistical analysis description
    Alpha-protected statistical analysis.
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [8] - Statistically significance was met if p-value < 0.05. Two-sided type I error rate of 0.05.

    Secondary: PSA Response Rate At Week 3 Day 1

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    End point title
    		 PSA Response Rate At Week 3 Day 1
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 5 Day 1 (Day 29)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    94.5 (92.44 to 96.19)
    79.2 (74.26 to 83.61)
    No statistical analyses for this end point

    Secondary: Testosterone Recovery Rate

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    End point title
    		 Testosterone Recovery Rate
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Day 90 follow-up
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
    number (confidence interval 95%)
        ≥ 50 ng/dL
    93.01 (87.82 to 96.54)
    10.12 (3.84 to 25.24)
        >280 ng/dL
    53.93 (45.20 to 63.16)
    3.23 (0.46 to 20.77)
        > Baseline level or 280 ng/dL
    54.73 (45.97 to 63.94)
    3.23 (0.46 to 20.77)
    No statistical analyses for this end point

    Secondary: Sustained Profound Castration Rate From Week 5 Day 1 Through Week 49 Day 1

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    End point title
    		 Sustained Profound Castration Rate From Week 5 Day 1 Through Week 49 Day 1
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 5 Day 1 (Day 29) through Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    81.6 (78.1 to 84.5)
    68.6 (63.0 to 73.5)
    Statistical analysis title
    		 Analysis 1 for Sustained Profound Castration Rate
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.9
         upper limit
    		 19.1

    Secondary: Profound Castration Rate At Week 1 Day 4 (Day 4)

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    End point title
    		 Profound Castration Rate At Week 1 Day 4 (Day 4)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    At Week 1 Day 4 (Day 4)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    6.92 (5.18 to 9.22)
    0.0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Sustained Profound Castration Rate From Week 25 Day 1 Through Week 49 Day 1

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    End point title
    		 Sustained Profound Castration Rate From Week 25 Day 1 Through Week 49 Day 1
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 25 Day 1 (Day 169) through Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    84.6 (81.3 to 87.3)
    87.5 (83.0 to 90.8)
    Statistical analysis title
    		 Analysis 1 for Sustained Profound Castration Rate
    Comparison groups
    Primary Analysis Population - Relugolix v Primary Analysis Population - Leuprolide Acetate
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 2

    Secondary: Undetectable PSA Rate

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    End point title
    		 Undetectable PSA Rate
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 25 Day 1 (Day 169)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    20.7 (17.62 to 24.14)
    20.8 (16.39 to 25.74)
    No statistical analyses for this end point

    Secondary: Rate of PSA Progression-free Survival

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    End point title
    		 Rate of PSA Progression-free Survival
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (confidence interval 95%)
    89.31 (86.52 to 91.55)
    89.50 (85.39 to 92.50)
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    		 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
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    543
    257
    Units: Score on a Scale
    least squares mean (standard deviation)
        Physical functioning
    -4.6 ± 13.09
    -4.4 ± 12.29
        Role functioning
    -6.2 ± 19.92
    -5.6 ± 17.84
        Emotional functioning
    0.5 ± 16.12
    -0.5 ± 13.23
        Cognitive functioning
    -3.7 ± 16.77
    -3.8 ± 16.37
        Social functioning
    -2.7 ± 18.31
    -4.0 ± 18.18
        Fatigue
    6.1 ± 19.46
    7.0 ± 18.40
        Nausea and vomiting
    0.2 ± 7.12
    0.8 ± 6.02
        Pain
    1.7 ± 20.19
    4.0 ± 21.96
        Dyspnoea
    5.3 ± 19.16
    7.9 ± 20.25
        Insomnia
    4.8 ± 25.88
    4.8 ± 21.82
        Appetite loss
    -0.6 ± 17.82
    -0.6 ± 14.86
        Constipation
    1.4 ± 23.26
    3.5 ± 18.88
        Diarrhoea
    2.0 ± 16.70
    1.4 ± 19.60
        Financial difficulties
    0.2 ± 18.28
    0.1 ± 19.21
    No statistical analyses for this end point

    Secondary: Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains

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    End point title
    		 Change From Baseline In QoL Total Score As Assessed By The EORTC-QLQ-PR25 Sexual Activity And Functioning And Hormonal-Treatment-Related Symptom Subdomains
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    537
    256
    Units: Score on a Scale
    least squares mean (standard deviation)
        Sexual activity
    13.9 ± 26.51
    10.8 ± 27.90
        Sexual functioning
    -9.0 ± 23.37
    -10.4 ± 21.10
        Hormonal treatment-related symptoms
    10.6 ± 12.25
    11.4 ± 13.30
    No statistical analyses for this end point

    Secondary: Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTCQLQ- PR25

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    End point title
    		 Change From Baseline In QoL Total Score For Urinary And Bowel Symptoms Domains As Assessed By The EORTCQLQ- PR25
    End point description
    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).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    537
    256
    Units: Score on a Scale
    least squares mean (standard deviation)
        Urinary symptoms
    1.1 ± 15.29
    -0.4 ± 13.78
        Incontinence aid use
    1.0 ± 15.41
    0.0 ± 19.80
        Bowel symptoms
    1.2 ± 8.92
    2.0 ± 9.51
    No statistical analyses for this end point

    Secondary: Change From Baseline In QoL Total Score As Assessed By The European Quality Of Life 5-Dimension 5-Level Questionnaire (EuroQoL EQ-5D-5L)

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    End point title
    		 Change From Baseline In QoL Total Score As Assessed By The European Quality Of Life 5-Dimension 5-Level Questionnaire (EuroQoL EQ-5D-5L)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    549
    259
    Units: Score on a Scale
        least squares mean (standard deviation)
    -1.5 ± 14.36
    -2.7 ± 14.57
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone

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    End point title
    		 Percent Change From Baseline In Serum Concentrations Of Luteinizing Hormone
    End point description
    Blood samples were collected from participants for hormonal measurements.
    End point type
    Secondary
    End point 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)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percent Change
    least squares mean (standard deviation)
        Week 1 Day 4 (Day 4)
    -88.25 ± 20.696
    147.71 ± 122.735
        Week 5 Day 1 (Day 29)
    -94.54 ± 8.500
    -82.67 ± 27.146
        Week 25 Day 1 (Day 169)
    -93.93 ± 7.242
    -93.45 ± 13.202
        Week 49 Day 1 (Day 337)
    -91.54 ± 16.779
    -95.14 ± 4.507
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline In Serum Concentrations Of FSH

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    End point title
    		 Percent Change From Baseline In Serum Concentrations Of FSH
    End point description
    Blood samples were collected from participants for hormonal measurements.
    End point type
    Secondary
    End point 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)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percent Change
    least squares mean (standard deviation)
        Week 1 Day 4 (Day 4)
    -62.59 ± 9.051
    -4.74 ± 36.121
        Week 5 Day 1 (Day 29)
    -90.80 ± 8.151
    -67.73 ± 27.311
        Week 25 Day 1 (Day 169)
    -86.32 ± 10.699
    -47.53 ± 32.560
        Week 49 Day 1 (Day 337)
    -79.39 ± 21.987
    -47.23 ± 30.112
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone

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    End point title
    		 Percent Change From Baseline In Serum Concentrations Of Dihydrotestosterone
    End point description
    Blood samples were collected from participants for hormonal measurements.
    End point type
    Secondary
    End point timeframe
    Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percent Change
    least squares mean (standard deviation)
        Week 5 Day 1 (Day 29)
    -87.61 ± 12.225
    -81.95 ± 23.733
        Week 25 Day 1 (Day 169)
    -88.06 ± 11.810
    -85.45 ± 32.261
        Week 49 Day 1 (Day 337
    -88.23 ± 11.235
    -87.56 ± 12.088
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin

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    End point title
    		 Percent Change From Baseline In Serum Concentrations Of Sex Hormone-Binding Globulin
    End point description
    Blood samples were collected from participants for hormonal measurements.
    End point type
    Secondary
    End point timeframe
    Week 5 Day 1 (Day 29), Week 25 Day 1 (Day 169), and Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percent Change
    least squares mean (standard deviation)
        Week 5 Day 1 (Day 29)
    1.08 ± 22.068
    -1.21 ± 20.430
        Week 25 Day 1 (Day 169)
    7.24 ± 28.265
    3.59 ± 24.947
        Week 49 Day 1 (Day 337)
    6.54 ± 28.787
    2.59 ± 27.051
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) Of Relugolix

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) Of Relugolix
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    7
    7
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    125 ± 220
    46.4 ± 141
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve (AUC0-τ) Of Relugolix

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    End point title
    		 Area Under The Concentration-Time Curve (AUC0-τ) Of Relugolix
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    7
    7
    Units: ng#hr/mL
        geometric mean (geometric coefficient of variation)
    663 ± 151
    373 ± 51
    No statistical analyses for this end point

    Secondary: Time To Maximum Observed Plasma Concentration (Tmax) Of Relugolix

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    End point title
    		 Time To Maximum Observed Plasma Concentration (Tmax) Of Relugolix
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Predose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose on Day 1 and Week 2
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    7
    7
    Units: Hours
        median (full range (min-max))
    1.03 (0.400 to 4.05)
    0.983 (0.433 to 4.08)
    No statistical analyses for this end point

    Secondary: Castration Resistance-Free Survival

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    End point title
    		 Castration Resistance-Free Survival
    End point description
    Castration resistance-free survival during the 48-week treatment in patients with or without metastatic prostate cancer
    End point type
    Secondary
    End point timeframe
    Day 337
    End point values
    		 Final Analysis Population - Relugolix Final Analysis Population - Leuprolide Acetate mITT Metastatic Population - Relugolix mITT Metastatic Population - Leuprolide Acetate Greater China Patient Population - Relugolix Greater China Patient Population - Leuprolide Acetate
    Number of subjects analysed
    717
    357
    290
    144
    63
    29
    Units: Percentage of Participants
        number (confidence interval 95%)
    86.82 (84.00 to 89.18)
    87.33 (83.21 to 90.50)
    74.31 (68.56 to 79.17)
    75.27 (66.71 to 81.93)
    68.71 (55.01 to 79.01)
    70.28 (49.09 to 83.96)
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants Who Experienced Major Adverse Cardiovascular Events (MACE)

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    End point title
    		 Percentage of Participants Who Experienced Major Adverse Cardiovascular Events (MACE)
    End point description
    MACE were defined as nonfatal myocardial infarction, nonfatal stroke, and death from any cause.
    End point type
    Other pre-specified
    End point timeframe
    Week 49 Day 1 (Day 337)
    End point values
    		 Primary Analysis Population - Relugolix Primary Analysis Population - Leuprolide Acetate
    Number of subjects analysed
    622
    308
    Units: Percentage of Participants
        number (not applicable)
    2.9
    6.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) through up to 52 weeks
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose of study drug in the primary analysis part of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Vocabulary
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Relugolix
    Reporting group description
    		 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.

    Reporting group title
    Leuprolide Acetate
    Reporting group description
    		 Leuprolide acetate depot suspension, 22.5 mg (or 11.25 mg in Japan, and Taiwan), every 3 months by subcutaneous injection.

    Serious adverse events
    		 Relugolix Leuprolide Acetate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    76 / 622 (12.22%)
    47 / 308 (15.26%)
         number of deaths (all causes)
    12
    10
         number of deaths resulting from adverse events
    7
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage II
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma stage I
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    2 / 622 (0.32%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Schwannoma
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Social circumstances
    Homicide
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood sodium decreased
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexus injury
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt aneurysm
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    5 / 622 (0.80%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 622 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus arrest
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 622 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 622 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 622 (0.64%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bladder neck obstruction
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower urinary tract symptoms
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Micturition urgency
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 622 (0.48%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Relugolix Leuprolide Acetate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    578 / 622 (92.93%)
    288 / 308 (93.51%)
    Investigations
    Weight increased
         subjects affected / exposed
    49 / 622 (7.88%)
    20 / 308 (6.49%)
         occurrences all number
    49
    20
    Vascular disorders
    Hot flush
         subjects affected / exposed
    338 / 622 (54.34%)
    159 / 308 (51.62%)
         occurrences all number
    338
    159
    Hypertension
         subjects affected / exposed
    49 / 622 (7.88%)
    36 / 308 (11.69%)
         occurrences all number
    49
    36
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    35 / 622 (5.63%)
    17 / 308 (5.52%)
         occurrences all number
    35
    17
    Headache
         subjects affected / exposed
    35 / 622 (5.63%)
    13 / 308 (4.22%)
         occurrences all number
    35
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    32 / 622 (5.14%)
    21 / 308 (6.82%)
         occurrences all number
    32
    21
    Fatigue
         subjects affected / exposed
    134 / 622 (21.54%)
    57 / 308 (18.51%)
         occurrences all number
    134
    57
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    76 / 622 (12.22%)
    30 / 308 (9.74%)
         occurrences all number
    76
    30
    Diarrhoea
         subjects affected / exposed
    76 / 622 (12.22%)
    21 / 308 (6.82%)
         occurrences all number
    76
    21
    Nausea
         subjects affected / exposed
    36 / 622 (5.79%)
    13 / 308 (4.22%)
         occurrences all number
    36
    13
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    15 / 622 (2.41%)
    16 / 308 (5.19%)
         occurrences all number
    15
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    43 / 622 (6.91%)
    14 / 308 (4.55%)
         occurrences all number
    43
    14
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    36 / 622 (5.79%)
    19 / 308 (6.17%)
         occurrences all number
    36
    19
    Pollakiuria
         subjects affected / exposed
    37 / 622 (5.95%)
    20 / 308 (6.49%)
         occurrences all number
    37
    20
    Urinary incontinence
         subjects affected / exposed
    30 / 622 (4.82%)
    16 / 308 (5.19%)
         occurrences all number
    30
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    75 / 622 (12.06%)
    28 / 308 (9.09%)
         occurrences all number
    75
    28
    Back pain
         subjects affected / exposed
    50 / 622 (8.04%)
    28 / 308 (9.09%)
         occurrences all number
    50
    28
    Pain in extremity
         subjects affected / exposed
    32 / 622 (5.14%)
    19 / 308 (6.17%)
         occurrences all number
    32
    19
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    59 / 622 (9.49%)
    29 / 308 (9.42%)
         occurrences all number
    59
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jan 2018
    The primary purpose of Amendment 1 was to provide clarification regarding entry criteria, prohibited medications, schedule of activities, and update on safety reporting. However, because of a typographical error in an exclusion criterion, the meaning of that criterion was inadvertently changed. This amendment was initially submitted to a regulatory authority, then withdrawn.
    18 Jan 2018
    The typographical error in the exclusion criterion was corrected and all other clarifications previously stated above were included in a new version, Amendment 2. To alleviate the burden of study visits on participants, this amendment also eliminated the Day 22 visit, resulting in fewer patients having data at this visit compared with the rest of the study visits. All patients enrolled under the original protocol and Amendment 2 were part of the primary analysis to assess the safety and efficacy of relugolix in achieving castration within 4 weeks and maintaining it over an additional 44 weeks.
    23 Oct 2018
    The primary purpose of Amendment 3 was to include an additional alpha-protected key secondary endpoint of castration resistance-free survival, an important indicator of disease progression, in the final analysis. To support this analysis, the protocol allowed for an additional cohort of approximately 100 patients with metastatic disease to be enrolled to ensure an appropriate level of statistical power for the analysis (targeting ~390 metastatic patients in total including those enrolled with the initial cohort of 925 patients). The choice to enrich the study with metastatic patients was due to the higher incidence of castration resistance in patients with metastatic disease. In addition, to support registration in China, a target number of 138 metastatic and nonmetastatic patients from China (enrolled in China and Taiwan) was specified, including those enrolled in Taiwan as part of the initial cohort of 915 patients.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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