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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase II, Efficacy and Safety Study of MDV3100 (ASP9785) vs. Bicalutamide in Castrate Men with Metastatic Prostate Cancer

    Summary
    EudraCT number
    2010-021868-15
    Trial protocol
    GB   BE   DE   DK  
    Global end of trial date
    08 Nov 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    30 Aug 2019
    First version publication date
    17 Nov 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    9785-CL-0222
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01288911
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), 800 888-7704, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc. (APGD), 800 888-7704, astellas.resultsdisclosure@astellas.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
    16 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the progression-free survival (PFS) of enzalutamide as compared to bicalutamide. All participants that entered the open-label period of the study received enzalutamide, including those that received biculatamide in the double-blind period.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Mar 2011
    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
    Belgium: 26
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    United Kingdom: 86
    Country: Number of subjects enrolled
    United States: 115
    Worldwide total number of subjects
    375
    EEA total number of subjects
    221
    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)
    92
    From 65 to 84 years
    260
    85 years and over
    23

    Subject disposition

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    Recruitment
    Recruitment details
    Men with metastatic castration-resistant prostate cancer (mCRPC) were enrolled at 84 sites in a total of 8 countries.

    Pre-assignment
    Screening details
    Participants were stratified by whether bilateral orchiectomy or receipt of luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy started before or after the diagnosis of metastases and by site.

    Period 1
    Period 1 title
    Double-blind Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Enzalutamide
    Arm description
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Arm title
    Bicalutamide
    Arm description
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.
    Arm type
    Active comparator

    Investigational medicinal product name
    Bicalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Number of subjects in period 1
    Enzalutamide Bicalutamide
    Started
    184
    191
    Received Treatment
    183
    189
    Completed
    42
    9
    Not completed
    142
    182
         Death
    11
    7
         Withdrawal by Subject
    25
    26
         Protocol Violation
    1
    -
         Progressive Disease
    75
    103
         Randomized but never received study drug
    1
    2
         Lost to Follow-up
    -
    2
         Miscellaneous Reason
    29
    42
    Period 2
    Period 2 title
    Open-label Period (all enzalutamide)
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OL Phase: Enzalutamide/Enzalutamide
    Arm description
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Arm title
    OL Phase: Bicalutamide/Enzalutamide
    Arm description
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Number of subjects in period 2
    OL Phase: Enzalutamide/Enzalutamide OL Phase: Bicalutamide/Enzalutamide
    Started
    42
    9
    Received Treatment
    42
    9
    Completed
    0
    0
    Not completed
    42
    9
         Death
    -
    1
         Withdrawal by Subject
    1
    -
         Transitioned to 9785-CL-0123 (NCT02960022)
    17
    5
         Progressive Disease
    18
    3
         Miscellaneous Reason
    5
    -
         Lost to Follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group title
    Bicalutamide
    Reporting group description
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group values
    Enzalutamide Bicalutamide Total
    Number of subjects
    184 191 375
    Age categorical
    Units: Subjects
        < 65 years
    45 47 92
        65-75 years
    85 80 165
        > 75 years
    54 64 118
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    70.3 ± 9.22 71.1 ± 8.89 -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    184 191 375
    Race
    Units: Subjects
        White
    172 176 348
        Black or African American
    8 10 18
        Asian
    3 2 5
        Native Hawaiian or Other Pacific Islander
    1 1 2
        Other
    0 2 2
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    184 187 371
        Hispanic or Latino
    0 4 4
    LHRH agonist/antagonist initiation or bilateral orchiectomy relative to diagnosis of metastasis
    Units: Subjects
        Before diagnosis of metastasis
    87 76 163
        After diagnosis of metastasis
    97 115 212

    End points

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    End points reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group title
    Bicalutamide
    Reporting group description
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.
    Reporting group title
    OL Phase: Enzalutamide/Enzalutamide
    Reporting group description
    Participants received enzalutamide 160 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group title
    OL Phase: Bicalutamide/Enzalutamide
    Reporting group description
    Participants received bicalutamide 50 mg orally once daily until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS consisted of all randomized participants.

    Subject analysis set title
    Total Enzalutamide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants received enzalutamide in the double-blind and/or open-label period (including participants who switched from bicalutamide to enzalutamide).

    Primary: Progression Free Survival (PFS) Based on Independent Central Review (ICR) Assessment

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    End point title
    Progression Free Survival (PFS) Based on Independent Central Review (ICR) Assessment
    End point description
    PFS is the time from randomization to the date of the first progression event detected. A progression event was defined as objective evidence of radiographic disease progression based on the assessments by the ICR, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Radiographic disease progression was defined as either a progression in soft tissue on computed tomography (CT)/magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and/or a progression in bone lesions on bone scan (≥ 2 new bone lesions) confirmed by the next bone scan. A skeletal-related event was any radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain. The initiation of new antineoplastic therapy included any new therapy for the treatment of disease progression after the study drug administration started. FAS.
    End point type
    Primary
    End point timeframe
    From randomization until the data cut-off date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    15.7 (11.5 to 19.4)
    5.8 (4.8 to 8.1)
    Statistical analysis title
    PFS on ICR Enzalutamide Vs. Bicalutamide
    Statistical analysis description
    The (unstratified) log-rank test with an overall significance level of 0.05 (two-sided) was used to compare the PFS of enzalutamide to bicalutamide. The (unstratified) Cox proportional hazards model was used to estimate the hazard ratio of enzalutamide to bicalutamide, calculate the corresponding two-sided 95% confidence intervals and test the hypothesis that the hazard ratio is equal to 1.
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.57

    Secondary: PFS Based on Investigator Assessment

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    End point title
    PFS Based on Investigator Assessment
    End point description
    PFS was calculated as the time from randomization to the date of the first progression event detected. A progression event was defined as objective evidence of radiographic disease progression based on the assessments by investigators, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Radiographic disease progression was defined as either a progression in soft tissue on CT/MRI scan according to RECIST 1.1, and/or a progression in bone lesions on bone scan (≥ 2 new bone lesions) confirmed by the next bone scan. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain. The initiation of new antineoplastic therapy included any new therapy for the treatment of disease progression after the study drug administration started. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    15.3 (11.8 to 19.4)
    5.7 (5.4 to 8.1)
    Statistical analysis title
    PFS on Inv. Assess. Enzalutamide Vs. Bicalutamide
    Comparison groups
    Bicalutamide v Enzalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.55

    Secondary: Prostate-specific Antigen (PSA) Response by Week 13

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    End point title
    Prostate-specific Antigen (PSA) Response by Week 13
    End point description
    The PSA response by Week 13 was defined as the percentage change from Baseline to the smallest PSA value after Baseline (i.e., a decrease of 100% represents the largest possible decrease to a value below the lower limit of quantification) and on or before day 99 (i.e., upper boundary of the Week 13 visit window). For participants with no decrease in PSA post-baseline by Week 13, the PSA response by Week 13 was the smallest increase in PSA up to day 99. For participants with no post-baseline PSA values up to day 99, the PSA response by Week 13 was set to missing. PSA was analyzed at a central laboratory. The analysis population consisted of the FAS with available PSA data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 13
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    171
    163
    Units: percent change
    median (full range (min-max))
        percent change
    -89.03 (-100.0 to 287.7)
    0.36 (-98.5 to 25700.0)
    Statistical analysis title
    PSA Response Enzalutamide Vs. Bicalutamide
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Wilcoxon rank sum test
    Confidence interval

    Secondary: Best PSA Response

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    End point title
    Best PSA Response
    End point description
    The best PSA response was defined as the percentage change from Baseline to the smallest PSA value after Baseline including PSA results from samples taken after the study drug was stopped. For participants with no decrease in PSA post-baseline, the best PSA response was the smallest increase in PSA. For participants with no post-baseline PSA values, the PSA response was set to missing. PSA was analyzed at a central laboratory. The analysis population consisted of the FAS with available PSA data.
    End point type
    Secondary
    End point timeframe
    Baseline to the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    174
    168
    Units: percent change
    median (full range (min-max))
        percent change
    -92.96 (-100.0 to 287.7)
    0.18 (-99.8 to 25700.0)
    Statistical analysis title
    Best PSA Response Enzalutamide Vs. Bicalutamide
    Comparison groups
    Bicalutamide v Enzalutamide
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Wilcoxon rank sum test
    Confidence interval

    Secondary: Time to PSA Progression

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    End point title
    Time to PSA Progression
    End point description
    Time to PSA progression was calculated as the time interval from the date of randomization to the date of first observation of PSA progression. PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir (or above the baseline value for participants who did not have a decline in PSA post-baseline values), and confirmed by a second consecutive PSA assessment at least 3 weeks later. For participants with no documented PSA progression, the time to PSA progression was censored on the date the last PSA sample was taken. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    19.4 (16.6 to 99999)
    5.8 (5.6 to 8.3)
    Statistical analysis title
    Time to PSA prog. Enzalutamide Vs. Bicalutamide
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.39

    Secondary: Time to PSA ≤ 4 ng/mL

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    End point title
    Time to PSA ≤ 4 ng/mL
    End point description
    Time to PSA ≤ 4 ng/mL was defined as the time interval from the date of randomization to the first date a decline in PSA to a result of 4 ng/mL or below was recorded. In participants without PSA results ≤ 4 ng/mL, the time to PSA ≤ 4 ng/mL was censored on the date of the last PSA sample taken. Participants with a PSA result ≤ 4 ng/mL at Baseline, participants with no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    3.0 (2.9 to 5.6)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to PSA Enzalutamide Vs. Bicalutamide
    Comparison groups
    Bicalutamide v Enzalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    5.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.18
         upper limit
    8.09

    Secondary: Time to ≥ 30% PSA Decline from Baseline

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    End point title
    Time to ≥ 30% PSA Decline from Baseline
    End point description
    The time to ≥ 30% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 30% was recorded. In participants without ≥ 30% PSA decline from Baseline, the time to ≥ 30% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    2.8 (2.8 to 2.8)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to ≥ 30% PSA Enzalutamide Vs. Bicalutamide
    Comparison groups
    Bicalutamide v Enzalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    5.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.96
         upper limit
    7.79

    Secondary: Time to ≥ 50% PSA Decline from Baseline

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    End point title
    Time to ≥ 50% PSA Decline from Baseline
    End point description
    The time to ≥ 50% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 50% was recorded. In participants without ≥ 50% PSA decline from Baseline, the time to ≥ 50% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    2.8 (2.8 to 2.8)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to ≥ 50% PSA Enzalutamide Vs. Bicalutamide
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    7.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.83
         upper limit
    10.16

    Secondary: Time to ≥ 90% PSA Decline from Baseline

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    End point title
    Time to ≥ 90% PSA Decline from Baseline
    End point description
    The time to ≥ 90% PSA decline from Baseline was defined as the time interval from the date of randomization to the first date a PSA decline from Baseline of at least 90% was recorded. In participants without ≥ 90% PSA decline from Baseline, the time to ≥ 90% PSA decline from Baseline was censored on the date of the last PSA sample taken. Participants who had no Baseline PSA and participants with no post-baseline PSA results were censored on the date of randomization. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    5.4 (3.0 to 5.7)
    99999 (99999 to 99999)
    Statistical analysis title
    Time to ≥ 90% PSA Enzalutamide Vs. Bicalutamide
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    13.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.23
         upper limit
    26.79

    Secondary: Radiographic PFS Based on ICR Assessment

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    End point title
    Radiographic PFS Based on ICR Assessment
    End point description
    Radiographic PFS was calculated as the time interval from the date of randomization to the first date of radiographic disease progression. Radiographic disease progression was defined as either a progression in soft tissue on CT/MRI scan according to RECIST 1.1, and/or a progression in bone lesions (a minimum of 2 new bone lesions as compared to previous scan) on bone scan and confirmed by the next bone scan. Data not reached due to the low number of events is denoted as "99999." The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: months
    median (confidence interval 95%)
        months
    99999 (25.6 to 99999)
    16.4 (11.1 to 18.1)
    Statistical analysis title
    Rad. PFS on ICR Enzalutamide Vs. Bicalutamide
    Comparison groups
    Enzalutamide v Bicalutamide
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    0.74

    Secondary: Percentage of Participants with an Objective Response

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    End point title
    Percentage of Participants with an Objective Response
    End point description
    Response assessments were reported by ICR for target lesions in soft tissues and non-target lesions in soft tissues based on CT and/or MRI according to RECIST version 1.1. Objective response was defined as the number of participants achieving either a complete response (CR) or a partial response (PR) based on participant’s best overall response assessed at the end of the treatment. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cutoff date of 19 October 2014, median duration of treatment was 11.6 months in the enzalutamide arm and 5.8 months in the bicalutamide arm.
    End point values
    Enzalutamide Bicalutamide
    Number of subjects analysed
    184
    191
    Units: percentage of participants
    number (not applicable)
        percentage of participants
    15.8
    2.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events

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    End point title
    Percentage of Participants with Adverse Events
    End point description
    A serious adverse event was defined as any untoward medical occurrence that at any dose: ● Resulted in death ● Was life threatening ● Resulted in persistent or significant disability/incapacity ● Resulted in congenital anomaly or birth defect ● Required inpatient hospitalization or led to prolongation of hospitalization ● Other medically important events. Treatment-related indicates adverse events assessed by the Investigator as probably or possibly related to study treatment. The analysis population consisted of the safety analysis set (SAF), which consisted of all participants who had initiated at least 1 dose of study drug. Treatment emergent adverse events (TEAEs) were defined as adverse events (AEs) that started or worsened after starting administration of study drug through end of the study (i.e., the treatment-emergent period).
    End point type
    Secondary
    End point timeframe
    From initiation of study drug up to 30 days after last dose of study drug or the 30-day safety follow-up visit, whichever was last (Median duration of treatment was 11.6 months in enzalutamide arm and 5.8 in bicalutamide arm, 12.6 in the total arm).
    End point values
    Enzalutamide Bicalutamide Total Enzalutamide
    Number of subjects analysed
    183
    189
    192
    Units: percentage of participants
    number (not applicable)
        TEAEs
    94.5
    94.2
    94.8
        Related TEAEs
    66.7
    49.7
    67.2
        Deaths
    5.5
    1.6
    5.7
        Serious TEAEs
    33.3
    23.8
    36.5
        Drug regimen-related serious TEAEs
    6.6
    3.2
    6.8
        TEAEs leading to discontinuation
    29.5
    23.8
    31.3
        Drug regimen-related TEAEs leading to discon.
    7.7
    5.3
    7.8
        TEAEs leading to study drug interruption
    10.4
    7.9
    10.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From initiation of study drug start up to 30 days after last dose or 30-day safety follow-up visit, whichever was last. Median duration of treatment (months) DB Phase: Enzalutamide 11.6, Bicalutamide 5.8, OL Phase: Enza./Enza. 21.6, Bica./Enza. 20.9.
    Adverse event reporting additional description
    The total number of deaths (all causes) includes deaths reported after the time frame above.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Double-blind Period: Enzalutamide
    Reporting group description
    Participants received enzalutamide 160 mg orally once daily in the double-blind period until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group title
    Double-blind Period: Bicalutamide
    Reporting group description
    Participants received bicalutamide 50 mg orally once daily in the double-blind period until confirmed radiographic disease progression, skeletal-related event or the initiation of a new antineoplastic therapy.

    Reporting group title
    Open-label Period: Enzalutamide/Enzalutamide
    Reporting group description
    Participants received enzalutamide in the double-blind period and received enzalutamide in the open-label period as well.

    Reporting group title
    Open-label Period: Bicalutamide/Enzalutamide
    Reporting group description
    Participants received bicalutamide in the double-blind period and switched over to enzalutamide in the open-label period.

    Serious adverse events
    Double-blind Period: Enzalutamide Double-blind Period: Bicalutamide Open-label Period: Enzalutamide/Enzalutamide Open-label Period: Bicalutamide/Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 141 (34.75%)
    43 / 180 (23.89%)
    18 / 42 (42.86%)
    4 / 9 (44.44%)
         number of deaths (all causes)
    11
    7
    0
    1
         number of deaths resulting from adverse events
    10
    3
    0
    1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Transurethral prostatectomy
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of conjunctiva
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Penile cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric cancer
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriogram coronary
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 141 (2.13%)
    3 / 180 (1.67%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 141 (2.84%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Ventricular tachyarrhythmia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous malformation
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 141 (3.55%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiduritis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incoherent
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 141 (1.42%)
    2 / 180 (1.11%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 141 (1.42%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder outlet obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric dilatation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint lock
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    5 / 141 (3.55%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess of salivary gland
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 180 (1.11%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Double-blind Period: Enzalutamide Double-blind Period: Bicalutamide Open-label Period: Enzalutamide/Enzalutamide Open-label Period: Bicalutamide/Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 141 (87.23%)
    149 / 180 (82.78%)
    42 / 42 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    15 / 141 (10.64%)
    17 / 180 (9.44%)
    12 / 42 (28.57%)
    4 / 9 (44.44%)
         occurrences all number
    16
    17
    12
    5
    Hypotension
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 180 (1.11%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    1
    Hypertension
         subjects affected / exposed
    18 / 141 (12.77%)
    14 / 180 (7.78%)
    13 / 42 (30.95%)
    0 / 9 (0.00%)
         occurrences all number
    29
    16
    16
    0
    Surgical and medical procedures
    Jaw operation
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 141 (5.67%)
    7 / 180 (3.89%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    10
    7
    2
    0
    Fatigue
         subjects affected / exposed
    35 / 141 (24.82%)
    38 / 180 (21.11%)
    18 / 42 (42.86%)
    3 / 9 (33.33%)
         occurrences all number
    40
    45
    24
    3
    Pain
         subjects affected / exposed
    1 / 141 (0.71%)
    8 / 180 (4.44%)
    2 / 42 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    8
    2
    1
    Oedema peripheral
         subjects affected / exposed
    10 / 141 (7.09%)
    13 / 180 (7.22%)
    5 / 42 (11.90%)
    0 / 9 (0.00%)
         occurrences all number
    10
    13
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 141 (6.38%)
    8 / 180 (4.44%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    9
    8
    1
    1
    Depressed mood
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    2
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    4 / 141 (2.84%)
    2 / 180 (1.11%)
    6 / 42 (14.29%)
    0 / 9 (0.00%)
         occurrences all number
    4
    2
    6
    0
    Testicular pain
         subjects affected / exposed
    5 / 141 (3.55%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    5
    0
    1
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Fall
         subjects affected / exposed
    9 / 141 (6.38%)
    6 / 180 (3.33%)
    4 / 42 (9.52%)
    2 / 9 (22.22%)
         occurrences all number
    11
    7
    6
    2
    Rib fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    2 / 42 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    1
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 141 (2.13%)
    5 / 180 (2.78%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    6
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 141 (0.00%)
    3 / 180 (1.67%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    1
    Haematocrit decreased
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 141 (2.13%)
    5 / 180 (2.78%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    4
    5
    1
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    Red blood cell count increased
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    4 / 141 (2.84%)
    2 / 180 (1.11%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    4
    2
    1
    1
    Weight decreased
         subjects affected / exposed
    16 / 141 (11.35%)
    15 / 180 (8.33%)
    5 / 42 (11.90%)
    0 / 9 (0.00%)
         occurrences all number
    19
    15
    6
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    Palpitations
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    1
    Bronchitis chronic
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    5 / 141 (3.55%)
    8 / 180 (4.44%)
    2 / 42 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    6
    8
    2
    1
    Dyspnoea
         subjects affected / exposed
    7 / 141 (4.96%)
    9 / 180 (5.00%)
    4 / 42 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    8
    10
    8
    0
    Nasal congestion
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    3
    1
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 141 (7.09%)
    5 / 180 (2.78%)
    4 / 42 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    10
    7
    4
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    4 / 141 (2.84%)
    0 / 180 (0.00%)
    2 / 42 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    5
    0
    2
    1
    Dizziness
         subjects affected / exposed
    12 / 141 (8.51%)
    15 / 180 (8.33%)
    6 / 42 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    15
    16
    6
    2
    Headache
         subjects affected / exposed
    11 / 141 (7.80%)
    6 / 180 (3.33%)
    8 / 42 (19.05%)
    3 / 9 (33.33%)
         occurrences all number
    14
    6
    10
    4
    Lethargy
         subjects affected / exposed
    5 / 141 (3.55%)
    4 / 180 (2.22%)
    3 / 42 (7.14%)
    1 / 9 (11.11%)
         occurrences all number
    6
    4
    3
    1
    Parkinson's disease
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Poor quality sleep
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    2
    Syncope
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 180 (1.11%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Glaucoma
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 141 (4.26%)
    7 / 180 (3.89%)
    3 / 42 (7.14%)
    1 / 9 (11.11%)
         occurrences all number
    6
    7
    4
    1
    Constipation
         subjects affected / exposed
    19 / 141 (13.48%)
    24 / 180 (13.33%)
    5 / 42 (11.90%)
    0 / 9 (0.00%)
         occurrences all number
    21
    25
    7
    0
    Diarrhoea
         subjects affected / exposed
    16 / 141 (11.35%)
    15 / 180 (8.33%)
    5 / 42 (11.90%)
    2 / 9 (22.22%)
         occurrences all number
    18
    18
    6
    2
    Dyspepsia
         subjects affected / exposed
    5 / 141 (3.55%)
    4 / 180 (2.22%)
    1 / 42 (2.38%)
    2 / 9 (22.22%)
         occurrences all number
    6
    4
    1
    2
    Haemorrhoids
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    1
    Nausea
         subjects affected / exposed
    18 / 141 (12.77%)
    33 / 180 (18.33%)
    10 / 42 (23.81%)
    0 / 9 (0.00%)
         occurrences all number
    22
    36
    11
    0
    Rectal haemorrhage
         subjects affected / exposed
    4 / 141 (2.84%)
    1 / 180 (0.56%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    4
    1
    1
    1
    Vomiting
         subjects affected / exposed
    5 / 141 (3.55%)
    9 / 180 (5.00%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences all number
    5
    10
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    5 / 141 (3.55%)
    4 / 180 (2.22%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    5
    4
    1
    1
    Haematuria
         subjects affected / exposed
    3 / 141 (2.13%)
    6 / 180 (3.33%)
    5 / 42 (11.90%)
    0 / 9 (0.00%)
         occurrences all number
    5
    7
    5
    0
    Hypertonic bladder
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    0
    2
    Pollakiuria
         subjects affected / exposed
    7 / 141 (4.96%)
    6 / 180 (3.33%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    7
    6
    1
    1
    Renal failure chronic
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    Renal pain
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Urinary retention
         subjects affected / exposed
    4 / 141 (2.84%)
    5 / 180 (2.78%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    4
    7
    1
    1
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 141 (11.35%)
    27 / 180 (15.00%)
    9 / 42 (21.43%)
    5 / 9 (55.56%)
         occurrences all number
    22
    39
    11
    6
    Back pain
         subjects affected / exposed
    29 / 141 (20.57%)
    34 / 180 (18.89%)
    11 / 42 (26.19%)
    1 / 9 (11.11%)
         occurrences all number
    39
    40
    15
    1
    Bone pain
         subjects affected / exposed
    10 / 141 (7.09%)
    12 / 180 (6.67%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    13
    15
    1
    1
    Flank pain
         subjects affected / exposed
    5 / 141 (3.55%)
    2 / 180 (1.11%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    5
    2
    3
    0
    Gouty arthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 141 (4.26%)
    4 / 180 (2.22%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    8
    4
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    8 / 141 (5.67%)
    17 / 180 (9.44%)
    5 / 42 (11.90%)
    1 / 9 (11.11%)
         occurrences all number
    9
    23
    5
    1
    Myalgia
         subjects affected / exposed
    9 / 141 (6.38%)
    5 / 180 (2.78%)
    1 / 42 (2.38%)
    0 / 9 (0.00%)
         occurrences all number
    10
    5
    2
    0
    Neck pain
         subjects affected / exposed
    2 / 141 (1.42%)
    2 / 180 (1.11%)
    4 / 42 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    3
    2
    4
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    4 / 42 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    6
    1
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    16 / 141 (11.35%)
    9 / 180 (5.00%)
    5 / 42 (11.90%)
    1 / 9 (11.11%)
         occurrences all number
    22
    12
    8
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 180 (0.56%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    Decreased appetite
         subjects affected / exposed
    16 / 141 (11.35%)
    13 / 180 (7.22%)
    2 / 42 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    19
    13
    3
    0
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 141 (2.13%)
    1 / 180 (0.56%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    3
    1
    3
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 180 (1.11%)
    2 / 42 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    2
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 180 (0.00%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 141 (1.42%)
    3 / 180 (1.67%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    2
    3
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 180 (1.11%)
    3 / 42 (7.14%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    4
    0
    Influenza
         subjects affected / exposed
    3 / 141 (2.13%)
    4 / 180 (2.22%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    4
    4
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 141 (7.80%)
    7 / 180 (3.89%)
    7 / 42 (16.67%)
    1 / 9 (11.11%)
         occurrences all number
    13
    8
    9
    1
    Osteomyelitis
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    1 / 42 (2.38%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    Scrotal infection
         subjects affected / exposed
    0 / 141 (0.00%)
    0 / 180 (0.00%)
    0 / 42 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    7 / 141 (4.96%)
    3 / 180 (1.67%)
    4 / 42 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    8
    3
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2010
    The changes include: ● Increased the number of eligible patients enrolled to 370 to ensure the target number of events was achieved ● Removed planned interim analysis because it was not required ● Clarified definition of mg abbreviation ● Corrected time points for administering the BPI-SF ● Updated sample size calculation considerations to ensure that the target number of progression events was achieved ● Expanded the definition of metastatic disease in inclusion criterion 5 to include patients with significant nodal metastases ● Amended exclusion criterion 12 to liberalize prior use of antiandrogens based on clinical practice/treatment paradigm for this patient population ● Lengthened visit window at weeks 13 and 25 to allow for CT/MRI and bone scan imaging to be scheduled and performed in association with the study visit ● Added instruction for Patient Dosing Diary to collect information on medication dosing and food intake prior to pharmacokinetic sampling ● Updated contact details of key sponsor personnel for safety information ● Separated out radiographic disease progression and a skeletal-related event as reasons for discontinuation of study drug to ensure consistency throughout protocol ● Updated name of software package used to perform sample size calculations ● Updated text regarding analysis of pharmacokinetics ● Updated text regarding imputation of missing data ● Added option to allow patients to resume study medication at a lower dose in order to reduce the likelihood the patient experienced a similar AE of grade 3 or greater toxicity ● Removed reference that blood sample for CTC enumeration was to be collected at screening ● Added testosterone laboratory test to be performed at screening for assessment of inclusion criterion 4 ● Updated Section header 2.3.4 T2:ERG, and subsequent section header, to accurately reflect secondary heading of ‘Exploratory Variables’
    07 Dec 2010
    Continued: ● Removed reference that laboratory tests were to be performed at a local laboratory because they were to be performed at a central laboratory instead ● Clarified that Data Monitoring Committee (i.e., DSMB) was to monitor only safety data on an ongoing basis ● Defined the QRS abbreviation as QRS interval ● Made administrative changes and typographical corrections.
    16 Jan 2012
    The changes include: ● Revised exclusion criteria to reflect the current medical practices and use of antiandrogens in the study patient population ● Included information on the assessment of potential drug induced liver injury to ensure complete review of all relevant discontinuation criteria by the investigator ● Updated the number of investigational sites ● Included updated safety reporting information to accurately reflect the serious adverse event (SAE) reporting process ● Revised process for ECG collection to remove sponsor collection of copies of the ECGs ● Clarified under what circumstances the sponsor could break the treatment code ● Updated the appendix for elements of Informed Consent to comply with 42 U.S.C 282(j)(1)(A) ● Updated the section on publication of the study to reflect the current Astellas publication policy ● Updated the safety language in Appendices 2 and 10 for consistency with FDA Guidance for Industry and Investigators Drug Induced Liver Injury, FDA Jul 2009 ● Made typographical corrections.
    19 Aug 2013
    The changes include: ● Revised confirmatory scan requirements to clarify timing, qualifications and baseline time point ● Clarified inclusion criterion 5 to distinguish requirement of metastatic disease at the time of the screening visit ● Added inclusion criterion 11 detailing the appropriate contraception methods available for participants of the clinical trial ● Revised exclusion criterion 10, correcting the dosage unit for spironolactone from 50 mg/kg to 50 mg/day ● Added statement indicating that waivers to the selection criteria will not be allowed ● Added denosumab to list of allowed medications and radiopharmaceuticals to the list of prohibited medications ● Revised information regarding cytochrome P450 (CYP) pathways used in the metabolism of enzalutamide and bicalutamide to state caution should be exercised when bicalutamide is co-administered with CYP3A4 substrates ● Provided clarity regarding the requirements for chest imaging and dictated the possibility for continued imaging for ongoing patients ● Added dosing diary dispensing and collection to the Schedule of Assessments ● Updated nonclinical and clinical data and safety information in the introduction sections to reflect the most current data available for enzalutamide ● Updated the risk benefit statement to reflect the most current safety data available for enzalutamide ● Updated the test drug section to reflect the most current clinical data available for enzalutamide ● Included instructions for restarting study drug in event of dose interruption due to a specified toxicity ● Updated drug-drug interaction information to reflect the most current safety data available for enzalutamide ● Added histological and clinical to diagnosis types documented at screening. ● Revised text describing body systems (without adding new body systems). Clarified the requirements for performing digital rectal examination (DRE)
    19 Aug 2013
    Continued: ● Updated definition of AEs to include undergoing study procedures. ● Included additional information regarding safety events of interest that could require expedited reporting and/or safety evaluation and their reporting requirements ● To provide clarity, rewrote section on Supply of New Information Affecting Conduct of the Study ● Added a new section and related appendix for common SAEs ● Defined protocol deviations and clarified the process of identifying the deviations by category/type in the summary tables ● Added a new section clarifying what was considered a deviation and explaining responsibilities of investigators ● Added a new section to define the end of trial in all participating countries as the ‘last patient’s last visit’ ● Specified signatories permitted to sign the CSR ● Deleted appendices that are not mandated by regulations (Appendix 12.2 Events Always Considered to be Serious) or are covered in ICH GCP and master informed consent form (ICF) (Appendix 12.3 Elements of Informed Consent; Appendix 12.4 Elements of HIPAA Authorization [US Site Only]) ● Made administrative changes and typographical corrections.
    19 Jul 2014
    The changes include: ● Added an open-label extension period to ensure continuing treatment of patients receiving clinical benefit from study participation after unblinding. Descriptions of double-blind and open-label period were added to the synopsis to clearly identify and delineate the study periods. Appendix 9 Open-Label Period was added to the protocol to describe the procedures associated with the open-label period in detail ● Added seizure as a possible reason for discontinuation in the eligibility criteria ● Added a statement to allow the final efficacy analysis to be performed when 85% power is reached and added the corresponding minimum number of progression events ● Added text regarding collection of T2:ERG tissue sample ● Revised the groupings of Gleason score and added the previous use of antiandrogen therapy as variables in the subgroup analyses ● Revised CTC conversion text ● For consistency with the revised SAP, added protocol deviation category PD5 Other to capture protocol deviations that fall outside the standard categories ● Corrected list of common SAEs with the appropriate list of common AEs specific to enzalutamide ● Made administrative changes and typographical corrections.
    24 Jun 2016
    The changes include: ● Revised the study design; patients who were continuing to derive clinical benefit from treatment with enzalutamide based on the investigator’s medical opinion and had not met any of the treatment discontinuation criteria, as outlined in Section 12.9 of the protocol, may have been eligible to continue receiving treatment with enzalutamide in the open-label extension study 9785-CL-0123 upon activation of this study at the participating institution. Patients who chose not to participate or were not eligible for study 9785-CL-0123 completed their participation in study 9785-CL-0222 by completing the 30 day safety follow up visit ● Updated sponsor contact information; details for 24 hour-Contact for SAEs, Clinical Research Contacts and Medical Monitors were updated ● Made administrative changes and typographical corrections.

    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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